Severe combined immunodeficiency refers to a spectrum of clinical conditions resulting in both B and T cell dysfunction. Clinically, manifestations include loss of T cell responses and immunoglobulin production. Most infected individuals die early following overwhelming viral or bacterial infections. One condition leading to severe combined immunodeficiency is the class II bare lymphocyte syndrome where affected patients fail to display class II major histocompatibility antigens on the surfaces of their B lymphocytes. This autosomal recessive syndrome represents the functional loss of a trans-acting factor which regulates class II gene expression. Previously, we described a variant of the bare lymphocyte syndrome as well as characterized B cell-specific and interferon-gamma-inducible regulation of class II genes. In this proposal we will identify factors that are defective in class II bare lymphocyte syndrome patients and clone the defective genes by a variety of biochemical and genetic approaches. These studies will further our understanding of normal and abnormal regulation of class II MHC genes, define the class II bare lymphocyte syndrome, lead to prenatal diagnosis by DNA probes and perhaps suggest new therapeutic approaches to treat this devastating severe combined immunodeficiency.
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