1. Failures against ‘self’ (Principles of Autoimmunity)

2. Mechanisms of autoimmunity
Individual’s immune system reacts to autologous antigens  pathologic tissue injury
“Horror autotoxicus” (P. Ehrlich, 1900s): immunity against self
Autoreactive lymphocytes:
B cells  autoantibodies
Autoreactive T cells
Breakdown/failure for maintaining self tolerance

3. Paul Ehrlich (1854-1915) : Horror autotoxicus, Nobel Prize 1908
Autoantigens
Autoreactive effector cells, Autoantibodies
5% population 3

4. Self tolerance of lymphocytes
Clonal deletion
Most effective mechanism
Deletion of self-recognizing B-and T cells prior to their maturation
Clonal anergy
Induced by encounter with self antigens
Self reactive B/T cells can survive, but not react to self antigens

5. 5

6. Negative selection 6

7. Negative selection
AIRE (Autoimmune Regulator) is a transcription factor that regulates the negative selection of autoreactive T cells by leading the transcription of tissue-specific antigens in the thymus.
AIRE mutations and polymorphisms have been
found in different autoimmune manifestations such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) with a semidominant effect. 7

8. 8

9. Cellular inactivation by weak signaling without co-stimulus9

10. Supression of cytokines, intercellular signaling10

11. Cytokine deviation
Differentiation of Th2 cells limiting inflammatory cytokine secretion 11

12. Elimination of B cells in germinal centers12

13. Pathogenesis of autoimmunity
Studies by using animal models:
Occurs spontaneously or induced by particular immunization
General properties:
Caused by multiple interacting factors
There are systemic and organ-specific autoimmune diseases

14. 14

15. Multiple interacting factors
Immunologic abnormalities
Genetic backgrounds
Predispose to autoimmunity: MHC/HLA genes
Microbial infections: virus, bacteria
Anatomic alterations
Sequestered/privilege sites of antigens
Hormonal influences
Systemic lupus erythematosus (SLE): affects females about 10 x as frequently as males

16. Role of MHC genes
Some HLA alleles occur at high frequency in patients with particular diseases
Estimation of the “relative risk”, exp:
Ankylosing spondylitis with HLA-B27 is 90
Rheumatoid arthritis with HLA-DR4 is 6
Insulin-dependent diabetes mellitus with HLA-DR3, DQw8 is 100

17. Table 1. HLA-linked immunologic diseases
HLA allele
Relative Risk
Rheumatoid arthritis
DR4 6
IDDM
DR3, DQw8
100
Pemphigus vulgaris 24
Chronic active hepatitis
DR3 14
Sjorgen’s syndrome 10
Celiac disease 12
Ankylosing spondylitis
B27 90

18. 18

19. Concluding remarks
Autoimmunity is an immunity against ‘self’ molecules/proteins/antigens. Basically, this is due to a breakdown of self tolerance that normally occurs within the body
Multiple interacting factors are documented to be the causes of autoimmunity/autoimmune diseases
There are organ-specific and/or systemic manifestations of the autoimmune diseases