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)

S y n d ro m e
A u t o im m u n e h e m o ly tic a n e m ia

A u to a n tig e n
R h blood group a ntige ns, I a ntige n

C onsequences
D e struction of re d blood ce lls by com ple m e nt a nd pha gocyte s, a ne m ia A bnorm a l ble e ding

A u t o im m u n e th r o m b o c y to p e n ic p u p u ra G o o d p a s tu r e s s yn d ro m e

P la te le t inte grin G pIIb:IIIa N on-colla ge nous dom a in of ba se m e nt m e m bra ne colla ge n type IV E pide rm a l ca dhe rin

G lom e rulone phritis, P ulm ona ry he m orrha ge

P e m p h a g u s v u lg a r is

B liste ring of skin

A c u te r h e u m a tic fe v e r

S tre ptococca l ce ll-w a ll a ntige ns, A ntibodie s cross-re a ct w ith ca rdia c m uscle

A rthritis, m ycoca rditis, la te sca rring of he a rt va lve s

Autoimmune diseases mediated by immune complexes (Type III)

Syndrome
Mixed essential cyroglobulinemia

Autoantigen
R eumatoid acto I G complexes (wit o wit out epatitis C anti ens) NA, istones, ibosomes, snRNP, scRNP

Consequences
ystemic asculitis

Systemic lupus erythematosis

Glome ulonep itis, asculitis, a t itis

Autoimmune diseases mediated by T-cells (Type IV)

Syndrome
Insulin-dependent diabetes mellitus

Autoantigen
anc eatic F-cell antigen

Consequences
F-cell destruction

Rheumatoid arthritis Unknown synovial joint antigen Experimental autoimmune encephalomyelitis (EAE), multiple sclerosis Myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein

Joint inflammation and destruction Brain invasion by CD4 T cells, paralysis

Autoimmune disease susceptibility



enetic predisposition


T in studies (Diabetes: 20% monozygotic vs. 5% dizigotic) Family studies

Association


ith MH genotype

HLA genotyping

Genetic organization of the MH in humans and the mouse

Detailed map of the human MH region

Association bet een HLA and susceptibilit y to autoimmune disease

Population studies sho association of susceptibility to insulin-dependent diabetes mellitus insulin(IDDM) ith HLA genotype

Family studies sho strong linkage of susceptibility to insulininsulindependent diabetes mellitus (IDDM) ith HLA genotype

Autoimmunity involves T cells



Ability of a T cell to respond is determined by MH genotype It has been hypothesized that susceptibility to an autoimmune disease is determined by differences in the ability of allelic variants of MH 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 lo 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 B-

Elimination of autoreactive B cells in germinal centers

Several ays in hich infectious agents could break self tolerance

Association of infection ith autoimmune disease

Some body sites are immunologically priviledged

Damage to an immunologically privileged site can induce an autoimmune response

Sjgren s Syndrome
 

hronic autoimmune disorder Major clinical manifestations resulting from changes in exocrine glands

Forms of Sjgren s Syndrome



Primary Sjgren s is characterized by inflammatory cell involvement of both the salivary and lacrimal glands Secondary Sjgren s includes other defined connective tissue disease auses are unkno n

Features of Sjgren 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 antigenEpithelial cell responses modulate mechanisms occurring in the salivary glands

Is Sjgren s Syndrome an Autoimmune Disorder?



Described as an autoimmune exocrinopathy (Strand and Talal 1980) Grouped ith other connective tissue diseases
 

heumatoid arthritis Systemic lupus erythematosis (SLE)

What is the evidence that it is an autoimmune disease?

Evidence that Sjgren s Syndrome is an Autoimmune Disease



A specific auto-immunogen and pathogenic autoantibodies have not been identified Autoantibodies that have been found have not been sho n 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 hyperMarked elevations of IgG Production of rheumatoid factors Presence of anti-nuclear antibodies anti

Extractable nuclear antigens Anti-SS-A ( o) and Anti-SSanti-SSanti-SS-B (La)

Antibodies are found directed against salivary duct cells (90% of patients)
 

Primarily against extractable nuclear antigens oncentration does not correlate ith gland destruction

Other haracteristics


Elevated sedimentation rates and decreased WB counts as seen in other autoimmune connective tissue diseases Specific extended MH haplotype at a higher frequency than controls MH -encoded proteins
  

Induction of tolerance to self proteins Selection of the T-cell repertoire TBinding and presentation of antigen to T-cells T-

Histopathology


   

Mononuclear infiltrate consisting primarily of TTcells (primarily D4+) Host of mediators Altered cell adhesion molecules expression Increased HLA class II antigens expression Immunosuppressive therapy often effective

Classical Histopathological Lesion



LymphoLympho-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 ell-formed lymphoid follicles typical ellof MALT and may give rise to lymphomas of the MALT type as an expansion of monoclonal B-cells

Salivary Gland Structure

Conclusion


umerous changes in immune factors in Sjgren s Syndrome Salivary glands appears as a highly active immuneimmunemediated inflammatory sites Salivary epithelial cells are immunologically-active immunologicallyparticipants in the disease process