The initiation of antigen-specific immune responses generally requires that the antigen be degraded into peptides, and that those peptides physically associate with host cell surface glycoproteins encoded in the major histocompatibility complex (MHC). Events required for the breakdown and subsequent handling of antigenic peptide and MHC molecule are collectively called antigen processing. We have discovered that much of the machinery required for antigen processing is encoded by MHC genes. The laboratory has cloned and characterized at least six MHC-linked genes required for antigen processing, and continues to characterize the function of the corresponding gene products. These include a large cytoplasmic protease called the proteasome, a peptide transporter (TAP) that mediates translocation of proteasome-produced peptides from the cytosol into the endoplasmic reticulum where they bind to MHC molecules, and a chaperone-like molecule (HLA-DM) required for catalyzing the binding of peptides to MHC molecules. In addition, we have begun characterizing and cloning previously unknown genes from other genomic regions which appear to have clusters of immunologically important genes, as well as other genes of unknown function in the MHC. The laboratory utilizes both biochemical (protein purification, 2D gel electrophoresis, mass spectrometry), and genetic (expression of recombinant protein, site-specific mutagenesis, and transgenic and 'knockout' mice), as well as immunological, techniques. Ultimately, this work should help in predicting antigenic epitopes within naturally occurring proteins, and may help elucidate the molecular mechanisms involved in certain autoimmune diseases.