In man multiple B cell alloantigenic systems encoded by the HLA-D region of the major histocompatibility complex have been defined. These are often referred to as Ia antigens. Recombinant DNA studies suggest that as many as six distinct Ia loci exist, although biochemical and genetic studies have only formally demonstrated the expression of three of them. The molecules encoded by the Ia loci display a high degree of polymorphism due to multiple amino acid sequence differences among allotypes. This polymorphism is manifested functionally in that different allotypes determine differences in immune responsiveness. In addition many diseases that display autoimmune characteristics such as rheumatoid arthritis and multiple sclerosis are associated with particular Ia allotypes. We wish to analyze the molecular basis of variability among Ia molecules using biochemical and recombinant DNA techniques. More specifically we wish to ask the following questions: How many different Ia molecules can a single individual express? What are the molecular relationships of different Ia molecules within the same individual? What are the molecular relationships of Ia molecules between individuals? We believe these studies will help us to understand how Ia molecules regulate immune responsiveness and determine disease susceptibility.