lecture 22 autoimmunity n.
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Lecture 22 Autoimmunity. 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.

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Presentation Transcript
autoimmune disease
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
autoimmune disease susceptibility
Autoimmune disease susceptibility
  • Genetic predisposition
    • Twin studies (Diabetes: 20% monozygotic vs. 5% dizigotic)
    • Family studies
  • Association with MHC genotype
    • HLA genotyping
slide10
Population studies show association of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype
slide11
Family studies show strong linkage of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype
autoimmunity involves t cells
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.
levels of autoantigens may drive t cell selection
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
sj gren s syndrome
Sjögren’s Syndrome

Chronic autoimmune disorder

Major clinical manifestations resulting from changes in exocrine glands

forms of sj gren s syndrome
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

features of sj gren s syndrome
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

is sj gren s syndrome an autoimmune disorder
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?

evidence that sj gren s syndrome is an autoimmune disease
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

polyclonal hypergammaglobulinemia
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

other characteristics
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

histopathology
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

classical histopathological lesion
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

conclusion
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