Previous studies of patients with systemic lupus erythematosus (SLE) have shown an increased frequency of certain major histocompatibility complex (MHC) markers, including HLA-DR2, DR3, and C4AQO (CIA-null), -in Caucasian patients. However, most of these studies were of randomly selected, unrelated patients; families were not included, and haplotypes were not determined. In order to define more accurately the possible role of MHC genes in lupus susceptibility, HLA-A, B, C, and DR, as well as BF, C2, C4A, C4B, and GLO, markers were determined in 62 Caucasian patients of known ethnic background, and in the members of their families. The distributions of extended haplotypes (fixed combinations of HLA-B, DR, and complotype alleles), fragments thereof, and individual alleles were determined in SLE patients and controls. The MHC distributions in all patients were compared with haplotypes in a normal Caucasian population. There were no statistically significant differences between the frequencies of any MHC marker, fragment, or extended haplotype in the patients compared with the controls. The notion that genetic factors play a role in susceptibility to systemic lupus erythematosus (SLE) is based on the following observations: 1) there is a high rate of concordance for disease in monozygotic twins (14); 2) SLE and its immunologic abnormalities are found with increased frequency in relatives of SLE patients (5-11); 3) SLE is found more commonly in certain ethnic groups (12.13); and 4) a number of genetic markers have been found more frequently among SLE patients than in the general population. These genetic markers include the Gm phenotype 1.3.17:5.13.21 (14-16) and, according to some observers, low levels of erythrocyte CRl (17.18).

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SummaryDermatitis herpetiformis (DH) shares some clinical features and major histocompatibility complex (MHC) markers with gluten-sensitive enteropathy (GSE) . We compared MHC haplotypes in 27 patients with DH, 35 patients with GSE, and normal controls. As in GSE, the frequencies of two extended haplotypes, [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7], were increased in patients with DH. Distributions of fragments of extended haplotypes, consisting of some but not all ofthe elements ofcomplete extended haplotypes, were analyzed to attempt to localize a susceptibility gene. Besides complete extended susceptibility haplotypes, (DR3, DQ2) and (DR7, DQ2) fragments were most common in GSE. In contrast, DH showed only a few such fragments but many instances of the fragment (SC01) . The differences in distribution of these fragments in the two diseases were highly significant (P <0.002). HLA-DQ2 and DR3 had the highest odds ratios for GSE, but the highest odds ratio for DH was for the complotype SCOL These findings suggest that the MHC susceptibility gene for DH is between class II and complotype regions, closest to the complotype, whereas that for GSE is in the class lI region . D ermatitis herpetiformis (DH)' is a chronic pruritic papulo-vesicular disease of the skin characterized by the granular deposition ofI&A in the dermal papillae and by patchy focal asymptomatic villous atrophy of the small intestine (1, 2). In Caucasian patients, there is a marked increase in HLA-B8, DR3, and DQ2 (3-7) . These genes are components of the fixed conserved extended haplotype [HLA-B8, SC01, DR31 (8) . The recent report of an increase in HLA-DPI (9) in patients with DH who carry markers of this haplotype may be secondary to their known linkage disequilibrium in general (10, 11) . A less striking increase in HLA-Dw7 in DH patients has also been reported (12). The same HLA markers have been noted to be increased in celiac disease (glutensensitive enteropathy [GSE]) (13-16) . Moreover, patients with DH and GSE share a number ofother features, such asjejunal atrophy correctable by elimination of gliadin from the diet, i Abbreviations used in this paper: DH, dermatitis herpetiformis; GSE, gluten-sensitive enteropathy. 2067and the presence of anti-a-gliadin (17, 18) and antireticulin (19,20) antibodies. We have reported family studies in GSE (21) that show that all increased available HLA markers are parts of two extended haplotypes : SC01, DR3] and FC31, DR7].Previous studies of DH have almost exclusively reported HLA phenotypes in patients rather than haplotypes determined in family studies . Haplotype comparisons, including analysis for complotypes and other MHC genes, are critical to localizing candidate susceptibility genes, and we undertook such studies in patients with DH. We present these results in this report and compare these DH haplotypes with those derived from our earlier studies in GSE . Our results suggest that, despite the similarity of individual MHC allele markers for GSE and DH, the susceptibility genes for the tw...

SUMMARYAmino acid residues involved in the peptide binding groove of HLA-DRB1 alleles were examined in three Nigerian ethnic groups with leprosy (n ¼ 287) and 170 controls to determine the role of DRB1 alleles in disease outcome with Mycobacterium leprae. Nine positively charged motifs and two others with neutral charge to the binding groove were detected. These motifs occurred more frequently in leprosy (leprogenic) than was expected by chance (P < 0·0001). In contrast, five motifs with net negative or 'modified' neutral charges to the pocket were negatively associated with leprosy. We conclude that clinical outcome of infection with M. leprae is largely determined by a shared epitope in DRB1 alleles marked by several motifs. These motifs occur in otherwise normal DRB1 alleles, characterized by net positive or neutral charges in the binding groove. We hypothesize that these polarities cause poor binding of DRB1 to M. leprae. On presentation, the signal via the T cell receptor results in muted cellmediated immunity. The resulting response translates to various forms of leprosy depending on degree of charge consonance between M. leprae and host DRB1 allele. Other factors within or without the HLA complex, such as the T cell receptor repertoire, may also influence the resulting disease.