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

Autoimmune diseases mediated by

cytotoxic antibodies (Type II)

Autoimmune diseases mediated

by immune complexes (Type III)

Autoimmune diseases mediated

by T-cells (Type IV)

Autoimmune disease
susceptibility

Genetic predisposition

Twin studies (Diabetes: 20%

monozygotic vs. 5% dizigotic)
Family studies

Association with MHC genotype

HLA genotyping

Genetic organization of the MHC in

humans and the mouse

Detailed map of the human MHC

region

Associatio
n between
HLA and
susceptibil
ity to
autoimmu
ne disease

Population studies show association of

susceptibility to insulin-dependent diabetes
mellitus (IDDM) with HLA genotype

Family studies show strong linkage of susceptibility to

insulin-dependent diabetes mellitus (IDDM) with HLA
genotype

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

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

Sjgrens Syndrome

Chronic autoimmune disorder

Major clinical manifestations
resulting from changes in exocrine
glands

Forms of Sjgrens
Syndrome

Primary Sjgrens is characterized

by inflammatory cell involvement
of both the salivary and lacrimal
glands
Secondary Sjgrens includes other
defined connective tissue disease
Causes are unknown

Features of Sjgrens
Syndrome

Glandularepithelialcellsparticipateinthe
autoimmunediseaseprocess
Epithelialcellsproduceanumberof
immunologicallyactivemediators
Mayserveasantigenpresentingcells
Epithelialcellresponsesmodulate
mechanismsoccurringinthesalivaryglands

Is Sjgrens 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 Sjgrens

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

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-SSB (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

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

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

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
Structur
e

Conclusion

Numerous changes in immune factors in

Sjgrens Syndrome
Salivary glands appears as a highly active,
immune-mediated inflammatory sites
Salivary epithelial cells are immunologicallyactive participants in the disease process