Involvement of regulatory T cells in the pathogenesis of Churg-Strauss syndrome

Background: Churg-Strauss syndrome (CSS) is a rare systemic necrotizing vasculitis that develops in some asthma patients. However, it remains unknown what types of asthma patients can develop this condition. In addition, CSS patients experience eosinophilic pneumonia (EP) before the onset, but some asthma patients do not develop CSS following EP. Few studies have addressed the immunological differences in both cases. Additionally, it is well known that abnormality or failure of immunological tolerance by regulatory T cells (Treg) directly triggers the onset of autoimmune diseases. To elucidate the involvement of Treg in the difference in the pathogenesis of patients with and without CSS, the frequency of naturally occurring Treg (nTreg) and Treg which dominantly produce IL-10 and TGF-beta (Tr1) was measured in peripheral blood. Methods: Mononuclear leukocytes were obtained from patients with asthma, asthma accompanying EP and CSS. The cells were stimulated with PMA and ionomycin in the presence of brefeldin A to generate and accumulate cytokines. Cytokines in the cells were detected after fixation and permeabilization of these cells. Tr1 cells were evaluated as CD4+CD25+ T cells dominantly producing IL-10 and TGF-beta, and nTreg were also evaluated as CD4+CD25+ T cells expressing FOXP3, a master transcriptional factor. Results: There was a significantly greater number of nTreg in the peripheral blood of EP patients in comparison to both patients with asthma and whole CSS. However, no significant difference was observed regarding the number of nTreg when patients with CSS were divided into inactive and active stage. In contrast, the detection frequency of Tr1 remarkably decreased in active CSS, especially at the time of onset of CSS, in comparison with asthma, EP and inactive CSS, while there was no difference between EP and inactive CSS. Additionally, the ability of CD4+CD25-T cells (responder T cells) to generate IL-2 when stimulated with PMA and ionomycin sharply decreased in active CSS. Conclusion: In the patient who does not develop CSS even after repeat EP, the frequency of Tr1 and the ability of responder T cells to generate IL-2 do not decrease, but show a remarkable decrease in the EP patient who develops CSS. These findings strongly suggest that Tr1 is responsible for maintaining immunological tolerance in peripheral blood, while also inhibiting the onset of CSS from EP. Copyright (C) 2008 S. Karger AG, Basel.