Luna Rosa María Licón, Körmendy Dezsö, Brunner-Weinzierl Monika C
Department of Experimental Pediatrics, Otto-von-Guericke University, Magdeburg, Germany.
Gend Med. 2010 Aug;7(4):296-308. doi: 10.1016/j.genm.2010.08.005.
Autoimmune reactions occur naturally and in most cases are controlled by regulatory mechanisms. However, unwanted autoimmune responses still appear in 5% to 7% of the population, in strikingly greater frequencies in women compared with men. The chronic inflammation characteristic of autoimmune diseases is mainly initiated and maintained by autoreactive CD4(+) T lymphocytes. Costimu-lation is required for an optimal response of T lymphocytes: CD28 is a T-cell activator, whereas CTLA-4 (cytotoxic T-lymphocyte antigen 4, also known as CD152) downregulates T-cell activity. Together these costimulatory molecules provide a balance in T-cell immune response.
The aim of this study was to elucidate the role of the inhibitory receptor CTLA-4 in the quality of sex-specific immune responses.
At the German Rheumatism Research Center (DRFZ), Berlin, Germany, between 2006 and 2010, we tested mouse strains commonly used for the development of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis (MS). The SJL mouse strain not only mimics MS pathogenesis, but also exhibits the female predominance that occurs in patients with MS.
Cells derived from SJL females revealed increased proliferation and a doubled frequency of T-helper (Th)1- and Th2-like cytokines, compared with their male counterparts. Moreover, activated Th cells from male mice express significantly higher frequencies (61%) of CTLA-4 expressed at the cell surface in comparison with those of females (46%). Accordingly, close to 50% reduction of CTLA-4 expression occurred in cells of both sexes after the addition of estrogen. We observed that interferon (IFN)-γ(high) production in females occurred in a higher frequency in CD4(+) T cells cultured under neutral conditions (24.6% in females, 15.9% in males). Moreover, we observed that the IFN-yhigh producers were mainly present in females (4.5% vs 0.4% in males).
Our results suggest that induction of CTLA-4 expression could serve as a target for an immunomodulatory strategy to downregulate immune responses in sexually dimorphic autoimmune diseases.
自身免疫反应自然发生，且在大多数情况下受调节机制控制。然而，仍有5%至7%的人群会出现不良的自身免疫反应，女性的出现频率显著高于男性。自身免疫性疾病的慢性炎症特征主要由自身反应性CD4(+) T淋巴细胞启动并维持。共刺激是T淋巴细胞产生最佳反应所必需的：CD28是一种T细胞激活剂，而细胞毒性T淋巴细胞相关抗原4（CTLA-4，也称为CD152）可下调T细胞活性。这些共刺激分子共同在T细胞免疫反应中提供平衡。
本研究旨在阐明抑制性受体CTLA-4在性别特异性免疫反应质量中的作用。
2006年至2010年期间，在德国柏林的德国风湿病研究中心（DRFZ），我们对常用于多发性硬化症（MS）动物模型实验性自身免疫性脑脊髓炎研究的小鼠品系进行了测试。SJL小鼠品系不仅模拟MS发病机制，还表现出MS患者中出现的女性优势。
与雄性SJL小鼠相比，雌性SJL小鼠来源的细胞增殖增加，T辅助（Th）1样和Th2样细胞因子频率翻倍。此外，与雌性小鼠（46%）相比，雄性小鼠活化的Th细胞在细胞表面表达CTLA-4的频率显著更高（61%）。因此添加雌激素后，两性细胞中CTLA-4表达均降低了近50%。我们观察到，在中性条件下培养的CD4(+) T细胞中，雌性产生干扰素（IFN）-γ高表达的频率更高（雌性为24.6%，雄性为15.9%）。此外还观察到，IFN-γ高表达者主要存在于雌性小鼠中（4.5%，雄性为0.4%）。
我们的结果表明，诱导CTLA-4表达可作为一种免疫调节策略的靶点，以下调性别差异自身免疫性疾病中的免疫反应。
