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Published ahead of print on February 19, 2004, doi:10.1165/rcmb.2003-0336OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 1, July 2004, 122-130

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Submitted on September 10, 2003
Revised on February 19, 2004

Beryllium-Induced TNF-{alpha} Production by CD4+ T Cells is Mediated by HLA-DP

Richard T Sawyer1*, Charles E Parsons2, Andrew P Fontenot3, Lisa A Maier1, May M Gillespie2, E. Brigitte Gottschall1, Lori Silveira2, and Lee S Newman1

1 Medicine, National Jewish Medical and Research Center, Denver, CO, USA; Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 2 Medicine, National Jewish Medical and Research Center, Denver, CO, USA, 3 Medicine, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: sawyerr{at}njc.org.

Beryllium (Be) presentation to CD4+ T cells from patients with chronic beryllium disease (CBD) results in T cell activation, and these Be-specific CD4+ T cells undergo clonal proliferation and Th1-type cytokine production. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with particular HLA-DPB1 alleles. We hypothesized that these HLA-DP molecules could mediate Be-stimulated TNF-{alpha} mRNA and protein production. Using intracellular cytokine staining, we found that treatment with an anti-HLA-DP, but not anti-HLA-DR, mAb inhibited Be-stimulated TNF-{alpha} expression in lung CD3+ CD4+ T cells. This mAb also blocked Be-specific T cell proliferation, increased production of TNF-{alpha} mature-mRNA transcripts, and increased TNF-{alpha} protein production by Be-stimulated CBD peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) cells. The Be-stimulated up-regulation of TNF-{alpha} mature-mRNA levels with TNF-{alpha} protein production was a unique property of CBD BAL cells, and did not occur in BAL cells from beryllium sensitized patients without CBD, or sarcoidosis BAL cells. This study identifies HLA-DP as a regulatory component in the activation of T cell receptors on Be-specific CD4+ T cells from CBD patients resulting in proliferation and pro-inflammatory cytokine production.




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