Cytokine Production Profile of CD4+ T Cells from Patients with Active Churg-Strauss Syndrome Tends Toward Th17

Abstract

Background: Churg-Strauss syndrome (CSS) is a rare systemic necrotizing vasculitis that develops in some asthma patients. What types of asthma make patients prone to develop this condition remains unknown. We found that inhibition of regulatory T cells (Treg) differentiation, especially by Tr1 cells, due to a decreased ability of responder T cells to generate IL-2, is associated with the onset and pathogenesis of CSS. In contrast, recent evidence suggests that IL-17-producing Th17 cells play a crucial role in autoimmune inflammation. However, few studies have addressed the role of Th17 in the pathogenesis of CSS. Methods: Mononuclear leukocytes were obtained from healthy subjects, patients with bronchial asthma (BA), asthma-accompanying chronic eosinophilic pneumonia (BA+CEP) and CSS. The cells were stimulated for 4–5 h with PMA and ionomycin in the presence of brefeldin A to generate and accumulate cytokines. Intracellular cytokines were detected after fixation and permeabilization of these cells. Tr1 cells were evaluated as CD4+CD25+ T cells dominantly producing IL-10 and TGF-β, nTreg as CD4+CD25+ T cells expressing Foxp3, a master transcriptional factor, and Th17 were also evaluated as CD4+ T cells mainly producing IL-17. Patients with CSS were classified into an active group and an inactive group in accordance with the disease state after treatment. Results: The frequency of Th17 in peripheral blood was significantly higher in active CSS patients than in healthy subjects, BA, BA+CEP, and inactive CSS patients. In contrast, the Tr1 cell detection frequency was remarkably decreased in active CSS in comparison with BA, BA+CEP, and inactive CSS patients. Also, there was a significant relation between the condition of a given CSS patient and the detection frequencies of both CD4+ helper T cells when CSS cases were divided into inactive and active stages. The Th17 detection frequency was increased in the active stage of CSS, while the Tr1 frequency decreased sharply but then reversed in the inactive stage of CSS. Conclusion: Active CSS patients have elevated intracellular IL-17 and decreased IL-10 levels, which correlate with measures of disease activity, suggesting that Th17 and Tr1 may play important roles in the pathogenesis of CSS.

The TLR7 Ligand 9-Benzyl-2-Butoxy-8-Hydroxy Adenine Inhibits IL-17 Response by Eliciting IL-10 and IL-10–Inducing Cytokines

“…Accordingly, the proportion of IL-10-producing T cells in SA-2-treated mice was inhibited by the anti-IFN-aR-and, poorly, anti-IL-10R Abs. These data are consistent with the increased IFN-a in the serum and elevated IL-10-producing T cells during the remission of respiratory symptoms in severe asthma and ChurgStrauss syndrome (41). Thus, it is reasonable to hypothesize that IL-10 and IL-10-inducing cytokines are the major players for the early and delayed inhibition of NKT cell-derived cytokines, including IL-17A.…”

Precarious Balance: Th17 Cells in Host Defense

“…The Th17 subset also appears to subvert Tregdriven immunosuppression; unlike IFN-␥, Th17-associated IL-6 inhibits rather than enhances tryptophan catabolism, which is a process associated with Treg induction (18). In the absence of attenuation, Th17-associated effector mechanisms can mediate tissue injury through protracted local inflammation, a feature of certain chronic biofilm infections (20,29,78,84).…”

The Etiology, Mechanisms, and Treatment of Churg-Strauss Syndrome

“…We confirmed that the percentage of CD4+ T cells producing IL-17 was significantly greater in patients with active CSS than in healthy control patients or in patients with asthma, BA + CEP, or inactive CSS ( producing IL-17 in active CSS who were at onset or at relapse was significantly greater than those in inactive CSS and the percentage of CD4+CD25+ T cells producing IL-10 (Tr1 cells) in active CSS significantly decreased than those in inactive CSS who achieved remission after treatment (Tr 1) ( Fig. 9) (Saito et al, 2009). Th17 cells were identified as CD4+ T cells that produced mainly IL-17 and IL-22.…”