Pathogenic T cell cytokines in multiple sclerosis

Wagner, Catriona A.; Roqué, Pamela J.; Goverman, Joan

doi:10.1084/jem.20190460

Cited by 73 publications

(64 citation statements)

References 134 publications

(175 reference statements)

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“…Although Th17 cells are dispensable for disease initiation, they either promote progression or increase severity of many autoimmune diseases (39,40). As in EAE, Th17 lymphocytes secrete various cytokines that are critical to permeabilize the BBB (41) and permit antibody entry in postinfectious BGE (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis

Platt

Bolding

Wayne

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group AStreptococcus(GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood–brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB). Whether these pathologies induce functional olfactory deficits, and the mechanistic role of Th17 lymphocytes, is unknown. Here, we demonstrate that, whereas loss of excitatory synapses in the OB is transient after multiple GAS infections, functional deficits in odor processing persist. Moreover, mice lacking Th17 lymphocytes have reduced BBB leakage, microglial activation, and antibody infiltration into the CNS, and have their olfactory function partially restored. Th17 lymphocytes are therefore critical for selective CNS entry of autoantibodies, microglial activation, and neural circuit impairment during postinfectious BGE.

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Section: Discussionmentioning

confidence: 99%

Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis

Platt

Bolding

Wayne

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…This is indicated, among other evidence, by the fact that mice lacking GM-CSF are resistant to the development of autoimmune inflammatory diseases, including experimental autoimmune encephalomyelitis (EAE), myocarditis, and collagen-induced arthritis (2)(3)(4)(5). IFN-g and IL-17 are also among the cytokines that can negatively affect MS disease or its animal model, EAE (1,6). For instance, the percentage of IL-17-producing T H 17 cells was expanded in MS patients and was shown to change with disease activity, increasing in patients with clinical exacerbation (7).…”

Section: Introductionmentioning

confidence: 99%

Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes

et al. 2020

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IFN-β treatment is a commonly used therapy for relapsing-remitting multiple sclerosis (MS), while vitamin D deficiency correlates with an increased risk of MS and/or its activity. MS is a demyelinating chronic inflammatory disease of the central nervous system, in which activated T lymphocytes play a major role, and may represent direct targets of IFN-β and vitamin D activities. However, the underlying mechanism of action of vitamin D and IFN-β, alone or in combination, remains incompletely understood, especially when considering their direct effects on the ability of T lymphocytes to produce inflammatory cytokines. We profiled the expression of immune-related genes and microRNAs in primary human T lymphocytes in response to vitamin D and IFN-β, and we dissected the impact of these treatments on cytokine production and T cell proliferation. We found that the treatments influenced primarily memory T cell plasticity, rather than polarization toward a stable phenotype. Moreover, our data revealed extensive reprogramming of the transcriptional output of primary T cells in response to vitamin D and IFN-β and provide the bases for further mechanistic insights into these commonly used treatments.

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“…Indeed, CD4 + T cells are enriched in lesions of MS patients and EAE studies further revealed two pathogenic T helper subsets important for disease: interferon gamma (IFN-γ)-producing type 1 T helper (T H 1) cells and IL-17 producing type 17 T helper (T H 17) cells (36). In line with this assertion, both IFN-γ and IL-17 are detected in the lesions of MS patients (37). IFN-γ also positively correlates with increased disease activity and increased disability (38).…”

Section: Ms Pathogenesis Cd4 + T Cells In Msmentioning

confidence: 81%

Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?

2020

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While the contribution of autoreactive CD4+ T cells to the pathogenesis of Multiple Sclerosis (MS) is widely accepted, the advent of B cell-depleting monoclonal antibody (mAb) therapies has shed new light on the complex cellular mechanisms underlying MS pathogenesis. Evidence supports the involvement of B cells in both antibody-dependent and -independent capacities. T cell-dependent B cell responses originate and take shape in germinal centers (GCs), specialized microenvironments that regulate B cell activation and subsequent differentiation into antibody-secreting cells (ASCs) or memory B cells, a process for which CD4+ T cells, namely follicular T helper (TFH) cells, are indispensable. ASCs carry out their effector function primarily via secreted Ig but also through the secretion of both pro- and anti-inflammatory cytokines. Memory B cells, in addition to being capable of rapidly differentiating into ASCs, can function as potent antigen-presenting cells (APCs) to cognate memory CD4+ T cells. Aberrant B cell responses are prevented, at least in part, by follicular regulatory T (TFR) cells, which are key suppressors of GC-derived autoreactive B cell responses through the expression of inhibitory receptors and cytokines, such as CTLA4 and IL-10, respectively. Therefore, GCs represent a critical site of peripheral B cell tolerance, and their dysregulation has been implicated in the pathogenesis of several autoimmune diseases. In MS patients, the presence of GC-like leptomeningeal ectopic lymphoid follicles (eLFs) has prompted their investigation as potential sources of pathogenic B and T cell responses. This hypothesis is supported by elevated levels of CXCL13 and circulating TFH cells in the cerebrospinal fluid (CSF) of MS patients, both of which are required to initiate and maintain GC reactions. Additionally, eLFs in post-mortem MS patient samples are notably devoid of TFR cells. The ability of GCs to generate and perpetuate, but also regulate autoreactive B and T cell responses driving MS pathology makes them an attractive target for therapeutic intervention. In this review, we will summarize the evidence from both humans and animal models supporting B cells as drivers of MS, the role of GC-like eLFs in the pathogenesis of MS, and mechanisms controlling GC-derived autoreactive B cell responses in MS.

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Pathogenic T cell cytokines in multiple sclerosis

Cited by 73 publications

References 134 publications

Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis

Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis

Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes

Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?

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