Immunological Response
There are 4 cell types that are part of the immunological response to T1D:
T Lymphocytes:
CD4⁺ T Cells: Th1 and Th17 cells promote inflammation and β-cell destruction¹¹,12.
CD8⁺ T Cells: These cells directly target and kill the insulin-producing β cells¹¹,12.
B Lymphocytes: Participate in the autoimmune response through antigen presentation and cytokine secretion¹¹. Natural Killer (NK) Cells: These cells help to initiate autoimmunity in T1D by causing early β-cell destruction¹¹. Antigen-Presenting Cells (APCs): Both dendritic cells and macrophages trigger an autoimmune attack by presenting β-cell antigens (self-antigens) to T cells¹¹,12.
Genetic Factors
On chromosome 6, there is a major histocompatible complex called Human Leukocyte Antigen (HLA) which is composed of over 200 genes⁵. There are both class I and II HLA molecules⁵. Class I is found on nucleated cells with HLA A/B/C loci and Class II is on antigen presenting cells⁵,⁷. Some HLA class II genes show a strong association with the development of Type 1 diabetes, such as HLA-DRB1, HLA-DQA1, HLA-DQB1⁷
Figure. A depiction of the HLA complex including Class I, II, and III ⁶
Environmental Factors¹³
Prenatal Triggers: - Maternal enteroviral infection - C-section birth - Older maternal age Postnatal Triggers: - Enteroviral infection - Weight gain - Respiratory infections Promotors of Progression - Overweight - Insulin resistance - Stress
Prenatal Protective Factors: - Higher vitamin D intake Postnatal protective factors: - Probiotics - Omega 4-fatty acids
Autoimmune Response
Detection:
The presence of 2 or more pancreatic islet autoantibodies (AAbs) is an indicator of beta-cell immunity⁸. Having 2 AAbs increases the risk to 50% chance of T1D in the next 5 years and increases to 80% in the next 15 years⁸,⁹. There are 3 key autoimmune cells:
B-cells: There is an increased presence of these cells specific to pancreatic islet antigens before the onset of T1D. However, B cells are dependent on the help of helper T cells for activation and antibody production⁸.
Follicular T helper Cells (Tfh): A specific type of T cell called a CXCR5 positive T cell is required for B cell maturation and potentially creating autoreactive B cells which then produce AAbs. However, Tfh cells can lose CXCR5 expression and upregulate other cytokines and thorugh that become Tph cells⁸.
Peripheral T helper cells (Tph): These cells can come from lymph nodes. They also produce CXCL13 that attract B cells and IL-21 which leads to B cell maturation which produces AAbs⁸.
As shown in the figure below, both Tfh and Tph work together in the pathogenesis of T1D¹⁰:
Figure. A model depicting the involvement of B cell helper T-cells the pancreatic lymph nodes and islets in T1D¹⁰
PULSE Team #20 - Journey to the Pancreas: Type 1 Diabetes
PULSE
Created on February 12, 2025
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Transcript
Immunological Response
There are 4 cell types that are part of the immunological response to T1D: T Lymphocytes: CD4⁺ T Cells: Th1 and Th17 cells promote inflammation and β-cell destruction¹¹,12. CD8⁺ T Cells: These cells directly target and kill the insulin-producing β cells¹¹,12. B Lymphocytes: Participate in the autoimmune response through antigen presentation and cytokine secretion¹¹. Natural Killer (NK) Cells: These cells help to initiate autoimmunity in T1D by causing early β-cell destruction¹¹. Antigen-Presenting Cells (APCs): Both dendritic cells and macrophages trigger an autoimmune attack by presenting β-cell antigens (self-antigens) to T cells¹¹,12.
Genetic Factors
On chromosome 6, there is a major histocompatible complex called Human Leukocyte Antigen (HLA) which is composed of over 200 genes⁵. There are both class I and II HLA molecules⁵. Class I is found on nucleated cells with HLA A/B/C loci and Class II is on antigen presenting cells⁵,⁷. Some HLA class II genes show a strong association with the development of Type 1 diabetes, such as HLA-DRB1, HLA-DQA1, HLA-DQB1⁷
Figure. A depiction of the HLA complex including Class I, II, and III ⁶
Environmental Factors¹³
Prenatal Triggers: - Maternal enteroviral infection - C-section birth - Older maternal age Postnatal Triggers: - Enteroviral infection - Weight gain - Respiratory infections Promotors of Progression - Overweight - Insulin resistance - Stress
Prenatal Protective Factors: - Higher vitamin D intake Postnatal protective factors: - Probiotics - Omega 4-fatty acids
Autoimmune Response
Detection: The presence of 2 or more pancreatic islet autoantibodies (AAbs) is an indicator of beta-cell immunity⁸. Having 2 AAbs increases the risk to 50% chance of T1D in the next 5 years and increases to 80% in the next 15 years⁸,⁹. There are 3 key autoimmune cells: B-cells: There is an increased presence of these cells specific to pancreatic islet antigens before the onset of T1D. However, B cells are dependent on the help of helper T cells for activation and antibody production⁸. Follicular T helper Cells (Tfh): A specific type of T cell called a CXCR5 positive T cell is required for B cell maturation and potentially creating autoreactive B cells which then produce AAbs. However, Tfh cells can lose CXCR5 expression and upregulate other cytokines and thorugh that become Tph cells⁸. Peripheral T helper cells (Tph): These cells can come from lymph nodes. They also produce CXCL13 that attract B cells and IL-21 which leads to B cell maturation which produces AAbs⁸. As shown in the figure below, both Tfh and Tph work together in the pathogenesis of T1D¹⁰:
Figure. A model depicting the involvement of B cell helper T-cells the pancreatic lymph nodes and islets in T1D¹⁰