Investigating aire deficiency in the context of human autoimmune disease associated HLA molecules




Nalawade, Saisha

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Autoimmunity arises as a result of the immune system initiating an attack on self-molecules. Autoreactive T cells are one of the key mediators in many autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Central tolerance induced in the thymus is the key mechanism involved in eliminating these autoreactive T cells that recognize self antigens. The autoimmune regulator (AIRE) gene regulates central tolerance by mediating ectopic transcription of self antigens in the thymus. Deficiency of AIRE in humans can break the central tolerance causing a multi-organ autoimmune disorder known as autoimmune polyendocrinopathy syndrome (APS I). Aire deficient mice (aire-/-) can develop spontaneous autoimmune disease characterized by multi-organ specific lymphocytic infiltrates. The association between HLA-DR2 and DR4 molecules to MS and also RA has been established. The aim of the study was to investigate aire deficiency in mice in the context of the human autoimmune disease associated MHC alleles; HLA-DR2 and HLA-DR4. The detection of T cell infiltrates in liver and pancreas and autoantibody production against the gastric tissue in a few older aire-/- DR2 and DR4 transgenic mice suggested that these mice develop mild spontaneous autoimmunity. Further we also observed that mild autoimmunity could be triggered in the aire-/- transgenic DR2 and DR4 mice by abrogation of T regulatory cell function through the use of blocking antibody against CTLA-4 and CD25. We also observed that aire deficiency appeared to have a mild effect on promoting experimental autoimmune encephalomyelitis (EAE), particularly in the DR2 transgenic background. Also, Treg inactivation after EAE induction in

aire-/- DR2 transgenic mice showed a mild disease enhancing effect in female mice. Thus, the study revealed that aire deficiency in the context of HLA-DR2 and DR4 molecules elicited a mild spontaneous autoimmune phenotype.


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Integrative Biology