Transcript Autoimmune Disease

Lecture 22
Autoimmunity
Autoimmune Disease
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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 diseases mediated by
cytotoxic antibodies (Type II)
Syndrome
Autoantigen
Consequences
Autoimmune
hemolytic anemia
Rh blood group
antigens, I antigen
Destruction of red blood
cells by complement
and phagocytes,
anemia
Autoimmune
thrombocytopenic
pupura
Platelet integrin
GpIIb:IIIa
Abnormal bleeding
Goodpasture’s
syndrome
Non-collagenous
domain of basement
membrane collagen
type IV
Glomerulonephritis,
Pulmonary hemorrhage
Pemphagus vulgaris
Epidermal cadherin
Blistering of skin
Acute rheumatic fever
Streptococcal cell-wall
antigens, Antibodies
cross-react with cardiac
muscle
Arthritis, mycocarditis,
late scarring of heart
valves
Autoimmune diseases mediated by
immune complexes (Type III)
Syndrome
Autoantigen
Consequences
Mixed essential
cyroglobulinemia
Rheumatoid factor IgG
complexes (with or
without hepatitis C
antigens)
Systemic vasculitis
Systemic lupus
erythematosis
DNA, histones,
ribosomes, snRNP,
scRNP
Glomerulonephritis,
vasculitis, arthritis
Autoimmune diseases mediated by
T-cells (Type IV)
Syndrome
Autoantigen
Consequences
Insulin-dependent
diabetes mellitus
Pancreatic -cell
antigen
-cell destruction
Rheumatoid arthritis Unknown synovial joint
antigen
Joint inflammation and
destruction
Experimental
autoimmune
encephalomyelitis
(EAE), multiple
sclerosis
Brain invasion by CD4 T
cells, paralysis
Myelin basic protein,
proteolipid protein,
myelin oligodendrocyte
glycoprotein
Autoimmune disease susceptibility
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Genetic predisposition
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Twin studies (Diabetes: 20%
monozygotic vs. 5% dizigotic)
Family studies
Association with MHC genotype
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HLA genotyping
Genetic organization of the MHC in
humans and the mouse
Detailed map of the human MHC region
Association
between
HLA and
susceptibilit
y to
autoimmune
disease
Population studies show association of
susceptibility to insulin-dependent diabetes mellitus
(IDDM) with HLA genotype
Family studies show strong linkage of susceptibility to insulindependent diabetes mellitus (IDDM) with HLA genotype
Autoimmunity involves T cells
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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
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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
Peripheral B-cell anergy
Elimination of
autoreactive B
cells in germinal
centers
Several ways in which infectious
agents could break self tolerance
Association of infection with
autoimmune disease
Some body sites are immunologically
priviledged
Damage to an immunologically privileged site can
induce an autoimmune response
Sjögren’s Syndrome
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Chronic autoimmune disorder
Major clinical manifestations resulting from
changes in exocrine glands
Forms of Sjögren’s Syndrome
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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 Sjögren’s Syndrome
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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 Sjögren’s Syndrome an Autoimmune
Disorder?
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Described as an autoimmune
exocrinopathy (Strand and Talal, 1980)
Grouped with other connective tissue
diseases
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Rheumatoid arthritis
Systemic lupus erythematosis (SLE)
What is the evidence that it is an
autoimmune disease?
Evidence that Sjögren’s Syndrome is
an Autoimmune Disease
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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
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B-cell hyper-responsiveness
Marked elevations of IgG Production of
rheumatoid factors
Presence of anti-nuclear antibodies
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Extractable nuclear antigens Anti-SS-A (Ro) and
anti-SS-B (La)
Antibodies are found directed against
salivary duct cells (90% of patients)
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Primarily against extractable nuclear antigens
Concentration does not correlate with gland
destruction
Other Characteristics
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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
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Induction of tolerance to self proteins
Selection of the T-cell repertoire
Binding and presentation of antigen to T-cells
Histopathology
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Mononuclear infiltrate consisting primarily of Tcells (primarily CD4+)
Host of mediators
Altered cell adhesion molecules expression
Increased HLA class II antigens expression
Immunosuppressive therapy often effective
Classical Histopathological Lesion
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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
Salivary
Gland
Structure
Conclusion
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Numerous changes in immune factors in Sjögren’s
Syndrome
Salivary glands appears as a highly active, immunemediated inflammatory sites
Salivary epithelial cells are immunologically-active
participants in the disease process