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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:

Defense mechanisms of the body
Anatomical and physiological barriers

Innate and adaptive immunity
Signaling pathways

Start

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

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Physical barriers include mechanical and physiological barriers.2

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Chemical defences are mostly secreted peptides and proteins that inhibit or destroy microbes.2,3

Reference & footnotes

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

Reference & footnotes

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.

Reference & footnotes

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

Reference & footnotes

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.

Reference & footnotes

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

Reference & footnotes

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

Reference & footnotes

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

Reference & footnotes

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.

Reference & footnotes

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

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.
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.

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Mast cells modulate vascular permeability and are thought to function in mucosal immunity.2

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Myeloid innate cells also include monocytes, which differentiate within the tissues into two types of APCs: macrophages and dendritic cells.2

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

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.

Reference & footnotes

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

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.
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.

Reference & footnotes

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

Reference & footnotes

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’.

Reference & footnotes

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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

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.
Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32.

CD, cluster of differentiation.

Reference & footnotes

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Both B-cells and T-cells arise in the bone marrow, where B-cells also mature.1

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Mature naïve B- and T-cells then enter the circulation and migrate out of the bloodstream into the secondary/peripheral lymphoid organs.1

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

T-cell progenitors must migrate to the thymus for maturation.1

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

If no antigen is encountered in the peripheral lymphoid organs, lymphocytes can re-enter the circulation either directly or via the lymphatic vessels.1

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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

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.

BALT, bronchial-associated lymphoid tissue; GALT, gut-associated lymphoid tissue; MALT, mucosal-associated lymphoid tissue.

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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)

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

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

Reference & footnotes

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

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.

APC, antigen-presenting cell; CD, cluster of differentiation; MHC, major histocompatibility complex; TCR, T-cell receptor.

Reference & footnotes

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

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Class I MHC molecules present peptides derived from proteins synthesized in the cytosol, such as viral proteins within an infected cell.1

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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

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.

APC, antigen-presenting cell; CD, cluster of differentiation; MHC, major histocompatibility complex; TCR, T-cell receptor.

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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.

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Interleukin is a general term that was originally coined to refer to cytokines produced by one type of leukocyte and acting on another.2

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

Transforming growth factor-β (TGF-β) is an inhibitory cytokine produced by a variety of cell types including T-cells.1

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

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

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

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

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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.

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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

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

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

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

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

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

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.

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

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

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

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

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.

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

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

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

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

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

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

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

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.

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

Disulfidebonds

Variableregion

Light chain

Disulfide bond

COOH

Constantregion

Heavy chain: IgA (α), IgD (δ), IgE (ε), IgG (γ), IgM (μ)

Did you know?

COOH

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

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

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

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)

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.

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

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

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

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

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.

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

MAPK

NF-κB

IκB

NF-κB

AP-1

Nucleus

Pro-inflammatory gene expression

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

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

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

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

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.

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

NFAT

MAPK

NF-κB

IκB

Calcineurin

NF-κB

AP-1

NFAT

Nucleus

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

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

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.

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

TNF translation

NF-κB

IκB

TNF transcription

NF-κB

Nucleus

TNF mRNA

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

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

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

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.

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

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

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

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

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.

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

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.

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

TYK2

JAK2

STAT6

SOCS3

STAT5

STAT3

STAT6

PTPN11

STAT5

MYD88

JAK

IRAK1.2.4

MAP2K6

JAK

STAT1

TRAF6

STAT3

STAT

MAP3K7

IKK

NF-KB1

MAPK1.3

STAT5

STAT3

JAK1

STAT4

JAK1

JAK3

STAT3

JAK1

CIKS

TYK2

JAK2

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

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

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.

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

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

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

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

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.

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

Summary

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

Reference & footnotes

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.

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

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

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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.

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

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

Reference & footnotes

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

Reference & footnotes

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.

Reference & footnotes

Defense mechanisms of the body

Anatomical and physiological barriers

Innate and adaptive immunity

Signaling pathways

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

Reference & footnotes

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.

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

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.
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.

Reference & footnotes

Immunology Compendium_Part 1_v7_31July25_Long AMA ref.pptx

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