Identification of HLA-DRPheβ47 as the susceptibility marker of hypersensitivity to beryllium in individuals lacking the berylliosis-associated supratypic marker HLA-DPGluβ69

Journal Article · Sun Aug 14 00:00:00 EDT 2005 · Respiratory Research (Online)

DOI:https://doi.org/10.1186/1465-9921-6-94· OSTI ID:1626250

Amicosante, Massimo ^[1]; Berretta, Floriana ^[1]; Rossman, Milton ^[2]; Butler, Richard H. ^[3]; Rogliani, Paola ^[1]; van den Berg-Loonen, Ella ^[4]; Saltini, Cesare ^[1]

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1. Tor Vergata Univ. of Rome (Italy). Dept. of Internal Medicine
2. Univ. of Pennsylvania, Philadelphia, PA (United States). Hospital. Dept. of Medicine. Pulmonary, Allergy and Critical Care Division
3. National Research Council, Monterotondo (Rome) (Italy). Inst. of Cell Biology
4. Univ. of Maastricht (Netherlands). Univ. Hospital. Tissure Typing Lab.

Background: Susceptibility to beryllium (Be)-hypersensitivity (BH) has been associated with HLA-DP alleles carrying a glutamate at position 69 of the HLA-DP β-chain (HLA-DPGlu69) and with several HLA-DP, -DQ and -DR alleles and polymorphisms. However, no genetic associations have been found between BH affected subjects not carrying the HLADPGlu69 susceptibility marker. Methods: In this report, we re-evaluated an already described patient populations after 7 years of follow-up including new 29 identified BH subjects. An overall population 36 berylliosis patients and 38 Be-sensitization without lung granulomas and 86 Be-exposed controls was analysed to assess the role of the individual HLA-class II polymorphisms associated with BH-susceptibility in HLA-DPGlu69 negative subjects by univariate and multivariate analysis. Results: As previously observed in this population the HLA-DPGlu69 markers was present in higher frequency in berylliosis patients (31 out of 36, 86%) than in Be-sensitized (21 out of 38, 55%, p = 0.008 vs berylliosis) and 41 out of 86 (48%, p < 0.0001 vs berylliosis, p = 0.55 vs Be-sensitized) Be-exposed controls. However, 22 subjects presenting BH did not carry the HLA-DPGlu69 marker. We thus evaluated the contribution of all the HLA-DR, -DP and -DQ polymorphisms in determining BH susceptibility in this subgroup of HLA-Glu69 subjects. In HLA-DPGlu69-negatives a significant association with BH was found for the HLA-DQLeu26, for the HLA-DRB1 locus residues Ser13, Tyr26, His32, Asn37, Phe47 and Arg74 and for the HLA-DRB3 locus clusterized residues Arg11, Tyr26, Asp28, Leu38, Ser60 and Arg74. HLA-DRPhe47 (OR 2.956, p < 0.05) resulting independently associated with BH. Further, Be-stimulated T-cell proliferation in the HLA-DPGlu69-negative subjects (all carrying HLA-DRPhe47) was inhibited by the anti-HLA-DR antibody (range 70–92% inhibition) significantly more than by the anti-HLA-DP antibody (range: 6–29%; p < 0.02 compared to anti-HLA-DR) while it was not affected by the anti-HLA-DQ antibody. Conclusion: We conclude that HLA-DPGlu69 is the primary marker of Be-hypersensitivity and HLA-DRPhe47 is associated with BH in Glu69-negative subjects, likely playing a role in Be-presentation and sensitization.

• Research Organization: USL of Modena 16 (Italy)
• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
• Grant/Contract Number: FG02-93ER61714
• OSTI ID: 1626250
• Journal Information: Respiratory Research (Online), Vol. 6, Issue 1; ISSN 1465-993X
• Publisher: BioMed Central
• Country of Publication: United States
• Language: English

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