PBS 803 Class 18 Autoimmune disorders Oct 25

PBS 803 Class #18 -Autoimmune disorders Oct. 25 th, 2016 Required reading: Abbas: pages 203 -210 Suggested reading: Doan: pages 245 -252, Flaherty: pages 133 -135 Abbas Fig. 9. 13

Learning Objectives for Class #18 part I • Describe how both genetic and environmental factors (microbial infection, inflammation) can lead to autoimmunity • Describe the role of MHC genes in autoimmunity and the concept of “relative risk” associated with particular HLA allele • Compare the role of non-MHC genes in complex autoimmune diseases with single-gene defects that can cause autoimmunity • Explain why single-gene defects in AIRE, FOXP 3, CTLA-4 or FAS result in autoimmunity; explain different inheritance pattern between APS-1 (AIRE) and mutations of CTLA-4 • Using Rheumatic fever as an example, explain how molecular mimicry can result in autoimmunity

Learning Objectives for Class #18 part II • Explain the concept of immune-privilege, and how breakdowns in immune-privilege can lead to autoimmunity • Using Rheumatoid factor as an example, illustrate how cryptic epitopes can lead to autoimmunity • List several examples of autoimmune diseases and the effected tissues (Doan Table 16. 1) (more details will be provided regarding some of these diseases in the future): -Ankylosing spondylitis -Goodpasture syndrome - Graves disease - Myasthenia gravis - Multiple sclerosis - Psoriasis - Reiter disease (reactive arthritis) - Rheumatoid arthritis - Systemic lupus erythematosus - Type 1 insulin-dependent diabetes mellitus -Sjogren syndrome - Male sterility (some forms)

Postulated mechanisms of autoimmunity Abbas Fig. 9. 10

Association of autoimmune diseases with alleles of the MHC locus Abbas Fig. 9. 11

Statistical association between autoimmune disease and specific HLA allele expressed as relative risk For example, FYI: Graves’ disease four times as more frequent in HLADR 3 individuals (risk of 4) SLE three times more frequent in HLA-DR 3 individuals Doan Fig. 16. 11

Role of non-MHC genes in autoimmunity Abbas Fig. 9. 12 A

Mendelian inheritance of single-gene defects roles of non-MHC genes in autoimmunity Abbas Fig. 9. 12 B

Role of infections in development of autoimmunity Flaherty Fig. 16. 11

Normal encounter of mature T cells with self-antigens presented by resting APCs promotes tolerance Abbas Fig. 9. 13 A

Cytokines produced by infection can upregulate costimulatory expression by bystander APCs presenting self-antigen Abbas Fig. 9. 13 B

Molecular mimicry strong cross-reaction with pathogenic antigens may cause immune responses against similar self-antigens Abbas Fig. 9. 13 C

Rheumatic fever Pharyngitis caused by Group A Strep can lead to Type II response Molecular mimicry also thought to be associated with the development of other diseases such as Type 1 Diabetes and rheumatoid arthritis Doan Fig. 16

Serial responses of autoimmune diseases Alternating periods of exacerbation and remission associated with some autoimmune diseases expression of alternate antigens may explain alternating periods of some diseases Doan Fig. 16. 7

Immune-privileged sites do not typically permit powerful immune responses, often through anatomical barriers Immune-privileged sites: CNS Eye Placenta and fetus Testes Breakdown of immune-privilege barriers can result in autoimmunity protection of eye from lymphocytes Doan Fig. 16. 8

Cryptic epitopes Altered structure of molecules may expose immune system to antigens not present during negative selection Doan Fig. 16. 9

Rheumatoid factors –autoantibodies directed against Fc portion of bound Ig. G First identified with Rheumatoid arthritis, believed to be involved with other diseases Conformational changes associated with Ig. G binding to epitope exposes cryptic antigens in Fc portion of Ig Doan Fig. 16. 10

Autoimmune diseases Doan Table 16. 1