Evolving views of the major histocompatibility complex.

T of parts of the MHC has grown substantially within the last year. HE MAJOR HISTOCOMPATIBILITY complex (MHC) is an extended cluster of genes that are remarkable for the number and importance of the immunological functions The MHC is of major biomedical interest because of its contribution to transplant rejection and to variation between they encode. Historically, interest in the MHC emanated from tissue transplantation experiments, hence the reference to histoindividuals in susceptibility to a variety of autoimmune disorders. In a number of cases it is clear that this suscepticompatibility. Now we know that this highly conserved region encodes genes that have many important and varied functions bility is determined by variation in the protein sequence of the class II molecules themselves. However, as will be both immune and nonimmune in nature. One family of MHC genes, the human leukocyte antigen (HLA) genes, are the most discussed below, the possibility must still be entertained that polymorphism in other immune system–related genes of the polymorphic yet discovered, with hundreds of alleles described so far. Serotyping of these polymorphisms has permitted MHC also contribute to these diseases. In addition to its role in influencing the propensity for genetic mapping with these loci in early disease-association studies. In addition, these polymorphisms have permitted exknown autoimmune diseases such as insulin-dependent diabetes mellitus, multiple sclerosis, systemic lupus erythematensive population studies revealing a number of interesting MHC associations and phenomena. Recent cDNA selections, tosus, myasthenia gravis, and rheumatoid arthritis (reviewed in Thomson, 1995), the MHC contains genes contributing genomic sequencing, and cosmid screenings have shown the existence of a large number of genes in the MHC, including to several other hereditary disorders that are either not autoimmune in nature or where the role of autoimmunity is una number that are expressed selectively in cells of the immune system. In this review we discuss recent data that considercertain. These include ankylosing spondyloarthropathies, where there is a clear association with the class I allele HLAably expands the number of immune-related genes encoded in the MHC and review factors that may underlie its large scale B27, and narcolepsy, equally clearly associated with certain class II alleles. The MHC also includes the genes for steroid organization. The MHC includes coding regions for the well-known 21-hydroxylase and hemochromatosis. Deficiency of 21-hydroxylase causes the adrenogenital syndrome, and hemoand eponymous polymorphic surface antigens of the HLA class I and class II type that, respectively, present antigen chromatosis is one of the most common simple Mendelian disorders of man. Recently, a major quantitative trait locus to CD8 and CD4 T cells. Intervening between the class II and the class I region of the human MHC is a class III region for dyslexia was mapped to the distal MHC. This is actively being pursued by several groups. that includes genes for several of the components of the complement system. Genes in the class II region have The MHC has been extensively studied and a large number of excellent reviews exist on a range of related topbeen found to encode components of the cytoplasmic proteasome that degrades proteins to peptides as well as peptide ics. The present review will largely be restricted to the newest developments in recognition of the complexity transporters for loading peptides onto class I proteins. The class II region also encodes DM, a gene that facilitates loadof the role of the human MHC in the immuno-hematologic systems and the relationship among segments of the MHC. ing and assembly of class II proteins. Just centromeric to the class I region is a cluster of genes encoding three A SUBREGION OF THE MHC CONTAINS AN UNUSUAL inflammation related proteins: tumor necrosis factor-a (TNFCONCENTRATION OF GENES RELATED TO a), lymphotoxin a (LTA), and lymphotoxin b (LTB). INFLAMMATION Remarkably, the list of immune system–related genes and By convention, the MHC is divided into three contiguous of chromosome segments potentially derived as duplications regions that approximate the location of genes with shared characteristics (Fig 1). Most centromeric on chromosome 6p is the class II region, which contains the 17 known HLA From the Department of Pediatrics, Yale Child Health Research class II genes and pseudogenes. Contiguous to that is the Center, Yale University School of Medicine; and the Department of Genetics, Boyer Center for Molecular Medicine, Yale University class III region, which encodes several of the components School of Medicine, New Haven, CT. of the complement system. Telomeric to the class III region Submitted March 27, 1997; accepted June 16, 1997. is the class I region, which encodes more than 18 HLA class J.R.G. is supported by the March of Dimes Birth Defects Research I–related genes and pseudogenes. Recently a number of Foundation, Clinical Research Grant No. 6-FY96-0272, and by Nagenes putatively involved in inflammation have been identitional Institutes of Health (NIH) Grant No. R29 DK45819-05. fied in the central MHC, at the telomeric end of the class S.M.W. is supported by NIH Outstanding Investigator Award III region. As presented below, this group of genes may have CA42556-11. roles in various aspects of stress, inflammation, or infection. Address reprint requests to Jeffrey R. Gruen, MD, Yale Child We suggest that this concentration of genes is sufficiently Health Research Center, Department of Pediatrics, Yale University distinct to be designated as the class IV region. School of Medicine, 464 Congress Ave, New Haven, CT 06520TNF family cluster. A cluster of genes for three related 8081. cytokines, TNF, LTA, and LTB, lies at the telomeric end of q 1997 by The American Society of Hematology. 0006-4971/97/9011-0002$3.00/0 the class III region, shortly before the most centromeric