title: Identification of HLA-DRPhebeta47 as the susceptibility marker of hypersensitivity to beryllium in individuals lacking the berylliosis-associated supratypic marker HLA-DPGlubeta69.
abstract: BACKGROUND
  Susceptibility to beryllium (Be)-hypersensitivity (BH) has been associated with HLA-DP alleles carrying a glutamate at position 69 of the HLA-DP beta-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 HLA-DPGlu69 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. amicosan@uniroma2.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Amicosante
authors.forename: Floriana
authors.initials: F
authors.lastname: Berretta
authors.forename: Milton
authors.initials: M
authors.lastname: Rossman
authors.forename: Richard H
authors.initials: RH
authors.lastname: Butler
authors.forename: Paola
authors.initials: P
authors.lastname: Rogliani
authors.forename: Ella
authors.initials: E
authors.lastname: van den Berg-Loonen
authors.forename: Cesare
authors.initials: C
authors.lastname: Saltini
mesh_terms: D000328:Adult; D000542:Alveolitis, Extrinsic Allergic / Q000453:epidemiology* / Q000235:genetics*; D001607:Berylliosis / Q000453:epidemiology* / Q000235:genetics*; D001608:Beryllium; D004252:DNA Mutational Analysis; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D005819:Genetic Markers; D006684:HLA-DR Antigens; D001608:Beryllium