Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Over the past two decades, the development of targeted immunotherapeutics for relapsing-remitting multiple sclerosis has been successfully orchestrated through the efficacious modulation of neuroinflammatory outcomes demonstrated in the experimental autoimmune encephalomyelitis (EAE) model. In this model, the focus of developing immunomodulatory therapeutics has been demonstrated through their effectiveness in modifying the pro-inflammatory Th1 and Th17-dependent neuropathological outcomes of demyelination, oligodendrocytopathy and axonal dystrophy. However, recent successful preclinical and clinical trials have advocated for the significance of B cell-dependent immunopathogenic responses and has led to the development of novel biologicals that target specific B cell phenotypes. In this context, a new molecule, B-cell activating factor (BAFF), has emerged as a positive regulator of B cell survival and differentiation functioning through various signaling pathways and potentiating the activity of various receptor complexes through pleiotropic means. One possible cognate receptor for BAFF includes the Nogo receptor (NgR) and its homologs, previously established as potent inhibitors of axonal regeneration during central nervous system (CNS) injury and disease. In this review we provide current evidence for BAFF-dependent signaling through the NgR multimeric complex, elucidating their association within the CNS compartment and underlying the importance of these potential pathogenic molecular regulators as possible therapeutic targets to limit relapse rates and potentially MS progression.

Automated summary

Over the past two decades, targeted immunotherapeutics for relapsing-remitting multiple sclerosis have been developed based on the modulation of neuroinflammatory outcomes in the EAE model. Recent studies have highlighted the importance of B cell-dependent immunopathogenic responses and led to the development of novel biologicals targeting specific B cell phenotypes. The molecule B-cell activating factor (BAFF) acts as a positive regulator of B cell survival and differentiation, potentiating the activity of various receptor complexes. This review provides evidence for the association of BAFF-dependent signaling with the Nogo receptor (NgR) complex and highlights the potential therapeutic targets for limiting relapse rates and MS progression.