Alper Laboratory

The Alper Laboratory studies the genetics of complex (polygenic) disease in humans, with a focus on autoimmunity, particularly within the genes of the major histocompatibility complex (MHC) of chromosome 6. Many human diseases of unknown origin, but mostly involving immune reactions against the patients’ own tissues, show genetic association with the MHC. Autoimmune diseases affect more than 5 percent of the U.S. population. They represent a major medical and public health challenge, and many are rising in incidence at an alarming rate.

Specifically, we investigate the relationship between genetic differences in the human MHC with differences in autoimmune phenomena and the immune function of a variety of "white blood cells," or leukocytes. Some serum protein products of the human MHC, in particular the complement proteins, are synthesized in the liver. Other products of the human MHC, some of which form a group collectively called human leukocyte antigens (HLA), are major proteins expressed on and within leukocytes. Many HLA proteins are used by the body to differentiate "self" from foreign cells, and HLA proteins play a critical role in organ and tissue recognition and rejection after transplantation as well as in detecting foreign pathogens.

More than 250 expressed genes, among more than 400 genetic loci, are located within the approximately 7½–megabase region of the human "extended" MHC at the center of the short arm of chromosome 6. As would be expected for a region that contains genes encoding proteins that help define "self," this region is among the most diverse of the human genome. The Alper Lab often studies samples from donors bearing MHC-conserved extended haplotypes (CEHs) or their fragments to explore autoimmune diseases and other immunological phenomena controlled by various MHC genes. Alper and colleagues established the concept of CEHs as a means of understanding the high degree of population-level structural genetic fixity within relatively large stretches (e.g., the MHC) of the human genome. Although the lab previously has studied the MHC genetics of a number of immune functions and diseases, we are focused currently on two specific areas. These are the genetic mechanisms of autoimmunity, with a particular focus on type 1 diabetes, and the population-level genomic architecture of the human MHC.