The complexity and variety of autoimmune diseases and phenotypes is a source of continuing fascination and frustration for both physicians and scientists. Even in the setting of exciting advances in understanding the molecular basis of immune recognition and regulation, the fundamental causes of the autoimmune diseases are unknown, and it is still unclear to what extent these diseases are pathogenically related. The mere presence of autoimmune phenomena is not a compelling unifying feature, since these phenomena can occur in a variety of circumstances, including in normal subjects. Studies in animal models and the discovery of a few rare highly penetrant genes involved in human polyendocrine syndromes [1], have provided some direct evidence that abnormalities in thymic selection [2] can cause autoimmunity in humans. However, it is still not clear to what extent altered thymic selection operates in the more common autoimmune diseases [3], and other peripheral regulatory mechanisms are also likely to be important [4, 5]. Comprehensive genetic analysis in humans is one of the most promising avenues of gaining insight into this question. In the last few years, this approach has begun to bear fruit.

The intracellular tyrosine phosphatase, PTPN22, has recently been associated with a variety of autoimmune diseases, including type 1 diabetes [6], rheumatoid arthritis [7], systemic lupus [8] and autoimmune thyroid disease [9-11]. These discoveries have provided some of the first direct evidence that these diseases are genetically related, and also raise a host of new questions to be addressed. As discussed in this review, the example of PTPN22 illustrates how human genetics is likely to provide new insights into pathogenesis and unravel new relationships among the autoimmune diseases.

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