Autoimmunity and Associated Diseases

Automimmune disorders are a significant clinical problem. In the US they are estimated at more than 8.5 million.

Common Autoimmune Diseases

Alzheimer's Disease:

Sjogren's syndrome (SS): is a relatively common autoimmune disorder. A key feature of SS is lymphocytic infiltration of the salivary and lacrimal glands, associated with the destruction of secretory functions of these glands. SS is characterized by the production of autoantibodies against normal cellular components, designated as autoantigens that may be overexpressed.

The green tea catechin EGCG has recently been shown to inhibit the transcription and translation of major autoantigens including SS-B/La, SS-A/Ro, coilin, DNA topoisomerase I, and alpha-fodrin.

Possible Triggers for Autoimmunity and Abnormalities Associated with Automimmune Diseases

1. Molecular mimicry can trigger self-reactive B cells to produce auto-antibodies through linked recognition. For example, antibodies produced in response to streptococcus bacteria cross-react with self-antigens in kidneys, joints and heart resulting in Rheumatic fever. How this can work is the following: When a B cells takes up and presents self antigen to a T cells, T cells do not react (reactive ones were deleted) so there is no Ig production. However, sometimes after infection self antigen gets presented along with the foreign peptide which activates T cells. B cells produce antibodies here against the self-peptide.

2. Bystander Activation: is due to tissue destruction caused by a pathogen which allows self-antigens to be presented in an inflammatory milieu.  A DC encounters a microbe and becomes stimulated which activates a T cells. For example, in response to theilers virus which infects neurons in the brain, T cells are recruited by inflammatory mediators. Cytotoxic T cells specific for viral antigens clear the virus. However, a breakdwon in degradation of meline as a consequence of neuronal death autoimmune disease begins mediated by myelinspecific CD4+ T cells. In the first stage, the CD4+ T cells respond to a single dominant eptiope in a myelin protein. Over time, the specificity of the CR4+ T cells response spreads form just one epitope to other epitopes in the same protein and in different proteins.

3. Dysregulation of the Innate Immune System: If infected mice with agonist for TLR 9 no disease. However, TLR 3 or 7 were sufficient. This suggested that getting Type I IFN in vivo might be enough to break the tolerant model. IFN-alpha levels are often increased in SLE pateints. TNF-alpha is increased in RA pateints.

There is growing evidence that TLRs respond to endogenous ligands (as well as TLRs) such as fibrinogen, heat shock proteins, mammalian DNA, etc. This might suggest that the primary lesion in some autoimmune diseases is due to the failure to properly discriminate self versus non-self by the innate immune system.

4. Hygiene Hypothesis: Autoimmunity is a product of both genetic and environmental factors. Interestingly, there has been a steady increase in the prevalence of autoimmune diesease, allergies and inflammatory bowel disease in developed countries. Under the "hygiene hypothesis" is is proposed that microbial exposure prevents immune mediated inflammatory disease. It is beleived that microbial antigens may compete with self-antigens for antigen processing machinery and/or binding to MHC molecules. Lymphocytes proliferating to pathogens might also out-compete self-reactive T cells for cytokines and MHC intereactions needed for survival.

5. Counter-Regulatory Theory: Tstates mircobial infections can induce regulatory T cells that make IL-10 and TGF-beta. here is literature reporting that DCs expressing indoleamine 2,3-dioxygenase (IDO), the rate limiting tryptophan-catalbolizing enzyme induce Treg responses and deplete responding T cells by eliminating tryptophan. (T cells can not make trypotphan, so if break it down, T cells die). Further, adminsitering certain TLR ligands for TLR9 and TLR4 induced IDO and can inhibit experimental asthma (see Rax et al.).

6. Susceptibility genes are shared by multiple autoimmune diseases while others are unique to a particular disease.

7. Depletion of Tregs: Depletion of different CD4+ T cell subsets results in manifestation of different autoimmune disease in mice. For example, depletion of mice of CD25-CD62L+ resulted in gastritis.

8. Aberrant expression of CD86: Several automimmune such as systemic lupus erythematosus (SLE) have aberrant CD86 expression.

9. Aberrant expression of chemokines: A hallmark of autoimmunity and other chronic diseases is the overexpression of chemokines, resulting in a detrimental local accumulation of proinflammatory immuen cells.