1. Lecture 22 Autoimmunity

2. Autoimmune Disease Self tolerance is lost
Specific adaptive immune responses mounted against self antigens
Inability to eliminate antigen leads to chronic inflammatory process
Ehrlich termed this horror autotoxicus

3. Autoimmune diseases mediated by cytotoxic antibodies (Type II)

4. Autoimmune diseases mediated by immune complexes (Type III)

5. Autoimmune diseases mediated by T-cells (Type IV)

6. Autoimmune disease susceptibility
Genetic predisposition
Twin studies (Diabetes: 20% monozygotic vs. 5% dizigotic)
Family studies
Association with MHC genotype
HLA genotyping

7. Genetic organization of the MHC in humans and the mouse

8. Detailed map of the human MHC region

9. Association between HLA and susceptibility to autoimmune disease

10. Population studies show association of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype

11. Family studies show strong linkage of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype

12. Autoimmunity involves T cells
Ability of a T cell to respond is determined by MHC genotype
It has been hypothesized that susceptibility to an autoimmune disease is determined by differences in the ability of allelic variants of MHC molecules to present autoantigenic peptides
Alternatively, self peptides may drive the positive selection of developing thymocytes that are specific for particular autoantigens.

13. Levels of autoantigens may drive T cell selection
If antigens are expressed at too low a level, they may not drive negative intrathymic selection, but sufficient to drive positive selection
Insulin genes transcribed at high level in thymus protect against diabetes

14. Peripheral B-cell anergy

15. Elimination of autoreactive B cells in germinal centers

16. Several ways in which infectious agents could break self tolerance

17. Association of infection with autoimmune disease

18. Some body sites are immunologically priviledged

19. Damage to an immunologically privileged site can induce an autoimmune response

20. Sjögren’s Syndrome Chronic autoimmune disorder
Major clinical manifestations resulting from changes in exocrine glands

21. Forms of Sjögren’s Syndrome
Primary Sjögren’s is characterized by inflammatory cell involvement of both the salivary and lacrimal glands
Secondary Sjögren’s includes other defined connective tissue disease
Causes are unknown

22. Features of Sjögren’s Syndrome
Glandular epithelial cells participate in the autoimmune disease process
Epithelial cells produce a number of immunologically active mediators
May serve as antigen-presenting cells
Epithelial cell responses modulate mechanisms occurring in the salivary glands

23. Is Sjögren’s Syndrome an Autoimmune Disorder?
Described as an autoimmune exocrinopathy (Strand and Talal, 1980)
Grouped with other connective tissue diseases
Rheumatoid arthritis
Systemic lupus erythematosis (SLE)
What is the evidence that it is an autoimmune disease?

24. Evidence that Sjögren’s Syndrome is an Autoimmune Disease
A specific auto-immunogen and pathogenic antibodies have not been identified
Autoantibodies that have been found have not been shown to have any direct pathogenic effects on exocrine tissues
There is substantial circumstantial evidence that tissue damage is the result of autoimmunity

25. Polyclonal Hypergammaglobulinemia
B-cell hyper-responsiveness
Marked elevations of IgG Production of rheumatoid factors
Presence of anti-nuclear antibodies
Extractable nuclear antigens Anti-SS-A (Ro) and anti-SS-B (La)
Antibodies are found directed against salivary duct cells (90% of patients)
Primarily against extractable nuclear antigens
Concentration does not correlate with gland destruction

26. Other Characteristics
Elevated sedimentation rates and decreased WBC counts, as seen in other autoimmune connective tissue diseases
Specific extended MHC haplotype at a higher frequency than controls
MHC-encoded proteins
Induction of tolerance to self proteins
Selection of the T-cell repertoire
Binding and presentation of antigen to T-cells

27. Histopathology
Mononuclear infiltrate consisting primarily of T-cells (primarily CD4+)
Host of mediators
Altered cell adhesion molecules expression
Increased HLA class II antigens expression
Immunosuppressive therapy often effective

28. Classical Histopathological Lesion
Lympho-epithelial lesion affecting the parotid gland
Progressive replacement of the salivary tissue by dense lymphoid infiltrates
Formation of proliferating islands of ductal epithelial cells
Creates well-formed lymphoid follicles typical of MALT and may give rise to lymphomas of the MALT type as an expansion of monoclonal B-cells

29. Salivary Gland Structure

31. Conclusion Numerous changes in immune factors in Sjögren’s Syndrome
Salivary glands appears as a highly active, immune-mediated inflammatory sites
Salivary epithelial cells are immunologically-active participants in the disease process