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

Interstitial Lung Disease Unit, Department of Occupational and Environmental Medicine, National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, London, UK.
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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    • "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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    • "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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