Lysosomes lose cations to balance the influx of protons as the organelle acidifies.

Introduction IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP. Methods 1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department. Results IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected. All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP. CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies). Conclusions Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.

No abstract

SignificanceCD8+ T lymphocytes, which are typically devoted to eliminate malignant and infected cells, have been described in the central nervous system (CNS) of patients and mice with amyotrophic lateral sclerosis (ALS). However, their role in ALS pathogenesis has yet to be unraveled. Here, we show that ablation of CD8+ T cells in ALS mice increased the number of surviving motoneurons. CD8+ T cells expressing the ALS-causing superoxide dismutase-1 mutant protein recognize and selectively kill motoneurons in vitro. To exert their cytotoxic function, mutant CD8+ T cells required presentation of the antigen-MHC-I complex at the surface of the motoneurons. Analysis of T cell receptor diversity supports the evidence that self-reactive CD8+ T lymphocytes infiltrate the CNS of ALS mice to exert cytotoxic function.