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.

Figure 1.

Beryllium-induced ear swelling in transgenic mice. The difference between the controls (C/C and C/Be) and the treatment (Be/Be) group are only statistically significant for the mice that possess the highest risk allele, HLA-DPB1*1701.

Figure 2.

Beryllium-induced ear swelling in inbred mouse strains. The greatest statistically significant difference from control was seen in the SJL/J, Balb/C, C57BL/6J, and DBA/2J. The strains that did not have a statistically significant increase in treatment over control were C3H/HeJ and FVB/N.

Figure 3.

Beryllium-induced ear swelling in SJL/J mice. The SJL/J mice were the highest responding strain in the inbred mouse ear swelling test. To ensure that the response was due to beryllium and not irritation, a second control (C/Be) was tested. In the C/Be group mice were sensitized on the back with vehicle (DBPT and water) and then challenged on the ear with beryllium (DPBT and BeSO₄). Both controls were statistically significant from the treatment group, but there was no statistical difference between the control groups.