Maier Lisa M, Anderson David E, Severson Christopher A, Baecher-Allan Clare, Healy Brian, Liu David V, Wittrup K Dane, De Jager Philip L, Hafler David A
Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2009 Feb 1;182(3):1541-7. doi: 10.4049/jimmunol.182.3.1541.
Multiple sclerosis (MS) is an organ-specific autoimmune disorder that is in part genetically determined. The gene encoding the alpha-chain of the IL-2 receptor, IL2RA, harbors alleles associated with risk to MS and other autoimmune diseases. In addition, IL2RA genetic variants correlate with the levels of a soluble form of the IL-2 receptor in subjects with type 1 diabetes and multiple sclerosis. Here, we show that the IL2RA genotypes differentially affects soluble IL-2RA (sIL-2RA) levels in MS cases vs healthy controls; the two variants associated with MS (rs12722489 and rs2104286) account for 15 and 18% of the total variance in log(10)-transformed sIL-2RA concentration in control subjects but less so in subjects with MS (2 and 5%), suggesting that perturbations associated with disease or treatment may influence sIL-2RA levels in subjects with MS. Whereas analyses demonstrate that sIL-2RA serum concentrations are a remarkably stable phenotype in both healthy controls and untreated MS subjects, a difference is observed between benign and malignant MS. These data indicate that, in addition to specific allelic variants at IL2RA, immunological perturbations associated with aggressive forms of the disease can influence sIL-2RA levels in serum of MS subjects. We also demonstrate, functionally, that sIL-2RA can inhibit IL-2 signaling, yet enhance T cell proliferation and expansion. In summary, we propose that before disease onset, strong genetic factors associated with disease risk dictate sIL-2RA levels that may be further modulated with onset of chronic systemic inflammation associated with MS.
多发性硬化症（MS）是一种部分由基因决定的器官特异性自身免疫性疾病。编码白细胞介素-2受体α链的基因IL2RA含有与MS及其他自身免疫性疾病风险相关的等位基因。此外，IL2RA基因变异与1型糖尿病和多发性硬化症患者中可溶性白细胞介素-2受体的水平相关。在此，我们表明IL2RA基因型对MS患者与健康对照者的可溶性IL-2RA（sIL-2RA）水平有不同影响；与MS相关的两个变异体（rs12722489和rs2104286）在对照受试者中占对数（10）转换后的sIL-2RA浓度总方差的15%和18%，但在MS患者中占比则较小（分别为2%和5%），这表明与疾病或治疗相关的扰动可能会影响MS患者的sIL-2RA水平。虽然分析表明sIL-2RA血清浓度在健康对照者和未经治疗的MS患者中都是一种非常稳定的表型，但在良性和恶性MS之间观察到了差异。这些数据表明，除了IL2RA的特定等位基因变异外，与疾病侵袭形式相关的免疫扰动可影响MS患者血清中的sIL-2RA水平。我们还在功能上证明，sIL-2RA可抑制IL-2信号传导，但能增强T细胞增殖和扩增。总之，我们提出在疾病发作前，与疾病风险相关的强大遗传因素决定了sIL-2RA水平，而随着与MS相关的慢性全身炎症的发作，该水平可能会进一步受到调节。
