Immunologic Factors In Progressive Autoimmune Disease

描述（由申请人提供）：多发性硬化症（MS）可分为四种临床形式：复发-缓解（RR）、原发性进行性（PP）、继发性进行性（SP）和进行性复发（PR）。进展型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疾病模式的动物模型。利用髓鞘少突胶质细胞糖蛋白（MOG）92-106的致脑肽，我们在两株MHC相同的H-2s小鼠SJL/J和a.w中建立了模拟不同形式MS的动物模型。我们用（MOG）92-106诱导实验性过敏性脑脊髓炎（EAE），在存在或不存在补充百日咳博德tella （BP）的情况下。无论是否给药，SJL/J小鼠均出现RR-EAE。有趣的是，A.SW小鼠在没有BP的情况下发生PP-EAE，在补充BP的情况下发生SP-EAE。组织学上，SJL/J小鼠表现为轻度脱髓鞘疾病，伴广泛的T细胞浸润，而A.SW小鼠表现为大斑块样脱髓鞘病变，伴免疫球蛋白沉积和中性粒细胞浸润，伴极少的T细胞浸润。在无BP的A.SW小鼠中检测到高滴度血清抗mog抗体，抗mog抗体IgG2a/IgG1比值与小鼠存活时间相关。我们假设，在A.SW小鼠中，Th2反应有利于髓毒性抗体的产生，导致EAE的进行性形式和早期死亡，而SJL小鼠中的Th1反应有利于RR形式和更长的生存期。为了验证这一假设，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。第二个目的是确定IL-4是否与（MOG）92-106致敏的A.SW小鼠的辅助性T (Th) 2表型和进行性EAE有关。第三个目的是研究抗髓磷脂抗体在疾病进展中的作用和对病变形成的贡献。第四个也是最后一个目标将研究与进行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多发性硬化症患者从RR疾病到进展性疾病的转变。

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.