The immunopathogenesis of celiac disease requires interactions between genetic, environmental and immunologic factors. Genes within the class II region of the major histocompatibility complex (HLA-D region) represent a major component contributing to disease susceptibility. Structural studies of genes within the HLA-D region have shown that the class II HLA haplotype associated with celiac disease is extended, and includes not only the HLA-DR and DQ subregions, but also the HLA-DP subregion. The celiac disease-associated haplotype is marked in the HLA-DP subregion by a polymorphic 4 kilobase Rsa I genomic fragment derived from a DP beta chain. Other studies suggest that, in addition to dietary gliadins, a viral protein may play a role in the pathogenesis of celiac disease, perhaps by virtue of immunologic cross reactivity between antigenic determinant shared by the viral protein and alpha gliadins.