Autoantibodies against glycine-associated synaptic proteins in stiff-person syndrome

Background and aims: Although interferon (IFN)-beta (β) is a firstline treatment in relapsing–remitting multiple sclerosis (RRMS), one-third of patients do not respond well to this therapy. A group of patients with multiple sclerosis (MS) have very high levels of serum Sema4A, and many of these patients are non-responders to IFN-β therapy. In this study, we investigated the association between Sema4A and IFN-β utilizing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We also investigated the effect of Sema4A on the efficacy of fingolimod for EAE. Methods: EAE was induced in C57BL/6 mice by immunization with MOG35–55 peptide emulsified in CFA followed by injection of pertussis toxin. The mice with EAE were divided into 4 groups as follows: 1. Control group, 2. IFN-β treated group, 3. Sema4A-Fc treated group, and 4. IFN-β and Sema4A-Fc treated group. CD4 T cells were purified from the draining lymph nodes in each group and restimulated with MOG35–55 peptide. Then, the production of cytokine was assessed by ELISA. We investigated the effect of Sema4A on T cell adhesion to endothelium. We also investigated whether fingolimod is effective for mice with EAE given Sema4A-Fc. Results: Although IFN-β alone was effective on EAE, mice treated with both IFN-β and Sema4A tended to exhibit more severe symptoms. The decreased production of IFN-gamma (γ) and IL-17 by CD4 T cells derived from IFN-β treated group was apparently up-regulated by the coadministered Sema4A. Sema4A increased adhesive activation of T cells to endothelial cells. The effect of fingolimod on EAE was not lost by the administration of Sema4A. Conclusions: Administration of Sema4A concurrently with IFN-β diminished the efficacy of IFN-β in EAE. These effects of Sema4A may be involved in the unresponsiveness of MS patients with high Sema4A levels to IFN-β treatment. By contrast, Sema4A did not abrogate the therapeutic effect of fingolimod in EAE. It is necessary to perform a prospective study to investigate the efficacy of fingolimod on MS patients with high Sema4A.