The autoimmune regulator : Studies of immunological tolerance in mouse and man

Sammanfattning: The aim of the work presented in this thesis was to investigate how failure in the mechanisms that regulate self-tolerance can lead to autoimmune disease. In particular, I have studied a key player in immunological tolerance, the autoimmune regulator gene (AIRE). Mutations in this gene lead to a severe autoimmune disorder called autoimmune polyendocrine syndrome type I (APS I). APS I patients suffer from a combination of diseases caused by the immunological destruction of various tissues and organs, mainly the endocrine organs. The most common disease components are hypoparathyroidism, adrenocortical insufficiency and chronic mucocutaneous candidiasis (CMC). It has been clearly shown that AIRE is involved in the negative selection of autoreactive thymocytes. The suggested mechanism is that AIRE induce expression of tissue-specific antigens (TSAs) in the thymus that are needed for the deletion of autoreactive thymocytes, but the exact molecular events and relative importance of this are controversial. The first publication on which this thesis is based, reports that AIRE is involved in the regulation of T cell-independent B cell-responses, and that B cells in Aire-/- mice have an increased activation status. This finding was thought to be connected to the increased serum levels of B cell activating factor of the TNF family (BAFF) found in both Aire-/- mice and APS I patients. The excessive BAFF was produced by AIRE-deficient dendritic cells upon IFN-gamma stimulation, which was independent of the presence of autoreactive T cells. It was suggested that AIRE regulates peripheral tolerance by inhibiting STAT1 signaling downstream of the IFN-gamma receptor. The second paper describes how AIRE deficiency results in impaired development of iNKT cells, which may contribute to the pathogenesis of APS I. This finding suggests that AIRE has other functions apart from inducing TSAs in the thymus, given that iNKT cells recognize lipid antigens and are not dependent on ectopic peptide expression in the thymus for their development. In the third paper, the mechanisms behind CMC in APS I are described. It is shown that APS I patients have defects in innate immune mechanisms, i.e. the anti-fungal activity of the saliva. The patients exhibit IgA autoantibodies recognizing salivary glands as an indication of ongoing immunological destruction. Furthermore, they lack expression of salivary cystatin SA1, a protein with potent anti-fungal activity. The final paper describes investigations into possible mechanisms governing thymocyte development in the absence of AIRE. This was performed in a system independent of TSA expression where endogenous superantigens mediate selection and activation of transgenic T cells specific for an ovalbumin peptide presented by H2-IAb (OT-II T cells). It was found that the OT-II T cells were reduced in Aire-/- mice compared to wild type littermates, and showed an immature phenotype. It was also found that the OT-II Aire-/- mice had increased TCR revision after activation in peripheral organs. The findings in Aire-/- mice and APS I patients presented in this thesis are not explained by reduced TSA expression in the thymus. They show that AIRE has additional functions in both central and peripheral tolerance.