Lummus Z L, Alam R, Bernstein J A, Bernstein D I
Department of Internal Medicine, University of Cincinnati College of Medicine, OH 45267-0563, USA.
Toxicology. 1996 Jul 17;111(1-3):191-206. doi: 10.1016/0300-483x(96)03376-8.
Immunologic mechanisms contributing to diisocyanate-induced occupational asthma (OA) are poorly defined. There is a relatively low incidence of diisocyanate-specific IgE antibody responses. The frequent occurrence of delayed onset asthmatic responses in workers with diisocyanate asthma suggests a role for cellular immune mechanisms. We have shown in vitro production of antigen-specific mononuclear cell-derived histamine releasing factors (HRF) by peripheral blood mononuclear cells (PBMCs) of workers with OA. Monocyte chemoattractant protein-1 (MCP-1) and RANTES (acronym for "regulated on activation normal T expressed and secreted") are chemokines found in PBMC supernatants that express HRF activity. Diisocyanate-exposed workers were tested for diisocyanate antigen-stimulated enhancement of HRF, MCP-1, and RANTES production in supernatants of PBMCs and for serum specific IgE and IgG antibody levels to diisocyanate antigens bound to human serum albumin (HSA). PBMCs of workers with diisocyanate OA showed significantly increased production of antigen-specific HRF activity and MCP-1 ( > 300 ng/ml) compared to diisocyanate-exposed asymptomatic workers (P < 0.05). Antigen-stimulated enhancement of MCP-1 mRNA was demonstrated by reverse-transcription PCR. RANTES mRNA and chemokine secretion ( < 1 ng/ml) was also demonstrated in PBMCs, but did not show antigen enhancement in OA workers. Hapten specificity for the diisocyanate chemical to which a patient had been exposed was demonstrated for HRF enhancement and for IgG antibody reactions, but not for IgE reactions. HRF production was demonstrated in PBMC subpopulations, including lymphocytes and purified T cells. OA subjects showed increased CD8+ cells by immunofluorescence (mean CD4+: CD8+ = 1.2 +/- 0.2). The results suggest that diisocyanate antigen enhancement of HRF and MCP-1 production are stimulated by hapten-specific T cell reactions. Since a weak association has been found between IgE antibody synthesis and induction of diisocyanate OA, the role of T cell cytokines and chemokines in the pathogenesis of OA requires further investigation.
二异氰酸酯诱发职业性哮喘（OA）的免疫机制尚不明确。二异氰酸酯特异性IgE抗体反应的发生率相对较低。二异氰酸酯哮喘患者中迟发性哮喘反应频繁发生，提示细胞免疫机制发挥了作用。我们已证实在体外，职业性哮喘患者的外周血单个核细胞（PBMC）可产生抗原特异性单核细胞衍生的组胺释放因子（HRF）。单核细胞趋化蛋白-1（MCP-1）和RANTES（“活化正常T细胞表达和分泌调控因子”的首字母缩写）是在表达HRF活性的PBMC上清液中发现的趋化因子。对接触二异氰酸酯的工人进行检测，以评估二异氰酸酯抗原刺激后PBMC上清液中HRF、MCP-1和RANTES产生的增强情况，以及血清中针对与人血清白蛋白（HSA）结合的二异氰酸酯抗原的特异性IgE和IgG抗体水平。与接触二异氰酸酯但无症状的工人相比，二异氰酸酯职业性哮喘患者的PBMC产生抗原特异性HRF活性和MCP-1（>300 ng/ml）的水平显著升高（P<0.05）。通过逆转录PCR证实了抗原刺激后MCP-1 mRNA的增强。在PBMC中也证实了RANTES mRNA和趋化因子分泌（<1 ng/ml），但在职业性哮喘患者中未显示出抗原增强。对于HRF增强和IgG抗体反应，证实了患者接触的二异氰酸酯化学物质的半抗原特异性，但对于IgE反应则未证实。在包括淋巴细胞和纯化T细胞在内的PBMC亚群中证实了HRF的产生。通过免疫荧光法，职业性哮喘患者的CD8+细胞增多（平均CD4+:CD8+ = 1.2 +/- 0.2）。结果表明，半抗原特异性T细胞反应刺激了二异氰酸酯抗原增强HRF和MCP-1的产生。由于已发现IgE抗体合成与二异氰酸酯职业性哮喘的诱导之间存在弱关联，T细胞细胞因子和趋化因子在职业性哮喘发病机制中的作用需要进一步研究。
