Starossom Sarah C, Veremeyko Tatyana, Yung Amanda W Y, Dukhinova Marina, Au Cheryl, Lau Alexander Y, Weiner Howard L, Ponomarev Eugene D
From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong.
Circ Res. 2015 Oct 9;117(9):779-92. doi: 10.1161/CIRCRESAHA.115.306847. Epub 2015 Aug 20.
Platelets are known to participate in vascular pathologies; however, their role in neuroinflammatory diseases, such as multiple sclerosis (MS), is unknown. Autoimmune CD4 T cells have been the main focus of studies of MS, although the factors that regulate T-cell differentiation toward pathogenic T helper-1/T helper-17 phenotypes are not completely understood.
We investigated the role of platelets in the modulation of CD4 T-cell functions in patients with MS and in mice with experimental autoimmune encephalitis, an animal model for MS.
We found that early in MS and experimental autoimmune encephalitis, platelets degranulated and produced soluble factors serotonin (5-hydroxytryptamine), platelet factor 4, and platelet-activating factor, which specifically stimulated differentiation of T cells toward pathogenic T helper-1, T helper-17, and interferon-γ/interleukin-17-producing CD4 T cells. At the later stages of MS and experimental autoimmune encephalitis, platelets became exhausted in their ability to produce proinflammatory factors and stimulate CD4 T cells but substantially increased their ability to form aggregates with CD4 T cells. Formation of platelet-CD4 T-cell aggregates involved the interaction of CD62P on activated platelets with adhesion molecule CD166 on activated CD4 T cells, contributing to downmodulation of CD4 T-cell activation, proliferation, and production of interferon-γ. Blocking of formation of platelet-CD4 T-cell aggregates during progression of experimental autoimmune encephalitis substantially enhanced proliferation of CD4 T cells in the central nervous system and the periphery leading to exacerbation of the disease.
Our study indicates differential roles for platelets in the regulation of functions of pathogenic CD4 T cells during initiation and progression of central nervous system autoimmune inflammation.
已知血小板参与血管病变；然而，它们在神经炎性疾病（如多发性硬化症，MS）中的作用尚不清楚。自身免疫性CD4 T细胞一直是MS研究的主要焦点，尽管调节T细胞向致病性辅助性T细胞1型/辅助性T细胞17表型分化的因素尚未完全明确。
我们研究了血小板在MS患者和实验性自身免疫性脑脊髓炎（一种MS动物模型）小鼠中对CD4 T细胞功能调节的作用。
我们发现，在MS和实验性自身免疫性脑脊髓炎早期，血小板脱颗粒并产生可溶性因子血清素（5-羟色胺）、血小板因子4和血小板活化因子，这些因子特异性刺激T细胞向致病性辅助性T细胞1型、辅助性T细胞17型以及产生干扰素-γ/白细胞介素-17的CD4 T细胞分化。在MS和实验性自身免疫性脑脊髓炎后期，血小板产生促炎因子并刺激CD4 T细胞的能力耗尽，但与CD4 T细胞形成聚集体的能力显著增强。血小板-CD4 T细胞聚集体的形成涉及活化血小板上的CD62P与活化CD4 T细胞上的黏附分子CD166之间的相互作用，导致CD4 T细胞活化、增殖和干扰素-γ产生的下调。在实验性自身免疫性脑脊髓炎进展过程中阻断血小板-CD4 T细胞聚集体的形成，可显著增强中枢神经系统和外周CD4 T细胞的增殖，导致疾病加重。
我们的研究表明，在中枢神经系统自身免疫性炎症的起始和进展过程中，血小板在调节致病性CD4 T细胞功能方面具有不同作用。
