Lecture 22 Autoimmunity

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Lecture 22Autoimmunity
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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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Autoimmune diseases mediated by cytotoxic
antibodies (Type II)
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Autoimmune diseases mediated by immune complexes
(Type III)
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Autoimmune diseases mediated by T-cells (Type IV)
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Autoimmune disease susceptibility

• Genetic predisposition
• Twin studies (Diabetes 20 monozygotic vs. 5
  dizigotic)
• Family studies
• Association with MHC genotype
• HLA genotyping

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Genetic organization of the MHC in humans and the
mouse
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Detailed map of the human MHC region
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Association between HLA and susceptibility to
autoimmune disease
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Population studies show association of
susceptibility to insulin-dependent diabetes
mellitus (IDDM) with HLA genotype
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Family studies show strong linkage of
susceptibility to insulin-dependent diabetes
mellitus (IDDM) with HLA genotype
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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.

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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

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Peripheral B-cell anergy
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Elimination of autoreactive B cells in germinal
centers
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Several ways in which infectious agents could
break self tolerance
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Association of infection with autoimmune disease
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Some body sites are immunologically priviledged
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Damage to an immunologically privileged site can
induce an autoimmune response
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Sjögrens Syndrome

• Chronic autoimmune disorder
• Major clinical manifestations resulting from
  changes in exocrine glands

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Forms of Sjögrens Syndrome

• Primary Sjögrens is characterized by
  inflammatory cell involvement of both the
  salivary and lacrimal glands
• Secondary Sjögrens includes other defined
  connective tissue disease
• Causes are unknown

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Features of Sjögrens 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

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Is Sjögrens 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?

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Evidence that Sjögrens 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

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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

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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

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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

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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

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Salivary Gland Structure
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Conclusion

• Numerous changes in immune factors in Sjögrens
  Syndrome
• Salivary glands appears as a highly active,
  immune-mediated inflammatory sites
• Salivary epithelial cells are immunologically-acti
  ve participants in the disease process