Editors' ChoiceAutoimmunity

TrIgGering inflammation in multiple sclerosis

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Science Translational Medicine  18 Nov 2020:
Vol. 12, Issue 570, eabf4691
DOI: 10.1126/scitranslmed.abf4691


Myelin-reactive IgG complexes enhance proinflammatory activation of microglia in multiple sclerosis.

Multiple sclerosis (MS) is a progressive and potentially debilitating autoimmune disease affecting the white matter of the central nervous system (CNS). The autoimmune response in MS, characterized primarily by T lymphocyte infiltration, attacks the myelin proteins surrounding nerve axons, disrupting the ability of neurons to communicate effectively. Microglia, CNS-resident phagocytic immune cells, are known to be important in regulating immune responses in the brain and spinal cord, homeostasis of the CNS, and synapse remodeling. In MS, microglial cells present autoantigens to autoreactive T lymphocytes and can produce inflammatory cytokines amplifying the pathogenic autoimmune response. The mechanism underlying this dysregulated activity has remained undefined. Oligoclonal immunoglobulin G (IgG) bands in cerebrospinal fluid are a diagnostic hallmark for MS, although their role in MS pathogenesis has also been unclear. Now, report by van der Poel et al. investigates the potential pathogenic role of IgG in MS and uncovers a possible mechanism for the induction of a proinflammatory environment in the CNS.

Using postmortem samples from patients with MS, the authors directly demonstrate the presence of IgG bound to myelin in CNS lesions. Importantly, IgG-myelin complexes potentiated in vitro stimulation of microglia isolated from MS-associated CNS lesions. This resulted in increased expression of genes such as TNF, IL1B, and IFNB, which produce known mediators of inflammatory damage in MS. Proinflammatory dysregulation by IgG-myelin complexes was dependent on IgG receptors FcγRI and FcγRIIa on microglial cells. Although the in vitro effects of IgG-myelin complexes demonstrated effects consistent with known proinflammatory mechanisms in MS, the presence of myelin-bound IgG was not universally found among MS lesion biopsy specimens. This may represent a limitation of the study or may reflect heterogeneity in the pathogenic processes underlying the breaking of immune tolerance in MS. However, these findings provide important insight into the role of the pathognomonic oligoclonal IgG observed in MS, indicating that these antibodies are not simply diagnostic but may have an important role in pathogenesis. This concept might open areas of investigation for inhibiting the autoimmune responses in MS and other CNS inflammatory diseases.

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