title: Genetic determinants of sensitivity to beryllium in mice.
abstract: Chronic beryllium disease (CBD), an irreversible, debilitating granulomatous lung disease is caused by exposure to beryllium. This occupational hazard occurs in primary production and machining of Be-metal, BeO, beryllium - containing alloys, and other beryllium products. CBD begins as an MHC Class II-restricted, T(H)1 hypersensitivity, and the Human Leukocyte Antigen, HLA-DPB1E(69), is associated with risk of developing CBD. Because inbred strains of mice have not provided good models of CBD to date, three strains of HLA-DPB1 transgenic mice in an FVB/N background were developed; each contains a single allele of HLA-DPB1 that confers a different magnitude of risk for chronic beryllium disease: HLA-DPB1*0401 (OR approximately 0.2), HLA-DPB1*0201 (OR approximately 3), and HLA-DPB1*1701 (OR approximately 46). The mouse ear swelling test (MEST) was employed to determine if these different alleles would support a hypersensitivity response to beryllium. Mice were first sensitized on the back and subsequently challenged on the ear. In separate experiments, mice were placed into one of three groups (sensitization/challenge): C/C, C/Be, and Be/Be. In the HLA-DPB1*1701 mice, the strain with the highest risk transgene, the Be/Be group was the only group that displayed significant maximum increased ear thickness of 19.6% +/- 3.0% over the baseline measurement (p < 0.05). No significant changes were observed in the other transgenic strains for any treatment condition. In addition, inter-strain differences in response to beryllium in seven inbred strains were investigated through use of the MEST, these included: FVB/N, AKR, Balb/c, C3H/HeJ, C57/BL6, DBA/2, and SJL/J. The FVB/N strain was least responsive, while the SJL/J and C57/BL6 strains were the highest responders. Our results suggest that the HLA-DPB1*1701 transgene product is an important risk factor for induction of the beryllium-sensitive phenotype. This model should be a useful tool for investigating beryllium sensitization.
authors: Department of Environmental Medicine, NYU School of Medicine, Tuxedo, New York 10987, USA.
authors: Lauren M
authors: LM
authors: Tarantino-Hutchison
authors: Claudio
authors: C
authors: Sorrentino
authors: Arthur
authors: A
authors: Nadas
authors: Yiwen
authors: Y
authors: Zhu
authors: Edward M
authors: EM
authors: Rubin
authors: Sally S
authors: SS
authors: Tinkle
authors: Ainsley
authors: A
authors: Weston
authors: Terry
authors: T
authors: Gordon
mesh_terms: D000483:Alleles; D000818:Animals; D001607:Berylliosis / Q000235:genetics* / Q000276:immunology*; D001608:Beryllium / Q000009:adverse effects; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006682:HLA-DP Antigens / Q000235:genetics* / Q000378:metabolism; D059868:HLA-DP beta-Chains; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012882:Skin Tests; D013045:Species Specificity; D018417:Th1 Cells / Q000276:immunology
chemical_list: D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D001608:Beryllium