Role of MHC-Linked Susceptibility Genes in the Pathogenesis of Human and Murine Lupus

Figure 1

HLA gene cluster and lupus susceptibility genes on human chromosome 6. Ideogram of chromosome 6 (left) and schematic diagram of the MHC-complex-associated genes ranging from 6p21.1 to 6p21.3 (middle). The class I gene complex contains three major loci (A, C, and B), as well as additional (unmentioned) loci. The resulting class I polypeptides associate with the invariable beta-2 microglobulin, encoded by a gene on chromosome 15. The HLA-B locus is known as the most polymorphic gene within the human genome. Class II MHC molecules are composed of two glycosylated polypeptide subunits (called α and β chain) of approximately equal length. Whereas HLA-DP and -DQ code for one alpha- and one beta-chain polypeptide, respectively, the genetics of HLA-DR is more complex: It consists of one locus coding for the alpha subunit and 4 loci coding for beta subunits. Unlike the other DR loci, DRA is not polymorphic. Even though the DR β-chain is encoded by 4 loci, no more than two are present on a single chromosome. DRB1 is the most polymorphic gene of the class II locus. Class I and class II antigens are membrane proteins whereas almost all class III polypeptides are serum proteins (including the complement components C2, C4A, C4B, and factor B) or can be detected in other body fluids. Therefore, the term “class III” is misleading, as this locus does not contain a distinct class of genes. The coding regions of the genes are shown as small blue (class I), green (class II), and red (class II) rectangles, respectively. Abbreviations: LTA: lymphotoxin A, LTB: lymphotoxin B, TNF: tumor necrosis factor alpha, HSPA1L: heat shock 70 kDa protein 1-like, HSPA1A: heat shock 70 kDa protein 1A, HSPA1B: heat shock 70 kDa protein 1B, BF: complement factor B, CYP21B: cytochrome P450 21-hydroxylase and Mb: mega base pairs.