Programmed cell death and natural killer cells in multiple sclerosis: new potential therapeutic targets?

Multiple sclerosis (MS) is a chronic, severe and complex disease of still uncertain etiopathogenesis, with lesions in the cerebral white matter and spinal cord. The disease is heterogeneous, but is characterized by neuroinflammatory and neurodegenerative processes, usually associated with altered activation of the immune system following presumable stimulation by still unknown autoantigens. Several data confirm that MS is a systemic disease involving the central and peripheral nervous systems (Macchi et al., 2015). The role of adaptive immunity, sustained by T and B cells, in MS has been studied for decades. More recently, however, increasing attention has been paid to the role of innate immunity in MS progression. Our understanding of the molecular and cellular bases of the innate immune responses, showing heterogeneity of their genotypic and phenotypic features, has been improved in recent years. Non-cellular components of the innate response include cellular sensors of microbial components including pattern recognition receptors (PRRs), mediators of the intracellular signaling triggered by PRRs, cytokines, and other effector molecules. Signaling pathways of programmed cell death (PCD) play important roles in the innate response. In addition, cellular components of the innate response include innate lymphoid cells (ILCs) exerting natural killer (NK) activity and interferon (IFN)γ production, plasmacytoid dendritic cells involved in IFNγ production, and monocytes/macrophages. Innate response effectors have also been recently recognized to exhibit memory of previous responses, and related phenomena have been termed “trained immunity” (Quintin et al., 2014).