CONCLUSIONS

Although animal studies in different species have demonstrated immunologic responses or pathologic changes similar to human CBD, animal models developed to date have varied between species, and none has adequately replicated the key features of human CBD, especially the persistence of granulomatous changes in the lung. The reason for the differences remains unclear, but the specific genes responsible for CBD in humans might not be present in animals. 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) deposited in the lungs will be retained with much longer half-lives and may lead to sensitivity reactions or toxicity even after a single exposure. No animal model has characteristics of human CBD that are sufficient for it to be used to establish the relative importance of the various chemical forms (including alloys) or physical characteristics of inhaled beryllium encountered in the workplace.

The mechanism underlying CBD pathogenesis involves an antigenic immune response to beryllium associated with beryllium-specific CD4+ T cells. Progress has made in characterizing the immune response to beryllium and host risk factors. More research is needed on the nature of the beryllium antigen recognized by the CD4+ T cells.

Research has also indicated that an allele of HLA-DPβGlu69 is the most important marker of susceptibility to CBD. However, the presence of that marker alone does not necessarily confer susceptibility, nor is its absence a guarantee of nonsusceptibility. T-cell-receptor expression, inflammation-related genes, and other potential modifier genes also appear to play roles in disease progression and warrant further investigation.

Efforts are under way to create humanized-mouse models in which human alleles are associated with a range of BeS and CBD risk that might be useful in experimental study of beryllium dose-response relationships, of beryllium types and characteristics that confer risk, and of therapeutic approaches to beryllium diseases. It is unclear whether expression of single target genes associated with sensitization will recapitulate the signs and symptoms of human CBD. There is no doubt that an animal model of immune-mediated CBD as it occurs in humans would aid substantially in developing an understanding of the mechanisms of CBD and the relative importance of the various forms of beryllium encountered in the workplace in the causation of CBD.



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