Autoimmune Diseases 

-  Definition: Autoimmunity implies that an immune response has been generated against self-antigens /Autoantigens/. Central to the concept of autoimmune diseases is a breakdown of the ability of the immune system to differentiate between self and non-self antigens. The presence of circulating autoantibodies does not necessarily indicate the presence of autoimmune disease. Thus, pathologic autoimmunity is characterized by

-  the autoimmune response is not secondary to tissue injury but it has primary pathologic significance 

-  Absence of other well-defined cause of disease.

 Mechanisms of autoimmune diseases 

1. Genetic: Evidences include 

-Familial clustering of several diseases such as SLE, autoimmune hemolytic anemia, Hashimoto’s thyroditis. 

-linkage of several autoimmune diseases such as Hashimotos thyroditis, pernicious anemia, Addion's disease, primary hypothyroidism, etc so-called Schmidt’s syndrome.

-Induction of autoimmune diseases with HLA  especially class ll antigens exemplified by HLA-B27

2. Immunologic:

-  Failure of peripheral tolerance: Breakdown of T-cell anergy  T-cell anergy may be broken if the APC can be induced to express co-stimulatory molecules such as B7-1 and to secrete cytokines such as IL-12 that stimulate the generation of TH 1 cells. This up regulation of co-stimulator molecule B7-1 has been noted in multiple sclerosis, Rheumatoid arthritis, psoriasis and Insulin dependant diabetes mellitus (IDD). 

Failure of activation induced cell death defects in Fas – Fas ligand 

-  System in generating apoptosis may allow persistence and proliferation of   auto reactive T- cells in peripheral tissues. No known disease is incremented but SLE suggested only on experimental basis.

Failure of T-cell – mediated suppression

-  Loss of regulatory or suppressor T-cells can limit the function of auto reactive T and B cells and thus, can lead to autoimmunity. There is evidence that patients with SLE have a deficiency of T-suppressor cells activity that would result in hypergamaglobinmea and the production of autoantibodies.

Molecular mimicry (cross – reacting antigens).

-  Some infections agents share epitopes with self-antigens. An immune response against such microbes may produce tissue-damaging reactions against the cross-reacting self-antigen. 

-  The classic example is streptococcal pharyngitis, in which antibodies are produced to the streptococcal M – protein and cross-react with M – protein of the sarcolemma of cardiac muscle to produce the acute rheumatic fever. Another example is the immunologic cross-reactivity between the glycoprotein D of the herpes simplex virus and certain bacterial antigens with acetylcholine receptor.

Polyclonal B-lymphocytic activation

-  Tolerance in some cases is maintained by clonal anergy.  Autoimmunity may occur if such self – reactive but anergic clones are stimulated by antigen-independent mechanisms. Several micro-organisms and their products are capable of polyclonal (i.e antigen nonspecific) activation of B –cells.Examples include Epestein-barr virus (in infections mononucleosis), gram-negative lipopolysaccharides (endotoxins). 

-  Among the T-cells activated by super-antigens, some may be reactive to self-antigens and thus, autoimmunity may result from arousal of such cells (Certain bacterial products can bind to and activate a large pool of CD4 + T-cells in an antigen independent manner.  They do so by binding to class II MHC molecules on  APCs and the (beta) B. chains of the T-cell receptor (TCR) outside the antigen –binding groove.  Because they stimulate all T-cells they are called superantigens)

Release of sequestrated antigens 

-  Regardless of the exact mechanism by  which self-tolerance is achieved (clonal deletion or anergy), it is clear that induction of tolerance requires interaction between the antigen and the immune system.  Thus, any self-antigen that is completely sequestrated during development is likely to be viewed as foreign if introduced into the circulation, and an immune response develops. 

-  Examples include the release of crystalline from the lens of the eye during cataract extraction, or antigens from the uveal tract due to trauma, is followed by autoimmune uveitis. Agglutinating antibodies to spermatozoa may be produced following testicular trauma or rupture of an epidermal retention cyst.

- The mere release of antigens is not sufficient to cause autoimmunity; the inflammation associated with the tissue injury is essential.

3. Microbial agents:

-  Some bacteria, mycoplasm and viruses are implicated. Viruses and other microbes may share cross-reacting epitopes with self-antigens. Example: Cross-reaction between certain coxsackieviruses and islet cells antigen glutamic acid decarboxylase. Microbial infections with resultant tissue necrosis and inflammation can cause up regulation of co-stimulatory molecules on resting antigen-presenting cells in tissue, thus favouring a breakdown of T- cell anergy.  The inflammatory response also facilitates presentation of cryptic antigens, and thus induces epitope spreading.  

References

Bezabeh ,M. ; Tesfaye,A.; Ergicho, B.; Erke, M.; Mengistu, S. and Bedane,A.; Desta, A.(2004). General Pathology. Jimma University, Gondar University Haramaya University, Dedub University.

مواضيع ذات صلة

Pathophysiology of Autoimmune disease

فقر الدم المناعي بالراصات الباردة Autoimmune hemolytic anemia due to Cold agglutinin

فقر الدم الانحلالي المناعي الذاتيAutoimmune hemolytic anemia

Hypersensitivity Reactions

Immunologic Tolerance

Classification of autoimmune diseases

Immunodeficiency Diseases

Acquired Immunodeficiency Syndrome