Managing Health Effects of Beryllium Exposure (2008) / Chapter Skim
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4 Mechanisms, Genetic Factors, and Animal Models of Chronic Beryllium Disease
4 Mechanisms, Genetic Factors, and Animal Models of Chronic Beryllium Disease
Pages 85-105
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From page 85... ...
It also provides a summary of studies to identify the genetic components involved in susceptibility to CBD and of attempts to develop animal models to study the disease. PATHOGENESIS AND MECHANISMS OF ACTION As early as 1951, Sterner and Eisenbud proposed that CBD was an immune-mediated hypersensitivity reaction directed against the inhaled beryllium antigen.
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From page 86... ...
CBD is a systemic granulomatous disorder that affects the lungs predominantly. The mechanism underlying CBD pathogenesis involves an immune response to beryllium (Figure 4-1)
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From page 87... ...
In many people, particularly CBD patients in the ceramics industry exposed to beryllium oxides, the T cells found in the BAL fluid express TCRBV3 genes with identical or homologous complementary-determining region 3 sequences. As further evidence that these are oligoclonal expansions, the beryllium-responsive T cells coexpress only a few homologous TCRα genes (Fontenot et al.
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From page 88... ...
Hence, beryllium presentation by some HLA-DP alleles to CD4+ T cells is the underlying mechanistic basis of CBD. Analysis of the amino acid residues shared by HLA-DP alleles that present beryllium revealed that those with a negatively charged glutamic acid residue at the 69th position of the β chain (Glu69)
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From page 89... ...
(2005) reported that dissolution of beryllium oxide particles in macrophage phagolysosomes may be an important source of dissolved beryllium for input into the cell-mediated immune reaction characteristic of beryllium disease.
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From page 90... ...
Immunopathogenic Hallmarks of Chronic Beryllium Disease The immunologic mechanisms underlying the progression of BeS to CBD are not well understood. Beryllium-sensitized people demonstrate a berylliumspecific immune response and show no evidence of lung disease.
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From page 91... ...
Attempts to identify the genetic components involved in susceptibility have centered primarily on the definition of CBD as a cell-mediated MHC class-II-restricted inflammatory disease. Accordingly, most studies have focused on specific genetic polymorphisms in MHC class II and proinflammatory genes, and a few others have considered the role of TCR-expression repertoires and other potential modifier genes.
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From page 92... ...
That remains the best-studied and strongest genetic association in this disease. They identified 33 CBD patients defined by a history of occupational exposure, x-ray abnormalities, abnormal lung function, presence of granulomas, and a positive BeLPT result.
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From page 93... ...
TABLE 4-1 Summary of Association Studies on HLA-DPB1 Glu69 and TNF-α as Susceptibility Factors in Chronic Beryllium Disease and Beryllium Sensitization Reference Subjects Number Subjects Frequency Homozygosity Alleles HLA-DPB1 Glu69 Glu69 Richeldi et al. 1993 CBD 33 97% -- 0201: 52% Controls 44 30% -- 18% Richeldi et al.
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From page 94... ...
2007 CBD 91 29% 2.2% TNF-α-238: 8.9% BeS 63 38% 6.4% 13% Controls 722 28% 2.6% 12% Sato et al. 2007 CBD 147 30% 0% TNF-α-1031, -863, -857, -238; all not BeS 112 36% 2.5% associated vs controls Controls 323 30% 2.3% Abbreviations: BeS, beryllium sensitization; CBD, chronic beryllium disease.
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From page 95... ...
They assigned odds ratios for specific alleles on the basis of the studies cited above and found a strong correlation between the reported hierarchic order of risk of CBD and the predicted surface electrostatic potential and charge of the corresponding isotypes. They concluded that alleles associated with the most negatively charged proteins carry the greatest risk of BeS and CBD.
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From page 96... ...
In addition, beryllium stimulation of CD4+ T cells from the BAL fluid of CBD patients, but not
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From page 97... ...
They reported that the high TNF-α–producing variant was present at increased frequency in CBD patients in the United States but not in those in Europe and Israel, but it is likely that the two groups had different beryllium exposure and disease severity. Recent large-scale studies have cast doubt on earlier findings of the importance of TNF-α polymorphisms in CBD.
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From page 98... ...
ANIMAL MODELS OF PULMONARY IMMUNOTOXICITY AND SENSITIZATION Beginning in the early 1950s, studies were conducted with beryllium to determine its chemical toxicity (see Table 4-2)
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Granulomatous lesions in strain 2 but not strain 13 guinea pigs Hart et al. 1984 Rat Inhalation Be at 500 ± 4.1 ng from BeO (single, lung burden; Lipids and enzymes increased in BAL particle size, 90% with mean diameter ≤ 1 µm fluid Sendelbach and Rat Inhalation Be at 3.3 or 7.0 µg/L from BeSO4 (single)
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From page 100... ...
1994 Monkey Intrabroncheal 1, 50, and 150 µg Be Pulmonary toxicity differed between 2.5, 12.5, and 37.5 µg BeO; particle size, for BeO, chemical form of beryllium (oxide less 1.6 µm; GSD = 1.9; for Be, 1.4 µm; GSD = 1.4 toxic than metal) Nikula et al.
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From page 101... ...
Pulmonary toxicity (histopathology and enzymology of the lungs) Freundt and Rat Oral 100 ppm BeSO4 for 91 d (drinking water)
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From page 102... ...
Peripheral blood lymphocytes responded to beryllium challenge in vitro, but positive proliferation results for lung lymphocytes were observed only in samples taken from dogs with high lung burdens of 500°C beryllium oxide. The granulomatous lung response was thought to be similar to that observed in humans with CBD, but the granulomas appeared to resolve within a year after the single treatment.
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From page 103... ...
The Hartley and strain 2 guinea pigs also showed evidence of beryllium sensitization, with positive delayed-type hypersensitivity skin tests and in vitro proliferation of lymphocytes in response to beryllium sulfate. Intravenous or oral exposure to beryllium sulfate induced tolerance to the intratracheally administered beryllium oxide.
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From page 104... ...
Granulomas and beryllium sensitization were found only in A/J mice treated with beryllium sulfate, and the granulomas regressed within 20 weeks. Similar experiments with beryllium sulfate in BALB/c and C57BL/6 mice did not produce any lung granulomas, nor were granulomas induced in mice treated with a single intratracheal instillation of beryllium oxide.
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From page 105... ...
Thus, animal studies cannot reliably predict exposure-response relationships, immunogenicity of different forms of beryllium, or mechanisms relevant to human CBD. Generally, more soluble forms of beryllium, such as beryllium salts as opposed to beryllium metal, have shorter half-lives in the lung and a greater potential for systemic absorption and sensitization; relatively insoluble forms of inhaled beryllium (beryllium metal and beryllium oxide)
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