ABSTRACT
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 T-helper 1-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 tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) and protein production. Using intracellular cytokine staining, we found that treatment with an anti-HLA-DP, but not anti-HLA-DR, monoclonal antibody inhibited Be-stimulated TNF-alpha expression in lung CD3+ CD4+ T cells. This monoclonal antibody 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 upregulation 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 Be-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 proinflammatory cytokine production.
Subject(s)
Berylliosis/immunology , Beryllium/adverse effects , CD4-Positive T-Lymphocytes/metabolism , HLA-DP Antigens/immunology , HLA-DP Antigens/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Antibodies, Monoclonal/pharmacology , Berylliosis/metabolism , Berylliosis/physiopathology , Bronchoalveolar Lavage Fluid/cytology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cell Division/drug effects , Cell Division/immunology , Cytokines/genetics , Cytokines/immunology , Cytokines/metabolism , Female , HLA-DP Antigens/drug effects , Humans , Inflammation Mediators/metabolism , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Male , Middle Aged , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Receptors, Antigen, T-Cell/drug effects , Receptors, Antigen, T-Cell/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Up-Regulation/drug effects , Up-Regulation/genetics , Up-Regulation/immunologyABSTRACT
The effect of dexamethasone on human MHC class II expression was examined on various cell types including lymphocytes, monocytes, and epithelial cells. Dexamethasone decreased the surface expression of HLA-DR and -DP, but not HLA-DQ, on lymphocytic cell lines that constitutively express these molecules. In addition, dexamethasome down-regulated the mRNA levels of HLA-DRA, but not of HLA-DQB, in Jijoye cells, a human lymphoblastic cell line. Similarly, dexamethasone decreased HLA-DR expression on epithelial and monocytic cell lines that express HLA-DR upon IFN-gamma treatment. In total, these results suggest that dexamethasone inhibits both constitutive and IFN-gamma-inducible MHC class II expression in several cell types. Moreover, these results indicate that the inhibitory effect of dexamethasone on MHC class II expression is selective for HLA-DR and -DP but not HLA-DQ. Possible mechanisms of dexamethasone-mediated regulation of MHC class II expression are discussed.
