Immunology 2008 Lecture 24 Genetic Control of Immune Responses 5 November

1. Immunology 2008 Lecture 24 Genetic Control of Immune Responses 5 November

2. MHC-linked Genetic control

3. Genetic Effects on Immune Responsiveness ● Genetic Immunodeficiencies Central: Bruton’s, etc… Efferent: Complement, Chronic Granulomatous Disease, etc. Defects in Ag Processing & Presentation Machinery; “Bare Lymphocyte Syndrome”, TAP mutants, etc. ● Aberrations in Homing & Recirculation Adhesion Molecule Defects (LAD) ● Antigen-Specific Effects? Defective Generation of Diversity? Doesn’t happen… ••Consequences of MHC Polymorphism •• MHC-Linked Responses & Diseases

4. Examples of HLA-associated autoimmune diseases relativeDisease HLA risk* IDDM DR4 6 DR3 3 DR3/4 33 Reiter's syndrome B27 40 Ankylosing Spondylitis B27 80 Birdshot retinopathy A29 170 *=odds ratio

5. Reiter’s Syndrome & HLA B27 ● HLA B27 is present in ~90% of patients, ~5% of general population ● Carrying B27 increases the risk of developing RS (“relative risk” = “odds ratio” = ~40) ● Testing for B27 contributes to diagnosis ● However, only a small fraction of those carrying B27 actually develop disease, following infection with Shigella et al. .● Environmental factors influence the risk…

6. MHC-Associated Diseases are Autoimmune and Inflammatory (1) ● Delicate balance between tolerance and immunity, especially for T-cells (i.e. pos/neg selection). ● Breaking of tolerance by cross-reactivity & “molecular mimicry”. ● Inflammation is both a cause and a result of pathology. (Remember viral association with human autoimmune diseases, e.g. ADEM)

7. Humoral Response to the Synthetic Antigen TGAL in Mice: A Model for Understanding MHC-Linked Immune Responsiveness The next few panels illustrate the following points: ● The ability to make Ab to TGAL is genetically determined. ● The locus controlling responsiveness is within the H-2 complex (mouse MHC). ● Non-responders fail to make antibody because none of their Class II molecules can effectively bind and present TGAL. ● The large number of possible Class II molecules (which are a/b heterodimers) makes such a situation relatively rare.

8. Synthetic Polypeptide Antigen TGAL

9. Genetics of TGAL responsiveness Strain a-TGAL response C3H (H-2k) low C57Bl/6 (H-2b) high (C3HxC57)F1 (H-2b/k) high F2 75% high, 25% low Segregation of H-2 types in F2 generation: k/k 25%; k/b 50%; b/b 25%

10. H-2-linkage of TGAL responsiveness C3H (H-2k) low C57Bl/6 (H-2b) high F1: all H-2k/b, all high responders F2:H-2: 0.25 k/k 0.50 k/b 0.25 b/bresponse:lowhighhigh H-2 linked, but not Class I; discovery of Class II Class II molecules of H-2k haplotype cannot bind TGAL, therefore no Ab response.

11. MHC Class II a and b chains

12. Human MHC Class I a-chain and b-2m

13. Organization of human Class I and Class II genes on Chromosome 6 Class II: 4 + 4 + 8 = 16 total Class I: 6 total But, if none of these can bind TGAL…

14. …but variation in efficiency of Class II peptide presentation is not the only model considered for HLA disease associations MHC Class I-Associated Autoimmunity by Molecular Mimicry Shigella pHS-2 peptide and HLA B27 fortuitously share a region of amino acid sequence identity and immunological cross-reactivity Tsuchiya et al., 1990 Am . Soc. Clin. Inv.

15. MHC Associated Diseases are Autoimmune and Inflammatory (2) ●There always exists a delicate balance between tolerance and immunity, especially for T-cells (since positive selection in the thymus puts T cells at the “edge” of self-reactivity). ●Breakage of tolerance by cross-reactivity & “molecular mimicry” requires only a small shift in this delicate balance. ●If one MHC molecule happens to efficiently present a microbial peptide which cross-reacts with “self”, autoimmunity may be the result. ●If no MHC molecule can effectively present a “self” peptide, generation of tolerance (TS/R) may fail.

16. Swine arthritis model: Synergistic genetic and environmental influences Contributing factor arthritishuman analog 1) Genetic only weak HLA-B27/Ank. spon. 2) + Erysipelothrix mild Shigella et al., 3) + Mycoplasma mild in Reiter’s ... + (2)+(3) moderate (additive) ... + (2)+(3) + housed on cement severefootball linemen

17. MHC Associated Diseases are Autoimmune and Inflammatory (3) Inflammation is both a cause and a consequence of pathology. Viral associations of several human autoimmune diseases, e.g. ADEM – viral infection causes the release of intracellular contents. These normally “sequestered” molecules may promote inflammation and local immune responses, and may also increase the burden of circulating immune complexes, thus predisposing to development of chronic autoimmune disease.

18. Why is HLA so highly polymorphic? Polymorphism increases likelihood of effectively binding and presenting peptides, and therefore generating protective immune responses Remember susceptibility of New World populations to smallpox and other pathogens. …“Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death.” Carrington et al. (1999) Science 283:12

19. THURSDAY (tomorrow) Clinical Correlate #2, Rheumatoid Disease Dr. Brian Andrews MONDAY Immunodeficiency, Chapter 21 THURSDAY (next week) Allergy, Chapter 18 Hybridomas, Appendix 10

20. Fin