Chapter 1 - Major Histocompatibility Complex Class II

Abstract

Human leukocyte antigen (HLA) class I and class II molecules are critical in mediating host defense responses through antigen presentation and immune tolerance by means of self/non-self recognition. Major histocompatibility complex (MHC) Class II molecules are found only on antigen-presenting cells. The MHC has only been significantly linked to systemic lupus erythematosus (SLE) in one of the 12 genome-wide linkage scans. The most consistent HLA associations with SLE reside with the class II alleles. The MHC class I specificities, A1 and B8, have been linked with SLE. However these alleles reside on the disease-associated B8-DR3 haplotype and this effect most likely results from LD. In the past, the strong LD observed at the MHC had made it difficult to determine whether single or multiple independent loci were responsible for the MHC associations observed in lupus. It is now clear that the latter is true and unraveling these complex interactions and associations will provide the next challenge in dissecting the MHC contribution to lupus susceptibility. The possibility that the major genetic influence at the MHC in lupus may arise from the class III region and not classical HLA class II alleles requires confirmation. A meta-analysis of high-density MHC SNP studies in SLE is currently underway as are transethnic subphenotype analyses. The results of these studies should also help to inform further research efforts in refining MHC association signals in lupus.