Immunologic Factors In Progressive Autoimmune Disease

描述(申请人提供)：多发性硬化症(MS)可分为四种临床类型：复发缓解(RR)、原发进展型(PP)、继发性进展型(SP)和进展型复发(PR)。进行性多发性硬化症的发病机制尚不清楚，部分原因是缺乏具有这些临床病型的动物模型。使用髓鞘少突胶质细胞糖蛋白(MOG)92-106的致脑肽，在两种MHC相合的H-2S小鼠SJL/J和A.Sw上建立了模拟不同形态MS的动物模型，在有或没有补充百日咳杆菌(BP)的情况下用(MOG)92-106诱导实验性变态反应性脑脊髓炎(EAE)。无论给药与否，SJL/J小鼠都会发生RR-EAE。有趣的是，A.sw小鼠发生了没有BP的PP-EAE和有BP补充的SP-EAE。组织学上，SJL/J小鼠出现轻度脱髓鞘疾病，伴有广泛的T细胞浸润，而A.SW小鼠出现大的斑块状脱髓鞘病变，伴有免疫球蛋白沉积和中性粒细胞浸润，与非常少量的T细胞浸润相关。在无BP的A.sw小鼠中，检测到高滴度的抗MOG抗体，且抗MOG IgG2a/IgG1比值与小鼠的生存时间相关。我们假设，在A.SW小鼠中，Th2反应有利于髓毒抗体的产生，导致进行性EAE形式的早期死亡，而在SJL小鼠中，Th1反应有利于存活时间更长的RR形式。为了验证这一假设，本文提出了四个具体目标。第一个目标是研究NK1.1+T细胞在进展性疾病中的作用。第二个目的将确定IL-4是否与(MOG)92-106致敏的A.SW小鼠中出现的辅助性T细胞(Th)2表型和进行性EAE有关。第三个目标是研究抗髓磷脂抗体在疾病进展和病变形成中的作用。第四个也是最后一个目标将研究与进展性疾病有关的其他因素，如环境和遗传因素。这些新模型可以帮助解释在MS患者中经常观察到的RR病向进展性疾病的转变。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) can be divided into four clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP) and progressive relapsing (PR). The pathogenesis of the progressive forms of MS remains unclear, partly due to the lack of animal models that have these clinical patterns of disease. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic the different forms of MS in two strains of MHC identical H-2s mice, SJL/J and A.SW. We induce experimental allergic encephalomyelitis (EAE) with (MOG)92-106 in the presence or absence of supplemental Bordetella pertussis (BP). SJL/J mice develop RR-EAE whether BP was administered or not. Interestingly, A.SW mice develop PP-EAE without BP and SP-EAE with BP supplementation. Histologically, SJL/J mice develop a mild demyelinating disease with extensive T cell infiltration, while A.SW mice develop large plaque-like demyelinating lesions with immunoglobulin deposition and neutrophil infiltration, associated with very minimal T cell infiltration. In A.SW mice without BP, high titer serum anti-MOG antibody is detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of the mice. We hypothesize that, in A.SW mice, a Th2 response favors the production of myelinotoxic antibodies, leading to progressive forms of EAE with early death, while a Th1 response in SJL mice favors a RR form with longer survival. To test this hypothesis, four specific aims are proposed. The first aim will study the role of NK1.1+ T cells in progressive disease. The second aim will determine whether IL-4 is responsible for the T helper (Th) 2 phenotype and progressive EAE seen in A.SW mice sensitized with (MOG)92-106. The third aim will be to investigate the role of anti-myelin antibodies in disease progression and contribution to lesion formation. The fourth and last aim will study other factors involved in progressive disease such as environmental and genetic contributions. These new models could help explain the transition from RR disease to progressive disease often observed in MS patients.