Identifying the culprits in neurological autoimmune diseases

Abstract

The target organ of neurological autoimmune diseases (NADs) is the central or peripheral nervous system. Multiple sclerosis (MS) is the most common NAD, whereas Guillain-Barré syndrome (GBS), myasthenia gravis (MG), and neuromyelitis optica (NMO) are less common NADs, but the incidence of these diseases has increased exponentially in the last few years. The identification of a specific culprit in NADs is challenging since a myriad of triggering factors interplay with each other to cause an autoimmune response. Among the factors that have been associated with NADs are genetic susceptibility, epigenetic mechanisms, and environmental factors such as infection, microbiota, vitamins, etc. This review focuses on the most studied culprits as well as the mechanisms used by these to trigger NADs.

Keywords: Environmental factors; Epigenetic; Infection; Microbiota; Neurological autoimmune diseases; Vitamins.

Graphical abstract

Fig. 1

Effects of environmental factors on the development of NADs. During infectious processes, virus and/or bacteria capable of disrupting the BBB, produce an immune response that is perpetuated by the continuous production of cytokines and chemokines and thus constitute an inflammatory milieu. These infectious agents can induce an autoimmune response through several mechanisms such as molecular mimicry and bystander activation which lead to demyelination. Vitamin D3 appears to regulate the inflammatory response induced by infectious agents by increasing Treg and reducing Th17 cells. APC: antigen-presenting cell, CNS: central nervous system, IFN: interferon, IL: interleukin, MHC: major histocompatibility complex, TCR: T cell receptor, Th: T helper cells, TNF: tumor necrosis factor, Tr: Type of regulatory T cells, Treg: regulatory T cells, VDR: vitamin D receptor.

Fig. 2

Gut microbiota dysbiosis in NADs. The interaction between gut and brain is bidirectional mainly through the vagus nerve and neurotransmitters. Under healthy conditions, the microbiota control the maturation and activation of the immune system, but an imbalance in its relative abundance can be associated with the risk of NADs. Neurological alterations include increased BBB permeability, neuroinflammation, and destruction of myelin in the nervous system. Disruption of homeostasis in gut microbiota leads to pro-inflammatory cytokine release, autoantibody production as well as an increase in DCs, B cells, Th1, and Th17 cells. However, it causes a reduction in Treg cells. BBB: blood brain barrier, NS: nervous system, DCs: dendritic cells, IL: interleukin, Th: T helper cells, Treg: regulatory T cells, IFN: interferon.

Fig. 3

Possible mechanisms underlying NADs due to smoking. Smoking can induce NADs mainly through two different pathways: 1. The reduction of IDO-1 enzymatic activity increases IL-6 and IL-13 production. 2. The upregulation of the renin-angiotensin system increases IL-17, IL-22, CCL2, CCL3, and CXCL10. Both pathways favor the increase in Th17 cells and the decrease in Treg cells. Oxidative stress favors the secretion of pro-inflammatory cytokines. The recruitment of inflammatory cells to the CNS and to the neuromuscular junction causes demyelination and the blockade of neuromuscular transmission. The epigenetic changes caused by smoking favor the development and progression of NADs. AhR: aryl hydrocarbon receptor, CCL: chemokine (C–C motif) ligand, CNS: central nervous system, CXCL10: C-X-C motif chemokine 10, DC: dendritic cell, DNA: desoxyribose nucleic acid, FoxP3: forkhead box P3, GRP15: G-proteinecoupled receptor 15 gene, IDO-1: indoleamine 2,3-dioxygenase 1, IL: interleukin, miRNA: microRNA, Treg: regulatory T cells.