Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system afflicting nearly three million individuals worldwide. Neuroimmune interactions between glial, neural, and immune cells play important roles in MS pathology and offer potential targets for therapeutic intervention. Here, we review underlying risk factors, mechanisms of MS pathogenesis, available disease modifying therapies, and examine the value of emerging technologies, which may address unmet clinical needs and identify novel therapeutic targets.

Keywords: B cells; T cells; astrocytes; autoimmunity; glia; microglia; multiple sclerosis; neuroimmunology; progressive MS.

Figure 1.. Genetic and environmental factors that shape MS pathogenesis

(A) Genetic studies linked MS susceptibility to autosomal and X chromosome genes. HLA variants were shown to promote pathogenic cross-talk between B and T lymphocytes. Autosomal variations are comparatively understudied, but increasing evidence suggest their involvement in dysregulated lymphocyte and glial responses. The impact of X-linked gene variants remains to be determined. (B) The gut microbiome is altered in MS. Specific bacterial species have been shown to promote pathogenic T and B cell responses while limiting Tregs. (C) EBV infection has been postulated to be a trigger of CNS autoimmunity in MS by boosting the production of pathogenic factors by B cells, by increasing the APC function of B cells, and by triggering cross-reactive responses with CNS antigens by molecular mimicry. (D) MS-promoting responses of immune and glial cells are influenced by environmental factors (e.g., exposure to chemicals) and lifestyle choices (e.g., diet).

Figure 2.. Immune mechanisms and CNS invasion in MS

(A) APCs (DCs, macrophages, B cells) and T cells first interact in the periphery, leading to activation and dysregulation of peripheral immunity and the secretion of inflammatory molecules. (B) Peripheral immune cells invade the CNS through the BLMB, BCSFB, and BBB where they can interact with local APC subsets. (C) Impaired Treg suppressive activity contributes to MS pathogenesis.

Figure 3.. Cell-cell interactions in the CNS

(A) Mechanisms driving cortical pathology identified in pre-clinical models and clinical samples. Remyelination deficits have been linked to microglia-oligodendrocyte cross-talk mediated via a type I interferon response. Additional mechanisms linked to neuron dysfunction include long non-coding RNAs, mitochondrial and endoplasmic reticulum-associated signaling pathways, and synaptic pruning controlled by calcium signaling. (B) Mechanisms that mediate cross-talk among CNS-resident and CNS-recruited immune cells. C3 has been implicated in the microglial pruning of neuronal synapses (top-left). Astrocyte-produced chemokines promote the recruitment of pro-inflammatory CCR2⁺ monocytes via CCL2 (bottom-left). Ligand-receptor pairs implicated in the cross-talk among CNS-resident astrocytes and microglia promote regulatory or pro-inflammatory signals (top-right). Bidirectional modulation of astrocyte-T cell responses can boost or limit MS pathogenesis via epigenetic modifications, apoptosis, and pro-inflammatory cytokine signaling (bottom-right).