Immunogenetic basis of environmental lung disease: lessons from the berylliosis model

Saltini, Cesare; Amicosante, Massimo; Franchi, Alberto; Lombardi, Giovanna; Richeldi, Luca

doi:10.1183/09031936.98.12061463

Cited by 76 publications

(59 citation statements)

References 109 publications

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“…Genetic susceptibility to both beryllium sensitization and CBD has been linked to particular alleles of the MHC class II molecule, HLA-DP (13)(14)(15)(16)(17). In particular, susceptibility has been most strongly associated with HLA-DPB1 alleles that encode a negatively charged glutamic acid (E) at position 69 (Glu 69 ) of the ␤-chain.…”

Section: Hronic Beryllium Disease (Cbd)mentioning

confidence: 99%

Beryllium Presentation to CD4+ T Cells Is Dependent on a Single Amino Acid Residue of the MHC Class II β-Chain

Bill¹,

Mack²,

Falta³

et al. 2005

The Journal of Immunology

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Chronic beryllium disease (CBD) is characterized by a CD4+ T cell alveolitis and granulomatous inflammation in the lung. Genetic susceptibility to this disease has been linked with HLA-DP alleles, particularly those possessing a glutamic acid at position 69 (Glu69) of the β-chain. However, 15% of CBD patients do not possess a Glu69-containing HLA-DP allele, suggesting that other MHC class II alleles may be involved in disease susceptibility. In CBD patients without a Glu69-containing HLA-DP allele, an increased frequency of HLA-DR13 alleles has been described, and these alleles possess a glutamic acid at position 71 of the β-chain (which corresponds to position 69 of HLA-DP). Thus, we hypothesized that beryllium presentation to CD4+ T cells was dependent on a glutamic acid residue at the identical position of both HLA-DP and -DR. The results show that HLA-DP Glu69- and HLA-DR Glu71-expressing molecules are capable of inducing beryllium-specific proliferation and IFN-γ expression by lung CD4+ T cells. Using fibroblasts expressing mutated HLA-DP2 and -DR13 molecules, beryllium recognition was dependent on the glutamic acid at position 69 of HLA-DP and 71 of HLA-DR, suggesting a critical role for this amino acid in beryllium presentation to Ag-specific CD4+ T cells. Thus, these results demonstrate that a single amino acid residue of the MHC class II β-chain dictates beryllium presentation and potentially, disease susceptibility.

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Section: Hronic Beryllium Disease (Cbd)mentioning

confidence: 99%

Beryllium Presentation to CD4+ T Cells Is Dependent on a Single Amino Acid Residue of the MHC Class II β-Chain

Bill¹,

Mack²,

Falta³

et al. 2005

The Journal of Immunology

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“…Susceptibility to CBD has been associated with particular alleles of the class II MHC molecule, HLA-DP (5)(6)(7)12). In the present study, we determined whether proliferation of beryllium-specific CD4 ϩ T cells from the lungs of CBD patients involved presentation by HLA-DP.…”

mentioning

confidence: 93%

Beryllium presentation to CD4⁺T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease

Fontenot

Torres

Marshall

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

126

156

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Chronic beryllium disease results from beryllium exposure in the workplace and is characterized by CD4 ؉ T cell-mediated inflammation in the lung. Susceptibility to this disease is associated with particular HLA-DP alleles. We isolated beryllium-specific T cell lines from the lungs of affected patients. These CD4 ؉ T cell lines specifically responded to beryllium in culture in the presence of antigen-presenting cells that expressed class II MHC molecules HLA-DR, -DQ, and -DP. The response to beryllium was nearly completely and selectively blocked by mAb to HLA-DP. Additional studies showed that only certain HLA-DP alleles allowed presentation of beryllium. Overall, the DP alleles that presented beryllium to disease-specific T cell lines match those implicated in disease susceptibility, providing a mechanism for this association. Based on amino acid residues shared by these restricting and susceptibility DP alleles, our results provide insight into the residues of the DP ␤-chain required for beryllium presentation.

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“…Although E69 is a strong marker of sensitization and disease, questions remain whether certain alleles confer greater risk of disease than others. Some studies have suggested that a greater prevalence of a non-*02 E69 variant is found in CBD and BeS (8,(10)(11)(12)(13), whereas others have not (14,15). Since the time of these first studies of associations between the HLA-DPB1 gene and CBD, many new alleles have been identified owing to improvements in typing methods.…”

mentioning

confidence: 99%

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

Silveira¹,

McCanlies²,

Fingerlin³

et al. 2011

C54. Hypersensitivity Pneumonitis and Berylliosis

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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 ...

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Immunogenetic basis of environmental lung disease: lessons from the berylliosis model

Cited by 76 publications

References 109 publications

Beryllium Presentation to CD4+ T Cells Is Dependent on a Single Amino Acid Residue of the MHC Class II β-Chain

Beryllium Presentation to CD4+ T Cells Is Dependent on a Single Amino Acid Residue of the MHC Class II β-Chain

Beryllium presentation to CD4⁺T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease

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

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Immunogenetic basis of environmental lung disease: lessons from the berylliosis model

Cited by 76 publications

References 109 publications

Beryllium Presentation to CD4+ T Cells Is Dependent on a Single Amino Acid Residue of the MHC Class II β-Chain

Beryllium Presentation to CD4+ T Cells Is Dependent on a Single Amino Acid Residue of the MHC Class II β-Chain

Beryllium presentation to CD4+T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease

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

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Beryllium presentation to CD4⁺T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease