The human MHC class II genes are closely linked on the short arm of chromosome 6 and include the genes of the subloci HLA-DP, DQ, DR that code for the immune response associated “la” like antigens (HLA-DP, DQ, and DR antigens) that are expressed on the surface of immunocompetent cells in man. Expression of these gene products is essential for the initiation of the immune response because helper T lymphocytes can recognize and respond to antigens only when these are presented in association with HLA-DR and possibly other D-region products on the surface of antigen-presenting cells. Tissue specific cis- and trans-acting factors regulate expression of the products of these genes but, although they appear to be under coordinate control, quantitative differences do exist that result in heterogeneity of expression. The cytokine interferon gamma can induce or enhance the expression of la and HLA D-region antigens and prostaglandins can down regulate their expression. Such variation of cell surface la levels influences immunoregulation and the expression of immunologically mediated disease.
There are many reports confirming that alveolar macrophages express la antigens, although the basal expression differs in different species, being very low in rodents (expressed on <=10 percent of cells) except during the evolution of a specific immune response. By contrast, more than 80 percent of normal human alveolar macrophages express HLA-DR antigens and similar percentages are observed in patients with chronic inflammatory lung diseases. Our results confirm these previous reports and also show that HLA-DQ and DP antigens are expressed on the majority of human alveolar macrophages from controls and patients with chronic inflammatory lung diseases. Venet et al have also studied HLA-DQ expression and have come to similar conclusions.
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Although a high percentage of human alveolar macrophages express HLA-D region antigens, they generally function poorly as antigen-presenting cells compared with blood monocytes or macrophages from other tissue sites, particularly at high alveolar macro- phage/T-cell ratios comparable to those encountered in bronchoalveolar lavage fluids from normal lungs. It has been suggested that this might relate to a diminished capacity of alveolar macrophages to secrete the mediator interleukin 1, reduced antigen processing/presentation activity, or increased secretion of lymphocytostatic molecules such as prostaglandins. This has led to the view that alveolar macrophages may play an important role in preventing immune hyperreactivity in the lungs by suppressing unwanted lymphocyte responses to the numerous inhaled innoc-
uous antigens while still protecting the lungs through their phagocytic and microbicidal functions. However, mechanisms appear to exist to amplify specific pulmonary immune defenses against pathogens, when necessary. Induction of an inflammatory response in the lungs can result in an influx of blood monocytes (more efficient accessory cells) overcoming the local lymphocytostatic activity of alveolar macrophages, and allowing T-lymphocyte activation to occur. Induction of a specific immune response in the lungs can also enhance the expression of la antigens on alveolar macrophages. Thus, failure in the mechanisms that regulate this process could be a contributory factor in chronic inflammatory lung diseases, such as pulmonary sarcoidosis, which are associated with increased numbers of T lymphocytes in the lung.
There is substantial evidence that the granulomatous clusters of macrophages, giant cells, epithelioid cells, and T lymphocytes in the lungs of patients with sarcoidosis are the result of cell-mediated hypersensitivity reactions. There are increased numbers of T lymphocytes in bronchoalveolar lavage samples from these patients and these lymphocytes show an increased ability to spontaneously proliferate in vitro; spontaneously secrete the T-cell growth factor inter- leukin 2; frequently show increased ratios of helper/inducer T cells:suppressor/cytotoxic T cells; and also spontaneously secrete lymphokines, including interferon gamma and factors that act on cells of the mononuclear phagocyte system, including macrophage migration inhibition factor and monocyte chemotactic factor. In keeping with this latter observation, increased numbers of monocytes have been reported in the lungs of patients with sarcoidosis and such cells have been proposed as one possible explanation for the local immune hyperreactivity in this disease. Moreover, there is evidence that macrophages in lavage samples of patients with sarcoidosis are actively engaged in antigen-presenting function since they have enhanced antigen-presenting capacity compared with normal alveolar macrophages, and they spontaneously release interleukin 1 in vitro, which is a monokine produced during the induction of lymphoproliferative responses. Viagra Soft Tabs