Chronic Beryllium Disease, HLA DPB1 And The DP Peptide Binding Groove

Abstract

Multiple epidemiologic studies demonstrate associations between chronic beryllium disease (CBD), beryllium sensitization (BeS), and HLA-DPB1 alleles with a glutamic acid residue at position 69 (E69). Results suggest that the less-frequent E69 variants (non-*0201/*0202 alleles) might be associated with greater risk of CBD. In this study, we sought to define specific E69-carrying alleles and their amino acid sequences in the DP peptide binding groove, as well as their relationship to CBD and BeS risk, using the largest case control study to date. We enrolled 502 BeS/CBD subjects and 653 beryllium-exposed controls from three beryllium industries who gave informed consent for participation. Non-Hispanic white cases and controls were frequencymatched by industry. HLA-DPB1 genotypes were determined using sequence-specific primer PCR. The E69 alleles were tested for association with disease individually and grouped by amino acid structure using logistic regression. The results show that CBD cases were more likely than controls to carry a non-*02 E69 allele than an *02 E69, with odds ratios (95% confidence interval) ranging from 3.1 (2.1-4.5) to 3.9 (2.6-5.9) (p < 0.0001). Polymorphic amino acids at positions 84 and 11 were associated with CBD: DD versus GG, 2.8 (1.8-4.6), p < 0.0001; GD versus GG, 2.1 (1.5-2.8), p < 0.0001; LL versus GG, 3.2 (1.8-5.6), p < 0.0001; GL versus GG, 2.8 (2.1-3.8), p < 0.0001. Similar results were found within the BeS group and CBD/BeS combined group. We conclude that the less frequent E69 alleles confer more risk for CBD than does *0201. Recent studies examining how the composition and structure of the binding pockets influence peptide binding in MHC genes, as well of studies showing the topology of the TCR to likely bind DPB1 preferentially, give plausible biological rationale for these findings.Copyright © 2012 by The American Association of Immunologists, Inc.Address correspondence and reprint requests to: Dr. Lori J. Silveira, National Jewish Health, 1400 Jackson, Denver, CO 80206. silveiral@njhealth.org. DisclosuresThe authors have no financial conflicts of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptChronic beryllium disease (CBD) is an immunologic lung disease caused by inhalation of beryllium dust and fume (1). Exposed workers can develop beryllium sensitization (BeS), a beryllium-specific, cell-mediated immune response, which is measured by the beryllium lymphocyte proliferation test (BeLPT) (2-5). Once workers develop BeS, they may subsequently develop CBD, a diffuse lung disease characterized by granulomatous inflammation in the lung. Differentiation between CBD and BeS is determined by performing a clinical evaluation consisting of a lung biopsy and bronchoalveolar lavage. BeS precedes CBD, and it is estimated that between 3 and 9% (6) of those who are sensitized progress to disease each year. Beryllium exposure is necessary for sensitization and disease, but not all who are exposed develop sensitization and not all ...

Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

“…To confirm the haplotypic relatedness of the 3 variants, we sequenced this region in 100 study subjects who were homozygous for the rs141530233 and rs1042169 markers. Our findings confirmed the organization of the 3 variants in 2 haplotype blocks (as shown in Supplementary Figure 6), which is consistent with the findings in prior studies of a dimorphic polymorphism (GGPM versus DEAV) at the corresponding amino acid positions 84–87 of the HLA–DPB chain .…”

“…To confirm the haplotypic relatedness of the 3 variants, we sequenced this region in 100 study subjects who were homozygous for the rs141530233 and rs1042169 markers. Our findings confirmed the organization of the 3 variants in 2 haplotype blocks (as shown in Supplementary Figure 6), which is consistent with the findings in prior studies of a dimorphic polymorphism (GGPM versus DEAV) at the corresponding amino acid positions 84-87 of the HLA-DPB chain (22,26,27). Effects of the rs141530233 SNP on gene expression have not been reported, but the linked missense rs1042169 G/A SNP has been catalogued as an eQTL, with presence of the homozygous GG genotype being correlated with increased expression of HLA-DPB1 in PBMCs (24).…”

“…This study identifies MHC and non-MHC gene variants that are associated with GPA/MPA susceptibility and with altered gene expression and/or function of proteins integral to immune responses. Our data reveal that the largest effect on risk emanates from a triallelic HLA-DPB1 haplotype underpinning a previously reported HLA-DPB amino acid polymorphism across positions 84-87 (22)(23)(24)(25)(26)(27). Our data also support major roles for the PRTN3, SERPINA1, and PTPN22 genes in AAV susceptibility, providing the first evidence of a genome-wide significant association with the PTPN22 rs2476601 functional variant, and identifying a correlation of the top-scoring variant at SERPINA1 as a null allele and at PRTN3 as an eQTL allele with increased PRTN3 expression in neutrophils.…”

Gene–Environment Interaction from International Cohorts: Impact on Development and Evolution of Occupational and Environmental Lung and Airway Disease

“…21 Several studies have suggested that specific characteristics of the peptidebinding pocket-for instance, a more negative charge-might explain why different alleles result in a differential ability to bind beryllium and mediate disease. 18,22,23 Together, this research tells a convincing story about the role that a specific genetic factor-Glu69-plays in the presentation of beryllium and the resultant immune response. However, some 15% of patients with sensitization or disease lack Glu69, suggesting that there must be other pathways by which beryllium can instigate a hypersensitivity response.…”

“…16 There is also evidence that it is not only the Glu69 marker but also the presence of specific (and uncommon) Glu69 alleles that puts individuals at the greatest risk. 17,18 In addition, genetic dose matters: allele number seems to be an important factor influencing the development of sensitization, the development of disease, and possibly the severity of disease. 14,15 Such work clearly demonstrates a role for HLA-DPB1Glu69 in the pathogenesis of beryllium sensitization and disease.…”