BACKGROUND: Inflammation at sites of target organs seems to be the pathologic hallmark of respiratory allergic diseases, but why this response cannot be turned off in atopic persons is not known. Programmed cell death (apoptosis) mediated by Fas/APO-1 (CD95), a 45-kD surface protein belonging to the tumor necrosis factor receptor family, is important in the resolution of all inflammatory immune responses. OBJECTIVE: To test whether the expression of Fas receptor is defective in allergen-specific pulmonary T lymphocytes from persons with asthma. DESIGN: 12-month prospective study. SETTING: University allergy and immunology clinic. PATIENTS: 12 untreated persons with newly diagnosed allergic asthma who underwent bronchoalveolar lavage. Ten normal persons served as controls. MEASUREMENTS: Fas receptor expression was studied by using surface double-color cytofluorometry on pulmonary and circulating T lymphocytes. Fas messenger RNA (mRNA) was searched for in bronchoalveolar lavage cells from patients and controls by reverse transcription polymerase chain reaction (PCR). In vitro induction of DNA fragmentation, as an expression of cell death induced by an IgM anti-Fas monoclonal antibody, was assessed by propidium iodide staining and agarose gel electrophoresis. In vitro modulation of surface Fas receptor was studied on pulmonary T lymphocytes stimulated with anti-CD3 monoclonal antibody and interleukin-2 or interleukin-4. RESULTS: Pulmonary T lymphocytes from patients as opposed to controls did not undergo DNA fragmentation after in vitro exposure to IgM anti-Fas. Other activation markers (CD25, HLA-DR, and CD45R0) were displayed, but surface Fas expression was always negative. A remarkable proportion of T cells from controls showed a clear double-staining pattern. Reverse transcription PCR for Fas mRNA yielded the same results. Circulating T lymphocytes from patients and controls included similar percentages of CD3+ Fas+ cells. Pulmonary T cells from both patients and controls showed upregulation of Fas receptor expression after in vitro anti-CD3 stimulation; co-culturing with interleukin-4 downmodulated surface Fas receptor expression on T cells from patients; it was less effective in controls. CONCLUSIONS: Hypoexpression of Fas mRNA and surface Fas receptor on pulmonary CD3+ T lymphocytes may explain the persistence of inflammatory cellular infiltrates in allergic bronchial asthma.
BACKGROUND: Inflammation at sites of target organs seems to be the pathologic hallmark of respiratory allergic diseases, but why this response cannot be turned off in atopic persons is not known. Programmed cell death (apoptosis) mediated by Fas/APO-1 (CD95), a 45-kD surface protein belonging to the tumor necrosis factor receptor family, is important in the resolution of all inflammatory immune responses. OBJECTIVE: To test whether the expression of Fas receptor is defective in allergen-specific pulmonary T lymphocytes from persons with asthma. DESIGN: 12-month prospective study. SETTING: University allergy and immunology clinic. PATIENTS: 12 untreated persons with newly diagnosed allergic asthma who underwent bronchoalveolar lavage. Ten normal persons served as controls. MEASUREMENTS: Fas receptor expression was studied by using surface double-color cytofluorometry on pulmonary and circulating T lymphocytes. Fas messenger RNA (mRNA) was searched for in bronchoalveolar lavage cells from patients and controls by reverse transcription polymerase chain reaction (PCR). In vitro induction of DNA fragmentation, as an expression of cell death induced by an IgM anti-Fas monoclonal antibody, was assessed by propidium iodide staining and agarose gel electrophoresis. In vitro modulation of surface Fas receptor was studied on pulmonary T lymphocytes stimulated with anti-CD3 monoclonal antibody and interleukin-2 or interleukin-4. RESULTS: Pulmonary T lymphocytes from patients as opposed to controls did not undergo DNA fragmentation after in vitro exposure to IgM anti-Fas. Other activation markers (CD25, HLA-DR, and CD45R0) were displayed, but surface Fas expression was always negative. A remarkable proportion of T cells from controls showed a clear double-staining pattern. Reverse transcription PCR for Fas mRNA yielded the same results. Circulating T lymphocytes from patients and controls included similar percentages of CD3+ Fas+ cells. Pulmonary T cells from both patients and controls showed upregulation of Fas receptor expression after in vitro anti-CD3 stimulation; co-culturing with interleukin-4 downmodulated surface Fas receptor expression on T cells from patients; it was less effective in controls. CONCLUSIONS: Hypoexpression of Fas mRNA and surface Fas receptor on pulmonary CD3+ T lymphocytes may explain the persistence of inflammatory cellular infiltrates in allergic bronchial asthma.
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