Saito Hiroshi, Tsurikisawa Naomi, Tsuburai Takahiro, Akiyama Kazuo
Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara Hospital, Sagamihara, Japan.
Int Arch Allergy Immunol. 2008;146 Suppl 1:73-6. doi: 10.1159/000126065. Epub 2008 May 27.
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.
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.
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.
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.
变应性肉芽肿性血管炎（CSS）是一种在部分哮喘患者中发生的罕见的系统性坏死性血管炎。然而，何种类型的哮喘患者会发展为此病仍不清楚。此外，CSS患者在发病前会经历嗜酸性粒细胞性肺炎（EP），但一些哮喘患者在发生EP后并未发展为CSS。很少有研究探讨这两种情况的免疫差异。另外，众所周知，调节性T细胞（Treg）介导的免疫耐受异常或缺失会直接引发自身免疫性疾病的发生。为阐明Treg在CSS患者与非CSS患者发病机制差异中的作用，对外周血中自然发生的Treg（nTreg）以及主要产生白细胞介素-10（IL-10）和转化生长因子-β（TGF-β）的Treg（Tr1）的频率进行了检测。
从哮喘患者、伴有EP的哮喘患者及CSS患者中获取单个核白细胞。在布雷菲德菌素A存在的情况下，用佛波酯（PMA）和离子霉素刺激细胞以产生并积累细胞因子。在对这些细胞进行固定和通透处理后检测细胞内的细胞因子。Tr1细胞被评估为主要产生IL-10和TGF-β的CD4⁺CD25⁺T细胞，nTreg也被评估为表达主转录因子叉头框蛋白P3（FOXP3）的CD4⁺CD25⁺T细胞。
与哮喘患者和整个CSS患者群体相比，EP患者外周血中的nTreg数量显著更多。然而，将CSS患者分为非活动期和活动期时，nTreg数量未观察到显著差异。相反，与哮喘、EP和非活动期CSS相比，活动期CSS中Tr1的检测频率显著降低，尤其是在CSS发病时，而EP与非活动期CSS之间无差异。此外，在活动期CSS中，用PMA和离子霉素刺激时，CD4⁺CD25⁻T细胞（反应性T细胞）产生IL-2的能力急剧下降。
即使反复发生EP仍未发展为CSS的患者中，Tr1的频率和反应性T细胞产生IL-2的能力并未降低，但在发展为CSS的EP患者中则显著降低。这些发现强烈表明，Tr1负责维持外周血中的免疫耐受，同时也抑制了从EP发展为CSS的过程。
