Neurofascin as a novel target for autoantibody-mediated axonal injury

Axonal injury is considered the major cause of disability in patients with multiple sclerosis (MS), but the underlying effector mechanisms are poorly understood. Starting with a proteomics-based approach, we identified neurofascin-specific autoantibodies in patients with MS. These autoantibodies recognize the native form of the extracellular domains of both neurofascin 186 (NF186), a neuronal protein concentrated in myelinated fibers at nodes of Ranvier, and NF155, the oligodendrocyte-specific isoform of neurofascin. Our in vitro studies with hippocampal slice cultures indicate that neurofascin antibodies inhibit axonal conduction in a complement-dependent manner. To evaluate whether circulating antineurofascin antibodies mediate a pathogenic effect in vivo, we cotransferred these antibodies with myelin oligodendrocyte glycoprotein–specific encephalitogenic T cells to mimic the inflammatory pathology of MS and breach the blood–brain barrier. In this animal model, antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation. Collectively, these results identify a novel mechanism of immune-mediated axonal injury that can contribute to axonal pathology in MS

Prevalence of tick-borne pathogens in Ixodes ricinus and Dermacentor reticulatus ticks from different geographical locations in Belarus.

Worldwide, ticks are important vectors of human and animal pathogens. Besides Lyme Borreliosis, a variety of other bacterial and protozoal tick-borne infections are of medical interest in Europe. In this study, 553 questing and feeding Ixodes ricinus (n = 327) and Dermacentor reticulatus ticks (n = 226) were analysed by PCR for Borrelia, Rickettsia, Anaplasma, Coxiella, Francisella and Babesia species. Overall, the pathogen prevalence in ticks was 30.6% for I. ricinus and 45.6% for D. reticulatus. The majority of infections were caused by members of the spotted-fever group rickettsiae (24.4%), 9.4% of ticks were positive for Borrelia burgdorferi sensu lato, with Borrelia afzelii being the most frequently detected species (40.4%). Pathogens with low prevalence rates in ticks were Anaplasma phagocytophilum (2.2%), Coxiella burnetii (0.9%), Francisella tularensis subspecies (0.7%), Bartonella henselae (0.7%), Babesia microti (0.5%) and Babesia venatorum (0.4%). On a regional level, hotspots of pathogens were identified for A. phagocytophilum (12.5-17.2%), F. tularensis ssp. (5.5%) and C. burnetii (9.1%), suggesting established zoonotic cycles of these pathogens at least at these sites. Our survey revealed a high burden of tick-borne pathogens in questing and feeding I. ricinus and D. reticulatus ticks collected in different regions in Belarus, indicating a potential risk for humans and animals. Identified hotspots of infected ticks should be included in future surveillance studies, especially when F. tularensis ssp. and C. burnetii are involved

Pathogen prevalence in questing and feeding ticks.

<p>I, Ixodes; D, Dermacentor; H, Host; V, Vegetation;-, not found; A, Anaplasma; Ba, Babesia; Bt, Bartonella;</p><p>B, Borrelia; s.l., sensu lato; C, Coxiella; F, Francisella; R, Rickettsia; RRG, Rickettsia rickettsii group.</p>*<p>Note that ticks with mixed infections are only counted once.</p

Coinfections in questing and feeding ticks.

<p>D, Dermacentor; I, Ixodes; F, Female; M, Male; C, Cattle; V, Vegetation; RRG, Rickettsia rickettsii group; s.s., sensu stricto; ssp., subspecies.</p

Administrative regions of Belarus showing the 32 collection sites and the total pathogen prevalence in ticks collected from each region.

<p>Administrative regions of Belarus showing the 32 collection sites and the total pathogen prevalence in ticks collected from each region.</p

Numbers of questing and feeding ticks collected in different regions of Belarus.

<p>I, Ixodes; D, Dermacentor; T, Total; F, Female; M, Male; N, Nymph; -, not found.</p

Pathogen diversity in questing I. ricinus and D. reticulatus ticks.

<p>I., Ixodes; D., Dermacentor; A., Anaplasma; B., Borrelia, Ba., Babesia; Bt., Bartonella; C., Coxiella; F., Francisella; R., Rickettsia; RRG, Rickettsia rickettsii group; s.s., sensu stricto; ssp., subspecies.</p