Human Leukocyte Antigen-DRB1 Position 11 Residues Are a Common Protective Marker for Sarcoidosis

Palacký University of Olomouc, Olmütz, Olomoucký, Czech Republic
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 10/2001; 25(3):272-7. DOI: 10.1165/ajrcmb.25.3.4261
Source: PubMed


Genetic factors, in particular human leukocyte antigens (HLAs) are important determinants of susceptibility to sarcoidosis, a chronic granulomatous disease of undetermined etiology. To clarify the role of HLA in sarcoidosis we determined HLA-DR and -DQ alleles in case-control samples from three European populations (United Kingdom, Czech, and Polish) and compared these results with those published for three additional populations (Italian, Japanese, and Scandinavian) to determine whether the HLA-DR and/or -DQ alleles act as ethnic-dependent, or ethnic-independent modifiers of disease risk. Although variations were apparent in the alleles associated with susceptibility, reductions in the frequency of alleles associated with protection were remarkably consistent in the six populations. Previously detected associations between single-nucleotide polymorphisms at the TAP2 locus and sarcoidosis were shown to be due to linkage disequilibrium with the HLA-DR locus. The protective HLA-DR alleles, which encode the DR1 and DR4 antigens, were found to share characteristic small hydrophobic residues at position 11, which were replaced by small hydrophilic residues in the remaining, nonprotective, HLA-DR alleles. This residue position is within a pocket of the HLA-DR complex antigen binding groove (designated P6), where it is the only variable amino acid and therefore determines the peptide binding preferences of this pocket. A highly significant reduction in the frequency of individuals carrying HLA-DR alleles with a hydrophobic residue at position 11 was observed in the sarcoidosis cases in the three populations we examined. This suggests this HLA-DR residue is an important protective marker in sarcoidosis.

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Available from: Jiří Drábek
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    • "X-ray crystallographic analysis of the human MHC class II molecule HLA-DR1 bearing an influenza virus haemagglutinin peptide has identified the residues that make up the ARS [3], and a recent study has specified the ARS residues of the DRb chain to be those occupying positions 9, 11, 13, 26, 28, 30, 37, 47, 57, 61, 67, 70, 71, 74, 78, 85, and 86 [4]. Notably, the ARS of human MHC II molecules is known to be a highly polymorphic site whose variability has been suggested to play a significant role in susceptibility to various diseases, including autoimmune hepatitis [5], rheumatoid arthritis [6], sarcoidosis [7], Vogt–Koyanagi–Harada's syndrome [8], insulin-dependent diabetes mellitus [9], tuberculoid leprosy [10], and severe malaria and hepatitis B virus infections [11]. These observations together show that much is known about the structures and functions of HLA molecules, including their peptide-binding activity and recognition by and activation of T cells. "
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    ABSTRACT: Major histocompatibility complex (MHC) genes are highly polymorphic and play key roles in immune susceptibility and resistance to pathogens. While the immunological and structural functions of several human and murine alleles have been analyzed, little is known about the MHC molecules of other animals. Here, we could classify five mammalian species into three groups (human, cow and dog, and cat and pig) on the basis of DRB nucleotide sequences, synonymous and nonsynonymous mutation rates, and natural selection of individual residues. These observations, along with the locations of the positively and negatively selected residues in three-dimensional DR structures, suggest that the antigen-recognition sites of swine and feline DR molecules have been negatively selected while those of bovine and canine DR molecules have been positively selected. Human DR molecules show evidence of high negative and positive selection. Our observations suggest that MHC-DR molecules are under different selective force depending on each species.
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    • "Amino acid residues at position 47 would affect pocket 7 (Androulakis et al. 1997; Chelvanayagam 1997), and mutations of the amino acid residues of pocket 7 peptides have been shown to affect T cell recognition (Evavold et al. 1993; Spain et al. 1994; Hsu et al. 1995). Foley et al., in a study of European patients with sarcoidosis that used low-resolution HLA typing, observed that HLA-DRB1-V 11 and –L 11 amino acid residues were associated with protection from sarcoidosis (Foley et al. 2001). In our study, HLA-DRB1-V 11 was associated with the control population, " protection, " and HLA-DRB1-S 11 was associated with sarcoidosis (table 5). "
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    ABSTRACT: Sarcoidosis is a granulomatous disorder of unknown etiology, associated with an accumulation of CD4+ T cells and a TH1 immune response. Since previous studies of HLA associations with sarcoidosis were limited by serologic or low-resolution molecular identification, we performed high-resolution typing for the HLA-DPB1, HLA-DQB1, HLA-DRB1, and HLA-DRB3 loci and the presence of the DRB4 or DRB5 locus, to define HLA class II associations with sarcoidosis. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled biopsy-confirmed cases (736 total) from 10 centers in the United States. Seven hundred six (706) controls were case matched for age, race, sex, and geographic area. We studied the first 474 ACCESS patients and case-matched controls. The HLA-DRB1 alleles were differentially distributed between cases and controls (P<.0001). The HLA-DRB1*1101 allele was associated (P<.01) with sarcoidosis in blacks and whites and had a population attributable risk of 16% in blacks and 9% in whites. HLA-DRB1-F(47) was the amino acid residue most associated with sarcoidosis and independently associated with sarcoidosis in whites. The HLA-DPB1 locus also contributed to susceptibility for sarcoidosis and, in contrast to chronic beryllium disease, a non-E(69)-containing allele, HLA-DPB1*0101, conveyed most of the risk. Although significant differences were observed in the distribution of HLA class II alleles between blacks and whites, only HLA-DRB1*1501 was differentially associated with sarcoidosis (P<.003). In addition to being susceptibility markers, HLA class II alleles may be markers for different phenotypes of sarcoidosis (DRB1*0401 for eye in blacks and whites, DRB3 for bone marrow in blacks, and DPB1*0101 for hypercalcemia in whites). These studies confirm a genetic predisposition for sarcoidosis and present evidence for the allelic variation at the HLA-DRB1 locus as a major contributor.
    Full-text · Article · Oct 2003 · The American Journal of Human Genetics

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