Chapter 1The immune systemand its players
In this chapter, you will gain understanding of the principles of clinical immunologyand learn about the system and its players Topics included:
- Defense mechanisms of the body
- Anatomical and physiological barriers
- Innate and adaptive immunity
- Signaling pathways
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Biogen-266406 | 07/2025
Intended for healthcare professionals only. This document has been funded and created by Biogen International GmbH, Baar, Switzerland.
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Defense mechanisms of the body
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The immune response is a collection of protective mechanisms to control and eliminate pathogenic microbes, viruses, external antigens, mutated cells and other harmful substances.1,2
- Anatomical barriers(e.g. skin, mucous membranes)
- Low pH
- Body temperature/fever response
- Mucus
Physical2
- Complement
- Antimicrobial proteins, e.g. defensins
- Lysozyme
- Cytokines
- Antibodies
Chemical2,3
- Endocytosis of macromolecules
- Phagocytosis of microorganisms
- Lysis of target cells by cytotoxic T-cells
- Neutrophil NETosis
Cellular1,2,4
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Physical barriers include mechanical and physiological barriers.2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
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Chemical defences are mostly secreted peptides and proteins that inhibit or destroy microbes.2,3
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Cellular responses include cells that internalize and break down foreign substances or lyse infected host cells.1,2,4
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S3–23.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.
- Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol. 2012;198(5):773–783.
NET, neutrophil extracellular trap.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Anatomical and physiological barriers
The first line of defense against infection comprises a variety of non-specific mechanical and physiological barriers that exclude pathogens from the body.1,2
Mechanical barriers1–3
- Physically block access of microbes to tissues e.g. keratinized outer layer of intact skin, mucous membranes
Muco-ciliary clearance1,3
- Mucus traps microbes
- Ciliary action propels entrapped microbes out of the airways
Secreted hydrolytic enzymes1,3
- Lysozyme in tears and saliva destroys bacterial cell walls
Low pH1,3
- Stomach acid kills most ingested microorganisms
- Low skin pH inhibits microbial growth
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med. 2000;343(1):37–49.
- Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Innate and adaptive immunity
Pathogens that successfully penetrate the anatomical and physiologic barriers of the body encounter further lines of defense.1,2
Immune response
Adaptive immunity
Innate immunity
Crosstalk
- Delayed response (hours to days)
- High specificity (peptide antigen)
- Unlimited pattern recognition
- Huge diversity of receptors
- Immunological memory is a hallmark
- Rapid response (minutes to hours)
- Low specificity (non-peptide target)
- Limited pattern recognition
- Limited range of receptors (PRMs)
- No immunological memory
Humoral components: complement, antimicrobial peptides, MBL, LPS-binding protein, CRP
Humoral components: antibodies
Cellular components: dendritic cells, neutrophils, natural killer cells, eosinophils, macrophages, mast cells, γδ T-cells5
Cellular components: T-cells, B-cells
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The innate immune system provides a rapid response with low specificity. It recognizes non-peptide elements – PAMPS and DAMPs – that arise as a consequence of infection and/or inflammation.3,4
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The adaptive immune system provides a slower but highly specific response. It recognizes foreign peptide antigens using receptors from an enormous and diverse repertoire.3
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med. 2000;343(1):37–49.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.
- Mak TW, Saunders ME, Jett BD. A primer to the immune response. 2nd ed. Elsevier; 2014.
- Wu YL, Ding YP, Tanaka Y, et al. γδ T cells and their potential for immunotherapy. Int J Biol Sci. 2014;10(2):119–135.
CRP, C-reactive protein; DAMPs, damage-associated molecular patterns; LPS, lipopolysaccharide; MBL, mannose-binding lectin; PAMPs, pathogen-associated molecular patterns; PRM, pattern recognition molecule.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Cells of the immune system
The white blood cells of the innate and adaptive immune systems arise through differentiation of hematopoietic stem cells in the bone marrow.1 Mature white blood cells arise from two different lineages: the myeloid lineage and the lymphoid lineage.1
Pluripotent hematopoietic stem cell
Common myeloid progenitor
Common lymphoid progenitor
Neutrophil
Eosinophil
Basophil
Monocyte
Non-cytotoxicILC
Mast cell
Naturalkiller cell
γδ T-cell
αβ T-cell
B-cell
Adaptiveimmunity
Macrophage
Dendritic cell
Innate immunity
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015;517(7534):293–301.
- Su D, Shen M, Sun L. Roles of γδ T cells in the pathogenesis of autoimmune diseases. Clin Dev Immunol. 2013;2013:985753. DOI: 10.1155/2013/985753.
- Giebel B, Punzel M. Lineage development of hematopoietic stem and progenitor cells. Biol Chem. 2008;389(7):813–824.
- Kondo M. Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors. Immunol Rev. 2010;238(1):37–46.
- Tanriver Y, Diefenbach A. Transcription factors controlling development and function of innate lymphoid cells. Int Immunol. 2014;26(3):119–128.
ILC, innate lymphoid cell.
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Defense mechanisms of the body
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Innate and adaptive immunity
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Summary
Innate immune system1–4
Innate immune cells of the myeloid lineage include mast cells, monocytes and granulocytes (neutrophils, eosinophils and basophils), which contain cytoplasmic secretory granules.2
Pluripotent hematopoietic stem cell
Common myeloid progenitor
Common lymphoid progenitor
Neutrophil
Eosinophil
Basophil
Monocyte
Non-cytotoxicILC
Mast cell
Naturalkiller cell
γδ T-cell
Granulocytes
APCs
Macrophage
Dendritic cell
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
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Summary
Neutrophils are the most numerous type of granulocytes. They play a key role in immunity against bacterial infections through their ability to destroy pathogens by phagocytosis or the formation of NETs.2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The other granulocytes – eosinophils and basophils – mediate immunity against parasites and modulate immunoglobulin-mediated responses.1,2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
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Mast cells modulate vascular permeability and are thought to function in mucosal immunity.2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
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Myeloid innate cells also include monocytes, which differentiate within the tissues into two types of APCs: macrophages and dendritic cells.2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
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In addition to phagocytosis, both macrophages and dendritic cells play a key role in taking up and presenting antigens to lymphocytes to initiate adaptive immunity.1,2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015;517(7534):293–301.
- Su D, Shen M, Sun L. Roles of γδ T cells in the pathogenesis of autoimmune diseases. Clin Dev Immunol. 2013;2013:985753. DOI: 10.1155/2013/985753.
APC, antigen-presenting cell; ILC, innate lymphoid cell; NET, neutrophil extracellular trap.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Humoral factors of the innate immune system
The humoral components of the innate immune system include a variety of soluble PRMs that function as pathogen sensors.1 Some PRMs can also exert direct antimicrobial action.1
Antimicrobial peptides1,2
- Small secreted proteins with direct antimicrobial action (e.g. defensins)
Complement system3,4
- Group of plasma proteins that act together to kill pathogens directly or facilitate their phagocytosis
CRP3,6
- Acute-phase protein
- Recognizes phosphatidyl-choline in the membranes of bacteria and dying eukaryotic cells
- Opsonizes, activates complement and binds to phagocytes
Collectins (e.g. MBL)5
- Recognize carbohydrate-containing patterns on microbes, marking them for destruction
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.
- Oppenheim JJ, Biragyn A, Kwak LW, et al. Roles of antimicrobial peptides such as defensins in innate and adaptive immunity. Ann Rheum Dis. 2003;62(Suppl 2):ii17–ii21.
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- van de Wetering JK, van Golde LMG, Batenburg JJ. Collectins: players of the innate immune system. Eur J Biochem. 2004;271(7):1229–1249.
- Salazar J, Martínez MS, Chávez-Castillo M, et al. C-reactive protein: an in-depth look into structure, function, and regulation. Int Sch Res Notices. 2014;2014:653045. DOI: 10.1155/2014/653045.
CM, cell membrane; CRP, C-reactive protein; IS, intracellular space; MBL, mannose-binding lectin; PRM, pattern recognition molecule.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Cells of the adaptive immune system: T-cells and B-cells1
Pluripotent hematopoietic stem cell
Common lymphoid progenitor
αβ T-cell
B-cell
Humoral immunity
Helper T-cell(CD4+)
Cytotoxic T-cell(CD8+)
Did you know?
Cell-mediated immunity
- The lymphoid lineage gives rise to the two cell types of the adaptive immune system – T-cells and B-cells1,2
- Every T-cell and B-cell expresses a unique variant of highly specific antigen receptor which is randomly generated through genetic rearrangements occurring during lymphocyte development1
- Collectively, they provide a huge repertoire of receptors capable of recognizing almost any foreign peptide-derived macromolecule1,3
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
In humans, the vast majority of T-cells express the αβ receptor. Conventionally, αβ T-cells are termed ‘T-cells’. This slide deck refers to αβ T-cells when using the term ‘T-cell’.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
There are two major subtypes of T-cells:2
- CD4-expressing helper T-cells (Th cells), which initiate and coordinate the adaptive immune response
- CD8-expressing cytotoxic T-cells, which destroy infected host cells
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
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Specific antigen–receptor interactions can trigger activation of T-cells and B-cells, leading to their proliferation and differentiation into the effector cells of the adaptive immune response.1,2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.
CD, cluster of differentiation.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Lymphocyte maturation and circulation1
Bone marrow
Common lymphoid progenitor
Naïve B-cell
T-cell progenitor
Primary/central
lymphoid organs
Thymus
NaïveT-cells
Bloodstream
Circulating naïvelymphocytes
Lymphaticvessels
Secondary/peripheral
lymphoid
organs
Spleen
Lymph node
GALT/BALT/MALT
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
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Both B-cells and T-cells arise in the bone marrow, where B-cells also mature.1
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Defense mechanisms of the body
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Mature naïve B- and T-cells then enter the circulation and migrate out of the bloodstream into the secondary/peripheral lymphoid organs.1
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Defense mechanisms of the body
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T-cell progenitors must migrate to the thymus for maturation.1
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Defense mechanisms of the body
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If no antigen is encountered in the peripheral lymphoid organs, lymphocytes can re-enter the circulation either directly or via the lymphatic vessels.1
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Defense mechanisms of the body
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Upon encountering their specific antigen, lymphocytes proliferate and differentiate within the peripheral lymphoid tissue before re-entering the bloodstream to combat infection in the tissues.1
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Defense mechanisms of the body
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Innate and adaptive immunity
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Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
BALT, bronchial-associated lymphoid tissue; GALT, gut-associated lymphoid tissue; MALT, mucosal-associated lymphoid tissue.
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Defense mechanisms of the body
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The need for co-stimulation in T-cell activation
- The antigen receptor expressed by T-cells is known as the T-cell receptor (TCR)1
- The TCR recognizes antigens presented as peptide fragments bound to MHC molecules on the surface of APCs1
- The T-cell expresses a co-receptor (either CD4 or CD8), which also binds to the MHC molecule on the surface of the APC1
- Once activated by signal 1 and 2 (see below), T-cells proliferate and differentiate under the predominant influence of cytokines1
Secondary lymphoid organ
Signal 1
MHC–antigen–TCR complex
CD4/CD8 co-receptor
APC
T-cell
Proliferation and differentiationdirected by cytokines
Effector T-cell
CD28
CD80/86
Signal 2 (co-stimulation)
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Defense mechanisms of the body
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Innate and adaptive immunity
Signaling pathways
Summary
The interaction of the TCR and co-receptor with the MHC–antigen complex provides an antigen-specific signal (Signal 1) that is necessary, but not sufficient, for T-cell activation.1
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
T-cell activation also requires a second signal (Signal 2), known as ‘co-stimulation’, which may be delivered by interaction of CD28 on the T-cell surface with the CD80 or CD86 receptor on the surface of the APC.1
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
APC, antigen-presenting cell; CD, cluster of differentiation; MHC, major histocompatibility complex; TCR, T-cell receptor.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Helper (CD4+) T-cell activation
The TCR interacts with two different types of MHC molecule: class I and class II.1,2
Secondary lymphoid organ
Secondary lymphoid organ
MHC Class II
MHC Class I
CD4 co-receptor
CD8 co-receptor
Cell infected with intracellular pathogen or cancer cell
Professional APC (e.g. macrophage,
dendritic cell)
HelperT-cell (CD4+)
Cytotoxic T-cell (CD8+)
Effector helper T-cell
Effectorcytotoxic T-cell
Antigen:Peptide derived from a pathogen ingested and processed by the APC
Antigen:Peptide derived from a protein synthesized within the MHC Class I-expressing cell
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Defense mechanisms of the body
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Class II MHC molecules present peptides derived from proteins within intracellular vesicles, including vesicular intracellular parasite proteins, or antigens internalized by phagocytes or B-cells.1
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Defense mechanisms of the body
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T-cell specificity for class II MHC molecules is provided by the CD4 co-receptor, which is expressed by the helper T-cell subset.1
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Defense mechanisms of the body
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Class I MHC molecules present peptides derived from proteins synthesized in the cytosol, such as viral proteins within an infected cell.1
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Defense mechanisms of the body
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Innate and adaptive immunity
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T-cell specificity for class I MHC molecules is provided by the CD8 co-receptor, which is expressed by the cytotoxic T-cell subset.1
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
APC, antigen-presenting cell; CD, cluster of differentiation; MHC, major histocompatibility complex; TCR, T-cell receptor.
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Defense mechanisms of the body
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Summary
Cytokines
- Cytokines play a major role in orchestrating and coordinating immune responses1
- They bind to receptors on target cells, triggering intracellular signaling cascades that modulate gene expression and biological activity1
Cytokine-producing cell
Did you know?
Target cell
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Defense mechanisms of the body
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Different cytokines interact via effects on target cells that may be antagonistic, additive or synergistic, or pro- or anti-inflammatory.1,2 They often show pleiotropy and redundancy in their function1,2 and they tend to function within cascades, whereby one cytokine enhances or suppresses the production of others.1,2
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Defense mechanisms of the body
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Cytokines are small, secreted signaling proteins/glycoproteins that play a key role in coordinating immune responses. They can act via autocrine, paracrine or endocrine action.1
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Defense mechanisms of the body
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Cytokines are produced by a wide range of cell types, including helper T-cells, macrophages and B-cells. They are often produced in a cascade.1
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Defense mechanisms of the body
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References:
- Wahab S, Hussain A. Cytokines as targets for immunomodulation. Int J Pharm Pharmaceut Sci. 2013;5(Suppl 3):60–64.
- Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45(2):27–37.
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Defense mechanisms of the body
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Types of cytokine
Interleukins
E.g. IL-1, IL-4,IL-6, IL‑10,
IL-17, IL-23
Cytokines can be grouped into different categories based on their functions or source, being produced by, and acting upon, many different cells.1
Interferons
Transforming growth factor
IFN-α,IFN-β,IFN-γ
TGF-β
Tumor necrosis factor
Chemokines
Click a section for moreinformation
RANTES,MCP-1,
IL-8
TNF-αTNF-βBAFF
Hematopoieticagents
GM-CSFM-CSF
Erythropoietin
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Defense mechanisms of the body
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Interleukin is a general term that was originally coined to refer to cytokines produced by one type of leukocyte and acting on another.2
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Transforming growth factor-β (TGF-β) is an inhibitory cytokine produced by a variety of cell types including T-cells.1
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Defense mechanisms of the body
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Interferons are cytokines that either inhibit viral replication in infected cells (type I interferon: IFN-α, IFN-β) or stimulate pathogen clearance mechanisms in the innate and adaptive immune systems (type II interferon: IFN-γ).3
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Chemokines are chemotactic cytokines that attract leukocytes to areas of inflammation (e.g. regulated on activation normal T-cell expressed and secreted [RANTES], macrophage chemoattractant protein-1 [MCP-1] and IL-8).4,5
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Hematopoietic agents regulate the proliferation and differentiation of hematopoietic cells.1,6
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Defense mechanisms of the body
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The members of the tumor necrosis factor (TNF)/TNF receptor (TNR-R) superfamily comprise a group of currently more than 40 ligand and receptor proteins which are mostly produced by cells of the immune system and which influence cell proliferation, cell survival, cell differentiation and apoptosis of the responding cells.2 TNF is a pleiotropic cytokine that plays a key role in the development of lymphoid organs, inflammation, tumor-cell killing and defense against intracellular pathogens.7
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Defense mechanisms of the body
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References:
- Wahab S, Hussain A. Cytokines as targets for immunomodulation. Int J Pharm Pharmaceut Sci. 2013;5(Suppl 3):60–64.
- Hoeve MA, Savage NDL, de Boer T, et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol. 2006;36(3):661–670.
- Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45(2):27–37.
- Mertelsmann R. Hematopoietins: biology, pathophysiology, and potential as therapeutic agents. Ann Oncol. 1991;2(4):251–263.
- Kopf M, Bachmann MF, Marsland BJ. Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov. 2010;9(9):703–718.
- Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244–279.
- Ng LG, Sutherland APR, Newton R, et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol. 2004;173(2):807–817.
BAFF, B-cell activating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin;M-CSF, macrophage colony-stimulating factor; MCP-1, macrophage chemoattractant protein-1; RANTES, regulated on activation normal T cell expressed and secreted; TGF, transforming growth factor; TNF, tumor necrosis factor; TNF-R, tumor necrosis factor receptor.
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Defense mechanisms of the body
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Helper T-cell differentiation
- A central way in which cytokines influence the nature of immune responses is by regulating the differentiation of helper (CD4+) T-cells into distinct subsets, including effector cell subtypes and regulatory T-cells (Treg).1,2
- Each of these T-cell subsets expresses a unique cytokine profile and so directs the immune response in different ways.1–7
APC
Naïve T-cell
IL-4 TGF-β
IL-12 IFN-γ
IL-4
IL-2 TGF-β
IL-6 TGF-β
Th9
Th1
Th2
Th17
Treg
IL-9, IL-10, IL-21
TNF, IFN-γ, IL-2, IL-18
IL-4, IL-5, IL-13, IL-25
IL-10, TGF-β, IL-35
TNF, IL-17, IL-22
Anti-helminth and anti-tumor immunity
Activation of cell-mediated immunity
Activation of humoral immunity
Downregulation of immune responses
Regulation of mucosal immunity
Effector T-cells
Inhibitory T-cells
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Naïve T-cells activated in the presence of IL-12 and IFN-γ differentiate into Th1 cells, which secrete IFN-γ and so activate cell-mediated immunity against intracellular pathogens such as viruses.1–3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
In the absence of TGF-β, IL-4 promotes the differentiation of activated T-cells into Th2 cells, which secrete cytokines that stimulate antibody production by B-cells, thereby promoting humoral immunity.4
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
IL-4 in combination with TGF-β stimulates the development of the Th9 immunophenotype, which is believed to play a role in immune responses against helminth parasites and tumor cells.5
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
CD4+ T-cells activated in the presence of IL-6 and TGF-β develop into Th17 cells, which regulate immunity at mucosal surfaces through the production of IL-17.2,6
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
IL-2 and TGF-β together direct differentiation of CD4+ cells into inhibitory Treg cells.2,7
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Coates LC, FitzGerald O, Helliwell PS, et al. Psoriasis, psoriatic arthritis, and rheumatoid arthritis: is all inflammation the same? Semin Arthritis Rheum. 2016;46(3):291–304.
- Simon EG, Ghosh S, Iacucci M, et al. Ustekinumab for the treatment of Crohn's disease: can it find its niche? Therap Adv Gastroenterol. 2016;9(1):26–36.
- Gálvez J. Role of Th17 Cells in the pathogenesis of human IBD. ISRN Inflamm. 2014;2014:928461.DOI: 10.1155/2014/928461.
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Kaplan MH, Hufford MM, Olson MR. The development and in vivo function of T helper 9 cells. Nat Rev Immunol. 2015;15(5):295–307.
- Guglani L, Khader SA. Th17 cytokines in mucosal immunity and inflammation. Curr Opin HIV AIDS. 2010;5(2):120–127.
- Sojka DK, Huang YH, Fowell DJ. Mechanisms of regulatory T-cell suppression – a diverse arsenal for a moving target. Immunology. 2008;124(1):13–22.
APC, antigen-presenting cell; IFN, interferon; IL, interleukin; TGF, transforming growth factor; Th, T helper; TNF, tumor necrosis factor; Treg, regulatory T-cell.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Leukocyte trafficking: Roles of chemokines and adhesion molecules1–3
Tethering
Endothelial cell
Rolling
Adhesion triggering
Leukocyte
Extravasation
Chemokines mediate the recruitment of immune cells to sites of inflammation during the innate response to infection by inducing nearby endothelial cells to express adhesion molecules called selectins.1
Inflammatorycytokines
Chemokines
Inflamed site
Chemotaxis
Selectin ligand
Selectin
Integrin
Integrin ligand
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Chemokines stimulate extravasation of leukocytes, which migrate to the site of inflammation in the tissue by following the chemokine gradient.2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Selectins interact with carbohydrates on the leukocyte cell surface, causing tethering and rolling of leukocytes along the endothelium.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Further signals trigger activation of leukocyte adhesion molecules called integrins, which establish more stable adhesive interactions with ligands expressed on the endothelial surface1–3, causing tethering and rolling of leukocytes along the endothelium.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Kunkel EJ, Butcher EC. Plasma-cell homing. Nat Rev Immunol. 2003;3(10):822–829.
- Evans R, Patzak I, Svensson L, et al. Integrins in immunity. J Cell Sci. 2009;122(Pt 2):215–225.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
B-cell activation
The antigen receptor on B-cells is known as the B-cell receptor (BCR) and consists of a membrane-bound form of an antibody.1 B-cells are activated by the binding of antigen to the BCR and then proliferate and differentiate into antibody-secreting plasma cells or long-lived memory B-cells.1–3
AntigenProcessed peptide derived from the same pathogen
Secondary lymphoid organ
MHC class II
TCR
BCR
Antigen No requirement for processing
Helper T-cell
Naïve B cell
CD40L
CD40
Plasma cell
T-cell help (required for Ig class switch fromIgM to IgA, IgD, IgG or IgE)
Memory B-cell
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Binding of antigen to the BCR leads to internalization and processing of the antigen. Fragments of the antigen are then presented by the B-cell in association with MHC class II molecules to helper T-cells.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Activation of the B-cell by thymus-dependent antigens requires a helper T-cell that has previously been activated in response to the same antigen.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Once activated, B-cells proliferate and differentiate into plasma cells, which secrete antibodies with the same specificity as the BCR expressed by the parent B-cell.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Interaction of the TCR with the MHC–antigen complex induces the T-cell to express the surface receptor CD40 ligand (CD40L), which in turn interacts with CD40 on the B-cell and helps drive B-cell activation (‘T-cell help’).1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Activated B-cells can also differentiate into long-lived memory B-cells, which continue to express antigen-binding receptors and can be reactivated rapidly on subsequent exposure to the same antigen.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Several antibody classes exist. Cytokines can direct the B-cell to change the class of antibody produced (‘class switching’) in a process that is dependent on CD40L.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- Kunkel EJ, Butcher EC. Plasma-cell homing. Nat Rev Immunol. 2003;3(10):822–829.
BCR, B-cell receptor; CD, cluster of differentiation; Ig, immunoglobulin; MHC, major histocompatibility complex; TCR, T-cell receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Antibody structure
Antibodies have a Y-shaped structure consisting of two light chains and two heavy chains linked together via disulfide bonds.1
Proteolytic cleavage products:
Antigen binding sites
Fab
NH2
NH2
NH2
NH2
Disulfidebonds
Variableregion
Light chain
Fc
Disulfide bond
COOH
COOH
Constantregion
Heavy chain: IgA (α), IgD (δ),
IgE (ε), IgG (γ), IgM (μ)
Did you know?
COOH
COOH
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The N-terminal portions of both the light and heavy chains are highly variable between different antibody molecules, permitting each antibody to exhibit unique antigen specificity.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Each antibody has two identical antigen-binding sites, comprising amino acids from the variable regions of the light and heavy chains.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Limited digestion of an antibody generates two fragment antigen-binding regions (Fab) containing the antigen-binding sites, and a crystallisable fragment (Fc) containing parts of the constant region.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Antibodies can come in monomeric, dimeric or pentameric structures:1
Pentameric (IgM)
Monomeric (IgD, IgE, IgG)
Dimeric (IgA)
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
Ig, immunoglobulin; Fab, fragment antigen-binding regions; Fc, crystallisable fragment.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Antibody function
The binding of antibodies to antigens on the surface of the pathogen can inhibit infection through three main mechanisms.1,2
Antigen
Antigen-binding site
Antibody (immunoglobulin)
Neutralization
Opsonization
Complement activation
Complement C1 complex
Membrane attack complex
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Neutralization involves the antibody blocking access of the pathogen to host cells.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
With opsonization, the antibody flags the pathogen for ingestion and digestion by phagocytes.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
In the process of complement activation, components of the activated complement system further promote pathogen phagocytosis and can directly lyse some bacteria via formation of the membrane attack complex.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Innate immune receptors and signaling pathways
The innate immune response is activated by interaction of host PRMs with PAMPs and DAMPs associated with infection.1
PAMPs
DAMPs
Innate immune cell
TLR
NLR
Cytoplasm
IKK
IκB
IκB
MAPK
NF-κB
IκB
NF-κB
AP-1
Nucleus
Pro-inflammatory gene expression
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TLRs are a major class of innate transmembrane receptors that recognize diverse microbial PAMPs such as LPS, flagellin or viral nucleic acids.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TLRs and NLRs stimulate signaling via nuclear factor-κB (NF-κB), a key immune intracellular signal transduction pathway target.1-3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
NLRs, another important group of innate PRMs, are intracellular proteins activated in response to common metabolic consequences of infection.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
A second inflammatory signaling pathway stimulated by NLRs is the mitogen-activated protein kinase (MAPK) cascade, which activates the transcription factor activator protein-1 (AP-1).2,4
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.
- Franchi L, Warner N, Viani K, et al. Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev. 2009;227(1):106–128.
- Liang Y, Zhou Y, Shen P. NF-kappaB and its regulation on the immune system. Cell Mol Immunol. 2004;1(5):343–350.
- Whitmarsh AJ, Davis RJ. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl). 1996;74(10):589–607.
AP-1, activator protein-1; DAMP, damage-associated molecular pattern; IκB, inhibitor of NF-κB; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; NLR, nucleotide oligomerization domain-like receptor; P, phosphorylation; PAMP, pathogen-associated molecular pattern; PRM, pattern recognition molecule; TLR, toll-like receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Adaptive immune receptors and signaling pathways
Adaptive immune receptors are activated either through antigen-induced cross-linking of BCRs or by TCR recognition of antigenic peptides in association with MHC molecules on the surface of APCs.1,2 The resulting signaling pathways induce gene expression leading to proliferation and differentiation of the activated B- or T-cell.1
Antigen
MHC
BCR
Antigen
APC
TCR
B-cell
T-cell
Cytoplasm
IKK
IκB
IκB
NFAT
MAPK
NF-κB
IκB
Calcineurin
NF-κB
AP-1
NFAT
Nucleus
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Receptor activation leads to activation of intracellular tyrosine kinases associated with the cytoplasmic domains of the receptor complexes, which trigger signaling through the NF-κB and MAPK pathways.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Calcineurin is also stimulated which dephosphorylates NFAT, allowing it to translocate to the nucleus.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. 6th ed. Garland Science; 2014.
AP-1, activator protein-1; APC, antigen-presenting cell; BCR, B-cell receptor; IκB, inhibitor of NF-κB; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; NFAT, nuclear factor of activated T-cells; NF-κB, nuclear factor-κB; P, phosphorylation; TCR, T-cell receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The TNF pathway I: regulation of TNF expression1–3
Proteolyticcleavage
PAMPs (e.g. LPS)
Soluble TNF trimer
TLR
Macrophage
Membrane-bound TNF
Cytoplasm
IKK
Vesicle
IκB
IκB
TNF translation
NF-κB
IκB
TNF transcription
NF-κB
Nucleus
TNF mRNA
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Activation of TLRs on the macrophage surface by bacterial components leads to activation of NF-κB, which in turn stimulates expression of the gene for TNF – a key inflammatory mediator.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
sTNF associates into homotrimers and freely diffuses to act on target cells.2,3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TNF is initially synthesized as a membrane-bound form, which is then proteolytically cleaved by the enzyme TACE at the cell surface to generate soluble TNF (sTNF).3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Liang Y, Zhou Y, Shen P. NF-kappaB and its regulation on the immune system. Cell Mol Immunol. 2004;1(5):343–350.
- Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10(1):45–65.
- Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond). 2005;109(2):135–142.
IκB, inhibitor of NF-κB; IKK, IκB kinase; LPS, lipopolysaccharide; mRNA, messenger RNA; NF-κB, nuclear factor-κB; P, phosphorylation; PAMP, pathogen-associated molecular pattern; RNA, ribonucleic acid; sTNF, soluble tumor necrosis factor; TLR, toll-like receptor; TNF, tumor necrosis factor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The TNF pathway II: TNF signaling
- The biological actions of TNF are mediated by binding to one of two TNF receptors: TNFR1 and TNFR21
- TNFRs activate intracellular signaling via interaction with death domain-containing proteins and/or TRAFs2
- The balance of signaling via TNFR1 vs TNFR2 dictates the type of biological response ultimately elicited1
TNF
TNFR2
TNFR1
Target cell
TRADD
Caspases
TRAF2
Cytoplasm
IKK
IκB
Apoptosis
IκB
MAPK
NF-κB
IκB
NF-κB
AP-1
Nucleus
Pro-inflammatory gene expression
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TNFR1 is widely expressed2 and promotes apoptosis via activation of caspases.1,3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TNFR2 expression is mostly restricted to cells of the immune system.2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TRAF2 is an adapter protein that facilitates interactions between a number of signal transduction proteins, leading to activation of pro-inflammatory NF-κB and MAPK signaling.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond). 2005;109(2):135–142.
- Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10(1):45–65.
- Gañán-Gómez I, Wei Y, Starczynowski DT, et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia. 2015;29(7):1458–1469.
AP-1, activator protein-1; IκB, inhibitor of NF-κB; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; P, phosphorylation; TNF, tumor necrosis factor; TNFR, TNF receptor; TRADD, tumor necrosis factor receptor-associated death domain; TRAF, tumor necrosis factor receptor-associated factors.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The TNF pathway III: biological actions of TNF
TNF is a major pro-inflammatory mediator that elicits a wide variety of biological responses in many different cell types.1 Target tissue type, cellular context, TNFR composition, timing and duration of TNF stimulation can all influence the biological effect of TNF.1
Macrophage Pro-inflammatory cytokine release
TNF
Hepatocyte Acute-phase reactants
Intestinal epithelium Expression of EGF, MHC molecules, MMPs
Lymphocyte Activation
Endothelial cell Adhesion molecule expression
Fibroblast Apoptosis
Monocyte Differentiation
Osteoclast Activation
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10(1):45–65.
- Korzenik JR, Podolsky DK. Evolving knowledge and therapy of inflammatory bowel disease. Nat Rev Drug Discov. 2006;5(3):197–209.
- Esposito E, Cuzzocrea S. Anti-TNF therapy in the injured spinal cord. Trends Pharmacol Sci. 2011;32(2):107–115.
EGF, epidermal growth factor; MHC, major histocompatibility complex; MMP, matrix metalloprotease; TNF, tumor necrosis factor; TNF, tumor necrosis factor receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Signaling pathways I: the interleukin pathways1–3
Interleukin-4 and Interleukin-13 signaling
Interleukin-3, Interleukin-5and GM-CSF signaling
Interleukin-2family signaling
Interleukin-1family signaling
IL-13
IL-4
IL-3
Interleukin-6family signaling
IL-4
IL-3
IL-2
IL-1
IL-13
IL-6
SHC1
IL-6
JAK2
JAK3
SHC1
GBR2
SOS1
GBR2
SOS1
JAK1
JAK3
JAK1
JAK2
JAK2
TYK2
JAK2
STAT6
SOCS3
STAT5
STAT5
STAT5
STAT3
STAT6
PTPN11
STAT5
MYD88
JAK
IRAK1.2.4
MAP2K6
JAK
STAT1
Ub
Ub
Ub
Ub
TRAF6
STAT3
Ub
Ub
Ub
Ub
STAT
STAT
MAP3K7
IKK
NF-KB1
MAPK1.3
STAT5
STAT5
STAT3
JAK1
STAT4
STAT4
JAK1
JAK3
STAT3
JAK1
CIKS
TYK2
JAK2
TYK2
TYK2
IL-?
IL-7
IL-20
IL-12
IL-10
Other Interleukinsignaling
Interleukin-7signaling
IL-10
IL-17
Interleukin-20family signaling
Interleukin-12family signaling
Did you know?
Interleukin-10signaling
Interleukin-17signaling
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
- Interleukins (ILs) consist of a large and diverse group of cytokines that can elicit many reactions in cells and tissues by binding to high-affinity cell surface receptors1–3
- These low molecular weight proteins play essential roles in the activation and differentiation of immune cells, as well as proliferation, maturation, migration and adhesion. They also have pro-inflammatory and anti-inflammatory properties1–3
- Initially thought to be expressed solely by leukocytes, ILs are now known to be produced by many other cells throughout the body1
- Cellular responses to ILs include up- and down-regulatory mechanisms with the induction and participation of genes that encode inhibitors of the cytokine receptors3
- Most cytokines act either on the same cell that secretes the cytokine, or on a nearby cell. However, they can may enter the circulation and act far from the site of production3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Vosshenrich CAJ, Di Santo JP. Interleukin signaling. Curr Biol. 2002;12(22):R760–R763.
- Akdis M, Burgler S, Crameri R, et al. Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2011;127(3):701–721
- Justiz Vaillant AA, Qurie A. Interleukin. StatPearls Publishing; 2022. Accessed July 2025. https://www.ncbi.nlm.nih.gov/books/NBK499840/
CIKS, connection to IκB kinase and stress-activated protein kinases; GM-CSF, granulocyte/macrophage-colony stimulating factor; GRB2, growth factor receptor-bound protein 2; IKK, I kappa B kinase; IL, interleukin; IRAK, members of the IL1R-associated kinase; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MYD88, myeloid differentiation primary response protein; NF-kB, nuclear factor NF-kappa-B; P, phosphate; PTPN11, tyrosine-protein phosphatase non-receptor type 11; SHC, transforming protein; SOS1, son of sevenless homolog 1; STAT, signal transducer and activator of transcription; TNF, tumor necrosis factor; TRAF, TNF receptor-associated factor; TYK, tyrosine kinase; Ub, ubiquitin.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Immune system regulation I: Treg cells1–3
In immunology, ‘tolerance’ refers to the adaptive immune system’s ability to avoid attacking host tissues.3
TCR
MHC Class II
T-cell
Dendritic cell
Inhibit T-cell function
CD28
Central tolerance is the destruction of self-reactive lymphocytes early during their maturation.3
CD80/CD86
CTLA4Blocks co-stimulation
Several mechanisms of peripheral tolerance also exist to eliminate self-reactive T-cells that escape into the circulation – one of these is mediated by Treg cells.4
Treg cell
IL-10
Immunosuppressive cytokines
CD25High-affinity binding to IL-2
TGF-β
IL-2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Suppressive action of Treg cells may be mediated by their secretion of the immunosuppressive cytokines IL-10 and TGF-β.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Treg cells can inhibit the activation of other T-cells via their surface expression of cytotoxic T lymphocyte-associated protein-4 (CTLA4), a checkpoint of the immune response with anti-inflammatory function. CTLA4 has high affinity for the dendritic cell proteins CD80 and CD86, and can prevent these proteins from delivering their co-stimulatory signal to naïve T-cells.3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Treg cells express the high-affinity IL-2 receptor, CD25, which can absorb IL-2 from the local intercellular milieu and so prevent it from activating other immune cells.2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Campbell DJ. Control of regulatory T cell migration, function, and homeostasis. J Immunol. 2015;195(6):2507–2513.
- Sakaguchi S, Wing K, Onishi Y, et al. Regulatory T cells: how do they suppress immune responses? Int Immunol. 2009;21(10):1105–1111.
CD, cluster of differentiation; CTLA4, cytotoxic T lymphocyte-associated protein-4; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor; TGF, transforming growth factor; Treg, regulatory T-cell.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Immune system regulation II: PD-1/PD-L1 pathway
A second tolerance mechanism that suppresses the adaptive immune response is mediated by programmed death-1 (PD-1), another checkpoint of the immune response with anti-inflammatory function.1 Expression of this protein is upregulated in T-cells following their activation.2 PD-1 suppresses immune responses through its interaction partner, programmed death ligand-1 (PD-L1), which is widely expressed in a variety of immune and non-immune tissues.2
MHC-antigen complex
TCR
T-cell
APC
Decreased T-cell proliferation
Reduced pro-inflammatorycytokine production
PD-L1
PD-1
Negative co-stimulation
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Defense mechanisms of the body
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- The PD-1/PD-L1 interaction delivers an inhibitory signal to the T-cell, which results in reduced T-cell proliferation2
- The inhibitory signal also diminishes T-cell production of pro-inflammatory cytokines such as TNF and IL-22
- A second mechanism by which PD-L1 inhibits T-cell responses is through the induction and maintenance of inhibitory Treg cells3
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity.Immunol Rev. 2010;236:219–242.
- Chinai JM, Janakiram M, Chen F, et al. New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci. 2015;36(9):587–595.
- Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–3029.
APC, antigen-presenting cell; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1;TCR, T-cell receptor; TNF, tumor necrosis factor; Treg, regulatory T-cells.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
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Summary
Altered signaling pathways in RA1,2
T-cell
CD80/86 inhibitorabatacept
CD80/86
CD28
Anti-CD20 drugrituximab
DCs
IL-2
IL-17 IFN-γ
Proliferation Migration Pannus formation Inflammation Bone and cartilage destruction
Macrophage
CD20
Co-stimulation
TCR
CD40
CD40L
Th1/Th17/Tfh
FCR
B cell
BCR
T-cell
IL-15IL-18
Autoantibody
TNFIL-1β
Osteoclast
RANKL
Plasma cell
Extensiveangiogenesis
IL-1
MMPs
IFN
TNFα
RANKL
MMPs
FLS
Figure adapted from Ding Q, et al. Signal Transduction Target Ther 2023;8:68.
TGFβ
VEGF
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In the presence of certain environmental or genetic factors, a stepwise progression occurs from activation of innate immunity by the stimulation of dendritic cells.2 This stimulates B cells, macrophages, synoviocytes, chondrocytes, and osteoclasts to secrete pro-inflammatory cytokines, resulting in bone and cartilage damage accompanied by synovial membrane thickening and angiogenesis to promote tissue remodelling and driving the chronic phase of RA.2
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Defense mechanisms of the body
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Summary
References:
- Zhu M, Ding Q, Lin Z, et al. New targets and strategies for rheumatoid arthritis: from signal transduction to epigenetic aspect. Biomolecules. 2023;13(5):766.
- Ding Q, Hu W, Wang R, et al. Signaling pathways in rheumatoid arthritis: implications for targeted therapy. Signal Transduction Target Ther. 2023;8(1):68.
BCR, B-cell receptor; DC, dendritic cell; FCR, Fc receptor; FLS, fibroblast-like synoviocytes; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinases; RANKL, receptor activator of nuclear factor κB ligand; TCR, T-cell receptor; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
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Defense mechanisms of the body
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Summary
Altered signaling pathways in IBD
Epithelial barrier defect
Intestinal epithelium
IFNγ TNFα
IL-17 GM-CSF TNFα IL-22
Changes in the balance and cellular crosstalk between innate lymphoid cells (ILC1s and ILC3s) is involved in mediation of many of the mechanisms which are potentially altered in IBD.1–3
IL-23, IL-1β, retinoic acid
IL-12, IL-18
ILC3
ILC1
IL-23 IL-1β
IL-12 IL-18
Macrophage
Dendritic cell
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Defense mechanisms of the body
Anatomical and physiological barriers
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Summary
Numbers of ILC1 are increased in IBD and produce large amounts of IFNγ and TNFα, leading to inflammation and tissue damage.1,2
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Defense mechanisms of the body
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ILC3 are abundant in the gut and in chronic inflammation, such as IBD, may transfer into a pro-inflammatory phenotype exacerbating inflammation via damaging epithelial cells and increasing permeability, decreasing the mucus layer, and promoting fibrosis.3
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Geremia A, Arancibia-Cárcamo CV. Innate lymphoid cells in intestinal inflammation. Front Immunol. 2017;8:1296.
- Saez A, Gomez-Bris R, Herrero-Fernandez B, et al. Innate lymphoid cells in intestinal homeostasis and inflammatory bowel disease. Int J Mol Sci. 2021;22(14):7618.
- Li M, Wang Z, Jiang W, et al. The role of group 3 innate lymphoid cell in intestinal disease. Front Immunol. 2023;14:1171826.
GM-CSF, granulocyte macrophage colony-stimulating factor; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; ILCs, innate lymphoid cells; RA, retinoic acid; TNF, tumor necrosis factor.
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Defense mechanisms of the body
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Summary
The immune system consists of a range of physical, chemical and cellular mechanisms that function to eliminate potentially harmful substances, such as microbes, viruses and toxins1,2
Innate immunity provides a rapid response with broad specificity based on recognition of conserved PAMPs and DAMPs by PRMs on innate immune cells (e.g. neutrophils)3,4
Adaptive immune responses are slower, but have high specificity based on recognition of particular non-self structures (antigens) by receptors (TCRs and BCRs) selected from an enormously diverse repertoire of variants3
T-cells recognize peptide antigens in association with MHC molecules on the surface of APCs and once activated, function either to destroy infected cells or cells expressing tumor antigens (cytotoxic T-cells) or to coordinate the actions of other cells (helper T-cells)2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S3–23.
- Warrington R, Watson W, Kim HL, et al. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(Suppl 1):S1.
- Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.
- Mak TW, Saunders ME, Jett BD. A primer to the immune response. 2nd ed. Elsevier; 2014.
APC, antigen-presenting cell; BCR, B-cell receptor; DAMP, damage-associated molecular pattern; IL, interleukin; MHC, major histocompatibility complex; PAMP, pathogen-associated molecular pattern; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PRM, pattern recognition molecule; TCR, T-cell receptor; TNF, tumor necrosis factor; Treg, regulatory T-cell.
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Defense mechanisms of the body
Anatomical and physiological barriers
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Summary
Summary (Cont.)
B-cells recognize free antigen and once activated, secrete antigen-specific humoral factors (antibodies), which neutralize, opsonize and target antigens for destruction1,2
Immune responses are orchestrated and coordinated by the actions of small, secreted (glyco) proteins known as cytokines (e.g. TNF, ILs)3,4
The type of immune response is determined in part by the profile of the cytokines secreted5
Tolerance mechanisms such as Treg cells and the PD-1/PD-L1 axis function to downregulate immune responses and so, prevent inappropriate attack of host tissues6
CTLA-4 and PD-1/PD-L1 are physiologic negative checkpoints of immune activation. Engagement of either pathway inhibits activation of effector T-cells
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
- Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.
- Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. Garland Science; 2016.
- Wahab S, Hussain A. Cytokines as targets for immunomodulation. Int J Pharm Pharmaceut Sci. 2013;5(Suppl 3):60–64.
- Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45(2):27–37.
- Simon EG, Ghosh S, Iacucci M, et al. Ustekinumab for the treatment of Crohn's disease: can it find its niche? Therap Adv Gastroenterol. 2016;9(1):26–36.
- Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity.Immunol Rev. 2010;236:219–242.
APC, antigen-presenting cell; BCR, B-cell receptor; CTLA-4, cytotoxic T-lymphocyte associated protein 4; DAMP, damage-associated molecular pattern; IL, interleukin; MHC, major histocompatibility complex; PAMP, pathogen-associated molecular pattern; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PRM, pattern recognition molecule; TCR, T-cell receptor; TNF, tumor necrosis factor; Treg, regulatory T-cell.
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Chapter 1The immune systemand its players
In this chapter, you will gain understanding of the principles of clinical immunologyand learn about the system and its players Topics included:
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Biogen-266406 | 07/2025
Intended for healthcare professionals only. This document has been funded and created by Biogen International GmbH, Baar, Switzerland.
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Defense mechanisms of the body
Click theto find more information
The immune response is a collection of protective mechanisms to control and eliminate pathogenic microbes, viruses, external antigens, mutated cells and other harmful substances.1,2
Physical2
Chemical2,3
Cellular1,2,4
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Physical barriers include mechanical and physiological barriers.2
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Defense mechanisms of the body
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Innate and adaptive immunity
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Summary
Chemical defences are mostly secreted peptides and proteins that inhibit or destroy microbes.2,3
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Cellular responses include cells that internalize and break down foreign substances or lyse infected host cells.1,2,4
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
NET, neutrophil extracellular trap.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Anatomical and physiological barriers
The first line of defense against infection comprises a variety of non-specific mechanical and physiological barriers that exclude pathogens from the body.1,2
Mechanical barriers1–3
Muco-ciliary clearance1,3
Secreted hydrolytic enzymes1,3
Low pH1,3
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Innate and adaptive immunity
Pathogens that successfully penetrate the anatomical and physiologic barriers of the body encounter further lines of defense.1,2
Immune response
Adaptive immunity
Innate immunity
Crosstalk
Humoral components: complement, antimicrobial peptides, MBL, LPS-binding protein, CRP
Humoral components: antibodies
Cellular components: dendritic cells, neutrophils, natural killer cells, eosinophils, macrophages, mast cells, γδ T-cells5
Cellular components: T-cells, B-cells
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The innate immune system provides a rapid response with low specificity. It recognizes non-peptide elements – PAMPS and DAMPs – that arise as a consequence of infection and/or inflammation.3,4
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The adaptive immune system provides a slower but highly specific response. It recognizes foreign peptide antigens using receptors from an enormous and diverse repertoire.3
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
CRP, C-reactive protein; DAMPs, damage-associated molecular patterns; LPS, lipopolysaccharide; MBL, mannose-binding lectin; PAMPs, pathogen-associated molecular patterns; PRM, pattern recognition molecule.
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
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Summary
Cells of the immune system
The white blood cells of the innate and adaptive immune systems arise through differentiation of hematopoietic stem cells in the bone marrow.1 Mature white blood cells arise from two different lineages: the myeloid lineage and the lymphoid lineage.1
Pluripotent hematopoietic stem cell
Common myeloid progenitor
Common lymphoid progenitor
Neutrophil
Eosinophil
Basophil
Monocyte
Non-cytotoxicILC
Mast cell
Naturalkiller cell
γδ T-cell
αβ T-cell
B-cell
Adaptiveimmunity
Macrophage
Dendritic cell
Innate immunity
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
ILC, innate lymphoid cell.
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Defense mechanisms of the body
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Summary
Innate immune system1–4
Innate immune cells of the myeloid lineage include mast cells, monocytes and granulocytes (neutrophils, eosinophils and basophils), which contain cytoplasmic secretory granules.2
Pluripotent hematopoietic stem cell
Common myeloid progenitor
Common lymphoid progenitor
Neutrophil
Eosinophil
Basophil
Monocyte
Non-cytotoxicILC
Mast cell
Naturalkiller cell
γδ T-cell
Granulocytes
APCs
Macrophage
Dendritic cell
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Defense mechanisms of the body
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Summary
Neutrophils are the most numerous type of granulocytes. They play a key role in immunity against bacterial infections through their ability to destroy pathogens by phagocytosis or the formation of NETs.2
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Defense mechanisms of the body
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Summary
The other granulocytes – eosinophils and basophils – mediate immunity against parasites and modulate immunoglobulin-mediated responses.1,2
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Defense mechanisms of the body
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Summary
Mast cells modulate vascular permeability and are thought to function in mucosal immunity.2
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Defense mechanisms of the body
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Myeloid innate cells also include monocytes, which differentiate within the tissues into two types of APCs: macrophages and dendritic cells.2
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Defense mechanisms of the body
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Summary
In addition to phagocytosis, both macrophages and dendritic cells play a key role in taking up and presenting antigens to lymphocytes to initiate adaptive immunity.1,2
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Defense mechanisms of the body
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Summary
References:
APC, antigen-presenting cell; ILC, innate lymphoid cell; NET, neutrophil extracellular trap.
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Defense mechanisms of the body
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Summary
Humoral factors of the innate immune system
The humoral components of the innate immune system include a variety of soluble PRMs that function as pathogen sensors.1 Some PRMs can also exert direct antimicrobial action.1
Antimicrobial peptides1,2
Complement system3,4
CRP3,6
Collectins (e.g. MBL)5
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
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Summary
References:
CM, cell membrane; CRP, C-reactive protein; IS, intracellular space; MBL, mannose-binding lectin; PRM, pattern recognition molecule.
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Defense mechanisms of the body
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Summary
Cells of the adaptive immune system: T-cells and B-cells1
Pluripotent hematopoietic stem cell
Common lymphoid progenitor
αβ T-cell
B-cell
Humoral immunity
Helper T-cell(CD4+)
Cytotoxic T-cell(CD8+)
Did you know?
Cell-mediated immunity
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Defense mechanisms of the body
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In humans, the vast majority of T-cells express the αβ receptor. Conventionally, αβ T-cells are termed ‘T-cells’. This slide deck refers to αβ T-cells when using the term ‘T-cell’.
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Defense mechanisms of the body
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There are two major subtypes of T-cells:2
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Defense mechanisms of the body
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Specific antigen–receptor interactions can trigger activation of T-cells and B-cells, leading to their proliferation and differentiation into the effector cells of the adaptive immune response.1,2
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Defense mechanisms of the body
Anatomical and physiological barriers
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Summary
References:
CD, cluster of differentiation.
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Defense mechanisms of the body
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Summary
Lymphocyte maturation and circulation1
Bone marrow
Common lymphoid progenitor
Naïve B-cell
T-cell progenitor
Primary/central lymphoid organs
Thymus
NaïveT-cells
Bloodstream
Circulating naïvelymphocytes
Lymphaticvessels
Secondary/peripheral lymphoid organs
Spleen
Lymph node
GALT/BALT/MALT
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Defense mechanisms of the body
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Summary
Both B-cells and T-cells arise in the bone marrow, where B-cells also mature.1
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Defense mechanisms of the body
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Summary
Mature naïve B- and T-cells then enter the circulation and migrate out of the bloodstream into the secondary/peripheral lymphoid organs.1
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Defense mechanisms of the body
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Summary
T-cell progenitors must migrate to the thymus for maturation.1
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Defense mechanisms of the body
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If no antigen is encountered in the peripheral lymphoid organs, lymphocytes can re-enter the circulation either directly or via the lymphatic vessels.1
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Defense mechanisms of the body
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Upon encountering their specific antigen, lymphocytes proliferate and differentiate within the peripheral lymphoid tissue before re-entering the bloodstream to combat infection in the tissues.1
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Defense mechanisms of the body
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Summary
References:
BALT, bronchial-associated lymphoid tissue; GALT, gut-associated lymphoid tissue; MALT, mucosal-associated lymphoid tissue.
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Defense mechanisms of the body
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The need for co-stimulation in T-cell activation
Secondary lymphoid organ
Signal 1
MHC–antigen–TCR complex
CD4/CD8 co-receptor
APC
T-cell
Proliferation and differentiationdirected by cytokines
Effector T-cell
CD28
CD80/86
Signal 2 (co-stimulation)
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Defense mechanisms of the body
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Summary
The interaction of the TCR and co-receptor with the MHC–antigen complex provides an antigen-specific signal (Signal 1) that is necessary, but not sufficient, for T-cell activation.1
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Defense mechanisms of the body
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T-cell activation also requires a second signal (Signal 2), known as ‘co-stimulation’, which may be delivered by interaction of CD28 on the T-cell surface with the CD80 or CD86 receptor on the surface of the APC.1
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Defense mechanisms of the body
Anatomical and physiological barriers
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Summary
References:
APC, antigen-presenting cell; CD, cluster of differentiation; MHC, major histocompatibility complex; TCR, T-cell receptor.
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Defense mechanisms of the body
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Helper (CD4+) T-cell activation
The TCR interacts with two different types of MHC molecule: class I and class II.1,2
Secondary lymphoid organ
Secondary lymphoid organ
MHC Class II
MHC Class I
CD4 co-receptor
CD8 co-receptor
Cell infected with intracellular pathogen or cancer cell
Professional APC (e.g. macrophage, dendritic cell)
HelperT-cell (CD4+)
Cytotoxic T-cell (CD8+)
Effector helper T-cell
Effectorcytotoxic T-cell
Antigen:Peptide derived from a pathogen ingested and processed by the APC
Antigen:Peptide derived from a protein synthesized within the MHC Class I-expressing cell
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Defense mechanisms of the body
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Summary
Class II MHC molecules present peptides derived from proteins within intracellular vesicles, including vesicular intracellular parasite proteins, or antigens internalized by phagocytes or B-cells.1
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Defense mechanisms of the body
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Summary
T-cell specificity for class II MHC molecules is provided by the CD4 co-receptor, which is expressed by the helper T-cell subset.1
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Defense mechanisms of the body
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Class I MHC molecules present peptides derived from proteins synthesized in the cytosol, such as viral proteins within an infected cell.1
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Defense mechanisms of the body
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T-cell specificity for class I MHC molecules is provided by the CD8 co-receptor, which is expressed by the cytotoxic T-cell subset.1
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
APC, antigen-presenting cell; CD, cluster of differentiation; MHC, major histocompatibility complex; TCR, T-cell receptor.
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Defense mechanisms of the body
Anatomical and physiological barriers
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Summary
Cytokines
Cytokine-producing cell
Did you know?
Target cell
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Defense mechanisms of the body
Anatomical and physiological barriers
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Summary
Different cytokines interact via effects on target cells that may be antagonistic, additive or synergistic, or pro- or anti-inflammatory.1,2 They often show pleiotropy and redundancy in their function1,2 and they tend to function within cascades, whereby one cytokine enhances or suppresses the production of others.1,2
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Defense mechanisms of the body
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Summary
Cytokines are small, secreted signaling proteins/glycoproteins that play a key role in coordinating immune responses. They can act via autocrine, paracrine or endocrine action.1
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Defense mechanisms of the body
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Cytokines are produced by a wide range of cell types, including helper T-cells, macrophages and B-cells. They are often produced in a cascade.1
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Defense mechanisms of the body
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References:
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Types of cytokine
Interleukins
E.g. IL-1, IL-4,IL-6, IL‑10, IL-17, IL-23
Cytokines can be grouped into different categories based on their functions or source, being produced by, and acting upon, many different cells.1
Interferons
Transforming growth factor
IFN-α,IFN-β,IFN-γ
TGF-β
Tumor necrosis factor
Chemokines
Click a section for moreinformation
RANTES,MCP-1, IL-8
TNF-αTNF-βBAFF
Hematopoieticagents
GM-CSFM-CSF Erythropoietin
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Defense mechanisms of the body
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Interleukin is a general term that was originally coined to refer to cytokines produced by one type of leukocyte and acting on another.2
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Transforming growth factor-β (TGF-β) is an inhibitory cytokine produced by a variety of cell types including T-cells.1
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Signaling pathways
Summary
Interferons are cytokines that either inhibit viral replication in infected cells (type I interferon: IFN-α, IFN-β) or stimulate pathogen clearance mechanisms in the innate and adaptive immune systems (type II interferon: IFN-γ).3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Chemokines are chemotactic cytokines that attract leukocytes to areas of inflammation (e.g. regulated on activation normal T-cell expressed and secreted [RANTES], macrophage chemoattractant protein-1 [MCP-1] and IL-8).4,5
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Hematopoietic agents regulate the proliferation and differentiation of hematopoietic cells.1,6
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The members of the tumor necrosis factor (TNF)/TNF receptor (TNR-R) superfamily comprise a group of currently more than 40 ligand and receptor proteins which are mostly produced by cells of the immune system and which influence cell proliferation, cell survival, cell differentiation and apoptosis of the responding cells.2 TNF is a pleiotropic cytokine that plays a key role in the development of lymphoid organs, inflammation, tumor-cell killing and defense against intracellular pathogens.7
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
BAFF, B-cell activating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin;M-CSF, macrophage colony-stimulating factor; MCP-1, macrophage chemoattractant protein-1; RANTES, regulated on activation normal T cell expressed and secreted; TGF, transforming growth factor; TNF, tumor necrosis factor; TNF-R, tumor necrosis factor receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Helper T-cell differentiation
APC
Naïve T-cell
IL-4 TGF-β
IL-12 IFN-γ
IL-4
IL-2 TGF-β
IL-6 TGF-β
Th9
Th1
Th2
Th17
Treg
IL-9, IL-10, IL-21
TNF, IFN-γ, IL-2, IL-18
IL-4, IL-5, IL-13, IL-25
IL-10, TGF-β, IL-35
TNF, IL-17, IL-22
Anti-helminth and anti-tumor immunity
Activation of cell-mediated immunity
Activation of humoral immunity
Downregulation of immune responses
Regulation of mucosal immunity
Effector T-cells
Inhibitory T-cells
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Naïve T-cells activated in the presence of IL-12 and IFN-γ differentiate into Th1 cells, which secrete IFN-γ and so activate cell-mediated immunity against intracellular pathogens such as viruses.1–3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
In the absence of TGF-β, IL-4 promotes the differentiation of activated T-cells into Th2 cells, which secrete cytokines that stimulate antibody production by B-cells, thereby promoting humoral immunity.4
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
IL-4 in combination with TGF-β stimulates the development of the Th9 immunophenotype, which is believed to play a role in immune responses against helminth parasites and tumor cells.5
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
CD4+ T-cells activated in the presence of IL-6 and TGF-β develop into Th17 cells, which regulate immunity at mucosal surfaces through the production of IL-17.2,6
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
IL-2 and TGF-β together direct differentiation of CD4+ cells into inhibitory Treg cells.2,7
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
APC, antigen-presenting cell; IFN, interferon; IL, interleukin; TGF, transforming growth factor; Th, T helper; TNF, tumor necrosis factor; Treg, regulatory T-cell.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Leukocyte trafficking: Roles of chemokines and adhesion molecules1–3
Tethering
Endothelial cell
Rolling
Adhesion triggering
Leukocyte
Extravasation
Chemokines mediate the recruitment of immune cells to sites of inflammation during the innate response to infection by inducing nearby endothelial cells to express adhesion molecules called selectins.1
Inflammatorycytokines
Chemokines
Inflamed site
Chemotaxis
Selectin ligand
Selectin
Integrin
Integrin ligand
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Chemokines stimulate extravasation of leukocytes, which migrate to the site of inflammation in the tissue by following the chemokine gradient.2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Selectins interact with carbohydrates on the leukocyte cell surface, causing tethering and rolling of leukocytes along the endothelium.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Further signals trigger activation of leukocyte adhesion molecules called integrins, which establish more stable adhesive interactions with ligands expressed on the endothelial surface1–3, causing tethering and rolling of leukocytes along the endothelium.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
B-cell activation
The antigen receptor on B-cells is known as the B-cell receptor (BCR) and consists of a membrane-bound form of an antibody.1 B-cells are activated by the binding of antigen to the BCR and then proliferate and differentiate into antibody-secreting plasma cells or long-lived memory B-cells.1–3
AntigenProcessed peptide derived from the same pathogen
Secondary lymphoid organ
MHC class II
TCR
BCR
Antigen No requirement for processing
Helper T-cell
Naïve B cell
CD40L
CD40
Plasma cell
T-cell help (required for Ig class switch fromIgM to IgA, IgD, IgG or IgE)
Memory B-cell
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Binding of antigen to the BCR leads to internalization and processing of the antigen. Fragments of the antigen are then presented by the B-cell in association with MHC class II molecules to helper T-cells.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Activation of the B-cell by thymus-dependent antigens requires a helper T-cell that has previously been activated in response to the same antigen.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Once activated, B-cells proliferate and differentiate into plasma cells, which secrete antibodies with the same specificity as the BCR expressed by the parent B-cell.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Interaction of the TCR with the MHC–antigen complex induces the T-cell to express the surface receptor CD40 ligand (CD40L), which in turn interacts with CD40 on the B-cell and helps drive B-cell activation (‘T-cell help’).1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Activated B-cells can also differentiate into long-lived memory B-cells, which continue to express antigen-binding receptors and can be reactivated rapidly on subsequent exposure to the same antigen.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Several antibody classes exist. Cytokines can direct the B-cell to change the class of antibody produced (‘class switching’) in a process that is dependent on CD40L.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
BCR, B-cell receptor; CD, cluster of differentiation; Ig, immunoglobulin; MHC, major histocompatibility complex; TCR, T-cell receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Antibody structure
Antibodies have a Y-shaped structure consisting of two light chains and two heavy chains linked together via disulfide bonds.1
Proteolytic cleavage products:
Antigen binding sites
Fab
NH2
NH2
NH2
NH2
Disulfidebonds
Variableregion
Light chain
Fc
Disulfide bond
COOH
COOH
Constantregion
Heavy chain: IgA (α), IgD (δ), IgE (ε), IgG (γ), IgM (μ)
Did you know?
COOH
COOH
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The N-terminal portions of both the light and heavy chains are highly variable between different antibody molecules, permitting each antibody to exhibit unique antigen specificity.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Each antibody has two identical antigen-binding sites, comprising amino acids from the variable regions of the light and heavy chains.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Limited digestion of an antibody generates two fragment antigen-binding regions (Fab) containing the antigen-binding sites, and a crystallisable fragment (Fc) containing parts of the constant region.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Antibodies can come in monomeric, dimeric or pentameric structures:1
Pentameric (IgM)
Monomeric (IgD, IgE, IgG)
Dimeric (IgA)
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
Ig, immunoglobulin; Fab, fragment antigen-binding regions; Fc, crystallisable fragment.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Antibody function
The binding of antibodies to antigens on the surface of the pathogen can inhibit infection through three main mechanisms.1,2
Antigen
Antigen-binding site
Antibody (immunoglobulin)
Neutralization
Opsonization
Complement activation
Complement C1 complex
Membrane attack complex
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Neutralization involves the antibody blocking access of the pathogen to host cells.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
With opsonization, the antibody flags the pathogen for ingestion and digestion by phagocytes.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
In the process of complement activation, components of the activated complement system further promote pathogen phagocytosis and can directly lyse some bacteria via formation of the membrane attack complex.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Innate immune receptors and signaling pathways
The innate immune response is activated by interaction of host PRMs with PAMPs and DAMPs associated with infection.1
PAMPs
DAMPs
Innate immune cell
TLR
NLR
Cytoplasm
IKK
IκB
IκB
MAPK
NF-κB
IκB
NF-κB
AP-1
Nucleus
Pro-inflammatory gene expression
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TLRs are a major class of innate transmembrane receptors that recognize diverse microbial PAMPs such as LPS, flagellin or viral nucleic acids.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TLRs and NLRs stimulate signaling via nuclear factor-κB (NF-κB), a key immune intracellular signal transduction pathway target.1-3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
NLRs, another important group of innate PRMs, are intracellular proteins activated in response to common metabolic consequences of infection.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
A second inflammatory signaling pathway stimulated by NLRs is the mitogen-activated protein kinase (MAPK) cascade, which activates the transcription factor activator protein-1 (AP-1).2,4
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
AP-1, activator protein-1; DAMP, damage-associated molecular pattern; IκB, inhibitor of NF-κB; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; NLR, nucleotide oligomerization domain-like receptor; P, phosphorylation; PAMP, pathogen-associated molecular pattern; PRM, pattern recognition molecule; TLR, toll-like receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Adaptive immune receptors and signaling pathways
Adaptive immune receptors are activated either through antigen-induced cross-linking of BCRs or by TCR recognition of antigenic peptides in association with MHC molecules on the surface of APCs.1,2 The resulting signaling pathways induce gene expression leading to proliferation and differentiation of the activated B- or T-cell.1
Antigen
MHC
BCR
Antigen
APC
TCR
B-cell
T-cell
Cytoplasm
IKK
IκB
IκB
NFAT
MAPK
NF-κB
IκB
Calcineurin
NF-κB
AP-1
NFAT
Nucleus
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Receptor activation leads to activation of intracellular tyrosine kinases associated with the cytoplasmic domains of the receptor complexes, which trigger signaling through the NF-κB and MAPK pathways.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Calcineurin is also stimulated which dephosphorylates NFAT, allowing it to translocate to the nucleus.1
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
AP-1, activator protein-1; APC, antigen-presenting cell; BCR, B-cell receptor; IκB, inhibitor of NF-κB; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; NFAT, nuclear factor of activated T-cells; NF-κB, nuclear factor-κB; P, phosphorylation; TCR, T-cell receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The TNF pathway I: regulation of TNF expression1–3
Proteolyticcleavage
PAMPs (e.g. LPS)
Soluble TNF trimer
TLR
Macrophage
Membrane-bound TNF
Cytoplasm
IKK
Vesicle
IκB
IκB
TNF translation
NF-κB
IκB
TNF transcription
NF-κB
Nucleus
TNF mRNA
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Activation of TLRs on the macrophage surface by bacterial components leads to activation of NF-κB, which in turn stimulates expression of the gene for TNF – a key inflammatory mediator.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
sTNF associates into homotrimers and freely diffuses to act on target cells.2,3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TNF is initially synthesized as a membrane-bound form, which is then proteolytically cleaved by the enzyme TACE at the cell surface to generate soluble TNF (sTNF).3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
IκB, inhibitor of NF-κB; IKK, IκB kinase; LPS, lipopolysaccharide; mRNA, messenger RNA; NF-κB, nuclear factor-κB; P, phosphorylation; PAMP, pathogen-associated molecular pattern; RNA, ribonucleic acid; sTNF, soluble tumor necrosis factor; TLR, toll-like receptor; TNF, tumor necrosis factor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The TNF pathway II: TNF signaling
TNF
TNFR2
TNFR1
Target cell
TRADD
Caspases
TRAF2
Cytoplasm
IKK
IκB
Apoptosis
IκB
MAPK
NF-κB
IκB
NF-κB
AP-1
Nucleus
Pro-inflammatory gene expression
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TNFR1 is widely expressed2 and promotes apoptosis via activation of caspases.1,3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TNFR2 expression is mostly restricted to cells of the immune system.2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
TRAF2 is an adapter protein that facilitates interactions between a number of signal transduction proteins, leading to activation of pro-inflammatory NF-κB and MAPK signaling.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
AP-1, activator protein-1; IκB, inhibitor of NF-κB; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; P, phosphorylation; TNF, tumor necrosis factor; TNFR, TNF receptor; TRADD, tumor necrosis factor receptor-associated death domain; TRAF, tumor necrosis factor receptor-associated factors.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
The TNF pathway III: biological actions of TNF
TNF is a major pro-inflammatory mediator that elicits a wide variety of biological responses in many different cell types.1 Target tissue type, cellular context, TNFR composition, timing and duration of TNF stimulation can all influence the biological effect of TNF.1
Macrophage Pro-inflammatory cytokine release
TNF
Hepatocyte Acute-phase reactants
Intestinal epithelium Expression of EGF, MHC molecules, MMPs
Lymphocyte Activation
Endothelial cell Adhesion molecule expression
Fibroblast Apoptosis
Monocyte Differentiation
Osteoclast Activation
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
EGF, epidermal growth factor; MHC, major histocompatibility complex; MMP, matrix metalloprotease; TNF, tumor necrosis factor; TNF, tumor necrosis factor receptor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Signaling pathways I: the interleukin pathways1–3
Interleukin-4 and Interleukin-13 signaling
Interleukin-3, Interleukin-5and GM-CSF signaling
Interleukin-2family signaling
Interleukin-1family signaling
IL-13
IL-4
IL-3
Interleukin-6family signaling
IL-4
IL-3
IL-2
IL-1
IL-13
IL-6
SHC1
IL-6
JAK2
JAK3
SHC1
GBR2
SOS1
GBR2
SOS1
JAK1
JAK3
JAK1
JAK2
JAK2
TYK2
JAK2
STAT6
SOCS3
STAT5
STAT5
STAT5
STAT3
STAT6
PTPN11
STAT5
MYD88
JAK
IRAK1.2.4
MAP2K6
JAK
STAT1
Ub
Ub
Ub
Ub
TRAF6
STAT3
Ub
Ub
Ub
Ub
STAT
STAT
MAP3K7
IKK
NF-KB1
MAPK1.3
STAT5
STAT5
STAT3
JAK1
STAT4
STAT4
JAK1
JAK3
STAT3
JAK1
CIKS
TYK2
JAK2
TYK2
TYK2
IL-?
IL-7
IL-20
IL-12
IL-10
Other Interleukinsignaling
Interleukin-7signaling
IL-10
IL-17
Interleukin-20family signaling
Interleukin-12family signaling
Did you know?
Interleukin-10signaling
Interleukin-17signaling
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
CIKS, connection to IκB kinase and stress-activated protein kinases; GM-CSF, granulocyte/macrophage-colony stimulating factor; GRB2, growth factor receptor-bound protein 2; IKK, I kappa B kinase; IL, interleukin; IRAK, members of the IL1R-associated kinase; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MYD88, myeloid differentiation primary response protein; NF-kB, nuclear factor NF-kappa-B; P, phosphate; PTPN11, tyrosine-protein phosphatase non-receptor type 11; SHC, transforming protein; SOS1, son of sevenless homolog 1; STAT, signal transducer and activator of transcription; TNF, tumor necrosis factor; TRAF, TNF receptor-associated factor; TYK, tyrosine kinase; Ub, ubiquitin.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Immune system regulation I: Treg cells1–3
In immunology, ‘tolerance’ refers to the adaptive immune system’s ability to avoid attacking host tissues.3
TCR
MHC Class II
T-cell
Dendritic cell
Inhibit T-cell function
CD28
Central tolerance is the destruction of self-reactive lymphocytes early during their maturation.3
CD80/CD86
CTLA4Blocks co-stimulation
Several mechanisms of peripheral tolerance also exist to eliminate self-reactive T-cells that escape into the circulation – one of these is mediated by Treg cells.4
Treg cell
IL-10
Immunosuppressive cytokines
CD25High-affinity binding to IL-2
TGF-β
IL-2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Suppressive action of Treg cells may be mediated by their secretion of the immunosuppressive cytokines IL-10 and TGF-β.1,2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Treg cells can inhibit the activation of other T-cells via their surface expression of cytotoxic T lymphocyte-associated protein-4 (CTLA4), a checkpoint of the immune response with anti-inflammatory function. CTLA4 has high affinity for the dendritic cell proteins CD80 and CD86, and can prevent these proteins from delivering their co-stimulatory signal to naïve T-cells.3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Treg cells express the high-affinity IL-2 receptor, CD25, which can absorb IL-2 from the local intercellular milieu and so prevent it from activating other immune cells.2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
CD, cluster of differentiation; CTLA4, cytotoxic T lymphocyte-associated protein-4; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor; TGF, transforming growth factor; Treg, regulatory T-cell.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Immune system regulation II: PD-1/PD-L1 pathway
A second tolerance mechanism that suppresses the adaptive immune response is mediated by programmed death-1 (PD-1), another checkpoint of the immune response with anti-inflammatory function.1 Expression of this protein is upregulated in T-cells following their activation.2 PD-1 suppresses immune responses through its interaction partner, programmed death ligand-1 (PD-L1), which is widely expressed in a variety of immune and non-immune tissues.2
MHC-antigen complex
TCR
T-cell
APC
Decreased T-cell proliferation
Reduced pro-inflammatorycytokine production
PD-L1
PD-1
Negative co-stimulation
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
APC, antigen-presenting cell; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1;TCR, T-cell receptor; TNF, tumor necrosis factor; Treg, regulatory T-cells.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Altered signaling pathways in RA1,2
T-cell
CD80/86 inhibitorabatacept
CD80/86
CD28
Anti-CD20 drugrituximab
DCs
IL-2
IL-17 IFN-γ
Proliferation Migration Pannus formation Inflammation Bone and cartilage destruction
Macrophage
CD20
Co-stimulation
TCR
CD40
CD40L
Th1/Th17/Tfh
FCR
B cell
BCR
T-cell
IL-15IL-18
Autoantibody
TNFIL-1β
Osteoclast
RANKL
Plasma cell
Extensiveangiogenesis
IL-1
MMPs
IFN
TNFα
RANKL
MMPs
FLS
Figure adapted from Ding Q, et al. Signal Transduction Target Ther 2023;8:68.
TGFβ
VEGF
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
In the presence of certain environmental or genetic factors, a stepwise progression occurs from activation of innate immunity by the stimulation of dendritic cells.2 This stimulates B cells, macrophages, synoviocytes, chondrocytes, and osteoclasts to secrete pro-inflammatory cytokines, resulting in bone and cartilage damage accompanied by synovial membrane thickening and angiogenesis to promote tissue remodelling and driving the chronic phase of RA.2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
BCR, B-cell receptor; DC, dendritic cell; FCR, Fc receptor; FLS, fibroblast-like synoviocytes; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinases; RANKL, receptor activator of nuclear factor κB ligand; TCR, T-cell receptor; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Altered signaling pathways in IBD
Epithelial barrier defect
Intestinal epithelium
IFNγ TNFα
IL-17 GM-CSF TNFα IL-22
Changes in the balance and cellular crosstalk between innate lymphoid cells (ILC1s and ILC3s) is involved in mediation of many of the mechanisms which are potentially altered in IBD.1–3
IL-23, IL-1β, retinoic acid
IL-12, IL-18
ILC3
ILC1
IL-23 IL-1β
IL-12 IL-18
Macrophage
Dendritic cell
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Reference & footnotes
Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Numbers of ILC1 are increased in IBD and produce large amounts of IFNγ and TNFα, leading to inflammation and tissue damage.1,2
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Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
ILC3 are abundant in the gut and in chronic inflammation, such as IBD, may transfer into a pro-inflammatory phenotype exacerbating inflammation via damaging epithelial cells and increasing permeability, decreasing the mucus layer, and promoting fibrosis.3
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
GM-CSF, granulocyte macrophage colony-stimulating factor; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; ILCs, innate lymphoid cells; RA, retinoic acid; TNF, tumor necrosis factor.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Summary
The immune system consists of a range of physical, chemical and cellular mechanisms that function to eliminate potentially harmful substances, such as microbes, viruses and toxins1,2
Innate immunity provides a rapid response with broad specificity based on recognition of conserved PAMPs and DAMPs by PRMs on innate immune cells (e.g. neutrophils)3,4
Adaptive immune responses are slower, but have high specificity based on recognition of particular non-self structures (antigens) by receptors (TCRs and BCRs) selected from an enormously diverse repertoire of variants3
T-cells recognize peptide antigens in association with MHC molecules on the surface of APCs and once activated, function either to destroy infected cells or cells expressing tumor antigens (cytotoxic T-cells) or to coordinate the actions of other cells (helper T-cells)2
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
APC, antigen-presenting cell; BCR, B-cell receptor; DAMP, damage-associated molecular pattern; IL, interleukin; MHC, major histocompatibility complex; PAMP, pathogen-associated molecular pattern; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PRM, pattern recognition molecule; TCR, T-cell receptor; TNF, tumor necrosis factor; Treg, regulatory T-cell.
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
Summary (Cont.)
B-cells recognize free antigen and once activated, secrete antigen-specific humoral factors (antibodies), which neutralize, opsonize and target antigens for destruction1,2
Immune responses are orchestrated and coordinated by the actions of small, secreted (glyco) proteins known as cytokines (e.g. TNF, ILs)3,4
The type of immune response is determined in part by the profile of the cytokines secreted5
Tolerance mechanisms such as Treg cells and the PD-1/PD-L1 axis function to downregulate immune responses and so, prevent inappropriate attack of host tissues6
CTLA-4 and PD-1/PD-L1 are physiologic negative checkpoints of immune activation. Engagement of either pathway inhibits activation of effector T-cells
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Reference & footnotes
Defense mechanisms of the body
Anatomical and physiological barriers
Innate and adaptive immunity
Signaling pathways
Summary
References:
APC, antigen-presenting cell; BCR, B-cell receptor; CTLA-4, cytotoxic T-lymphocyte associated protein 4; DAMP, damage-associated molecular pattern; IL, interleukin; MHC, major histocompatibility complex; PAMP, pathogen-associated molecular pattern; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PRM, pattern recognition molecule; TCR, T-cell receptor; TNF, tumor necrosis factor; Treg, regulatory T-cell.
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Reference & footnotes