Campylobacter jejuni Mediated Autoimmune Neuropathy in Hu-microbiota Mouse Model

在世界范围内，由空肠弯曲杆菌引起的食源性疾病的发病率仍然很高。胃肠道（Gl）感染空肠梭菌可引起严重的疾病后遗症。急性神经病变格林-巴利综合征（GBS）和米勒-费雪综合征（MFS）是与近期Campy/o/jacter感染相关的自身免疫性疾病。GBS是世界上导致急性神经肌肉麻痹的主要原因。5%的GBS患者死亡；15-20%的人留下终身残疾。我们的长期目标是了解C.ye/un/感染引发自身免疫的机制。我们这个提案的短期目标是

The incidence of foodborne disease due to Campylobacter jejuni remains very high woridwide. Serious disease sequelae can follow gastrointestinal (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 initiation of autoimmunity. Early work by our group showed that autoantibodies and neurological disease develop spontaneously in Non-Obese Diabetic (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 antibodies 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 potential to improve these murine models. Our overall hypothesis is that murine model(s) with a "humanized" microbiome develop spontaneous autoimmune sequelae secondary to C. jejuni infection 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 ""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.