Campylobacter jejuni Mediated Autoimmune Neuropathy in Hu-microbiota Mouse Model

空肠弯曲菌引起的食源性疾病的发病率在世界范围内仍然很高。严重的疾病后遗症可以跟随胃肠（GI）感染C。空肠。急性神经病变格林巴利综合征（GBS）和米勒费舍尔综合征（MFS）是与近期Campy/o/jacter感染相关的自身免疫性疾病。格林-巴利综合征是世界上引起急性神经肌肉麻痹的主要原因。5%的GBS患者死亡; 15-20%的患者终身残疾。我们的长期目标是了解引发继发于C.ye/un/infection的自身免疫的机制。我们的短期目标是进一步发展GBS和MFS的小鼠模型，以了解特定的C。空肠菌株导致自身免疫性感染。我们小组的早期工作表明，自身抗体和神经系统疾病在非肥胖糖尿病（NOD）WT、NOD IL-10-/-和NOD B7-/-中自发发生。 2-1-小鼠经口感染C. GBS患者的空肠菌株。所有基因型的一些感染的小鼠具有针对神经节苷脂GDla和GMl的自身反应性IgGl抗体，并且显示出运动神经元功能障碍的神经学表型特征，伴有四肢松弛。C57 BL/6 IL-10-小鼠感染C.空肠MFS品系发展为神经系统疾病，伴有震颤和不对称后肢无力。用在区域1中验证的人粪便样品定殖的小鼠具有改善这些小鼠模型的潜力。我们的总体假设是具有“人源化”微生物组的鼠模型发展继发于C.空肠感染A类LOS菌株。我们的具体目标是：（1）明确描述与GBS和MFS相关的神经系统体征和疾病病变， 小鼠模型;（2）确定自身免疫后遗症是否随C.（3）研究补体在C. jejuni LOS中的作用。（4）确定先天性应答和适应性应答是否介导鼠模型中的GBS和MFS;（5）确定自身抗体或自身反应性T细胞是否将应答转移至幼稚小鼠;和（6）确定在存在和不存在空肠弯曲杆菌的三种病理型的情况下（Hu）微生物群对鼠宿主先天性、适应性和自身免疫应答的影响。这些模型可用于剖析自身免疫机制，并作为GBS和MFS患者的治疗和预防替代品。

The incidence of foodborne disease due to Campylobacter jejuni remains very high woridwide. Serious disease sequelae can follow gastrointesfinal (Gl) infections with C. jejuni. The acute neuropathies Guillain Barre Syndrome (GBS) and Miller Fisher Syndrome (MFS) are autoimmune conditions associated with recent Campy/o/jacter infection. GBS is the worid's leading cause of acute neuromuscular paralysis. 5% of GBS patients die; 15-20% are left with life-long disability. Our long-term goal is to understand the mechanisms that initiate autoimmunity secondary to C.ye/un/infection. Our short-term goal in this proposal is to further develop murine models of GBS and MFS to allow understanding of how infection with particular C. jejuni strains leads to inifiafion of autoimmunity. Eariy work by our group showed that autoantibodies and neurological disease develop spontaneously in Non-Obese Diabefic (NOD) WT, NOD IL-10-/- and NOD B7- 2-1- mice after oral infection with C. jejuni strains from GBS patients. Some infected mice of all genotypes had autoreactive IgGI anfibodies directed against gangliosides GDI a and GM1 and displayed a neurological phenotype characteristic of motor neuron dysfunction with flaccid limbs. C57BL/6 IL-IO''- mice infected with a C. jejuni MFS strain developed neurological disease with tremors and asymmetric hind limb weakness. Mice colonized with human fecal samples validated in Area 1 have the potenfial to improve these murine models. Our overall hvpothesis is that murine model(s) with a "humanized" microbiome develop spontaneous autoimmune sequelae secondary to C. jejuni infecfion with strains with class A LOS. Our Specific Aims are to: (1) Characterize definitively the neurological signs and disease lesions associated with GBS and MFS in murine models; (2) Determine whether autoimmune sequelae vary with C. jejuni LOS profiles and LOS genes; (3) Characterize the role of complement in C. ye/t/n/-induced MFS lesions; (4) Determine whether innate responses and adaptive responses mediate GBS and MFS in murine models; (5) Determine whether autoantibody or autoreactive T cells transfer the response to naive mice; and (6) Determine effects of (Hu) microbiota on murine host innate, adaptive and autoimmune responses in the presence and absence of three pathotypes of Campylobacter jejuni. These models can be used to dissect mechanisms of autoimmunity and to serve as treatment and prevention surrogates for GBS and MFS patients.