The enteric nervous system is a potential autoimmune target in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in young adults that has serious negative socioeconomic effects. In addition to symptoms caused by CNS pathology, the majority of MS patients frequently exhibit gastrointestinal dysfunction, which was previously either explained by the presence of spinal cord lesions or not directly linked to the autoimmune etiology of the disease. Here, we studied the enteric nervous system (ENS) in a B cell- and antibody-dependent mouse model of MS by immunohistochemistry and electron microscopy at different stages of the disease. ENS degeneration was evident prior to the development of CNS lesions and the onset of neurological deficits in mice. The pathology was antibody mediated and caused a significant decrease in gastrointestinal motility, which was associated with ENS gliosis and neuronal loss. We identified autoantibodies against four potential target antigens derived from enteric glia and/or neurons by immunoprecipitation and mass spectrometry. Antibodies against three of the target antigens were also present in the plasma of MS patients as confirmed by ELISA. The analysis of human colon resectates provided evidence of gliosis and ENS degeneration in MS patients compared to non-MS controls. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and ENS pathology in MS, which might provide a paradigm shift in our current understanding of the immunopathogenesis of the disease with broad diagnostic and therapeutic implications.

High prevalence and functional effects of serum antineuronal antibodies in patients with gastrointestinal disorders

“…Also, organ bath functional assays with IgG from patients with systemic sclerosis and Sjögren's syndrome demonstrated an inhibitory antibody effect on M3‐muscarinic receptor agonist‐evoked colonic smooth muscle contraction . A recent study discussed the role of anti‐ENS antibodies in patients with multiple sclerosis, possibly linking GI dysfunction with antibody‐mediated ENS degeneration …”

Bowel symptoms predate the diagnosis among many patients with multiple sclerosis: A 14‐year cohort study

“…Additionally, recent work in animal models of MS has demonstrated that the enteric nervous system (ENS), where myelination is minimal, may be a target of autoimmunity in MS. Notably, ENS degeneration occurred in murine models prior to central nervous system (CNS) plaque formation, the pathophysiologic and radiologic hallmark of MS . Moreover, objective GI alterations were observed throughout the gut in animal models without any CNS spinal cord involvement, suggesting ENS dysfunction as the cause .…”

“…The interplay between the gut and the central nervous system and its role with other neurodegenerative diseases has been re- Additionally, recent work in animal models of MS has demonstrated that the enteric nervous system (ENS), where myelination is minimal, may be a target of autoimmunity in MS. Notably, ENS degeneration occurred in murine models prior to central nervous system (CNS) plaque formation, the pathophysiologic and radiologic hallmark of MS. 27 Moreover, objective GI alterations were observed throughout the gut in animal models without any CNS spinal cord involvement, suggesting ENS dysfunction as the cause. 27,28 Such a connection between early ENS dysfunction and subsequent development of MS may reflect the increasingly recognized interplay between gut microbiota, permeability of the GI tract, and the enteric neuro-inflammatory pathway.…”

“…Notably, ENS degeneration occurred in murine models prior to central nervous system (CNS) plaque formation, the pathophysiologic and radiologic hallmark of MS. 27 Moreover, objective GI alterations were observed throughout the gut in animal models without any CNS spinal cord involvement, suggesting ENS dysfunction as the cause. 27,28 Such a connection between early ENS dysfunction and subsequent development of MS may reflect the increasingly recognized interplay between gut microbiota, permeability of the GI tract, and the enteric neuro-inflammatory pathway. 23 in this cohort, our findings nevertheless posit a role for bowel complaints as an indication of future, more severe CNS dysfunction more typical of MS.…”

The enteric nervous system: “A little brain in the gut”

“…GI pathologies were previously thought to be primarily explained by spinal cord lesions causing dysfunction of the autonomous nervous system. However, recently it has been suggested that the autoimmune process, which attacks the CNS, directly affects the ENS (Wunsch et al, 2017). In a mouse model of MS called experimental autoimmune encephalomyelitis (EAE), macrophages and T-and B-lymphocytes were observed in the myenteric plexus of the gut, even in the preclinical state.…”