Ablation of IL-17 expression moderates experimental autoimmune myasthenia gravis disease severity

Aguilo-Seara, Gabriela; Xie, Yanyan; Sheehan, Jarrod; Kusner, Linda L.; Kaminski, Henry J.

doi:10.1016/j.cyto.2017.05.008

Cited by 23 publications

(20 citation statements)

References 26 publications

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“…Excessive activation and/or altered differentiation of specific CD4 + T cell subsets may lead to the development of variable immune-based disorders, depending on the type of CD4 + T cell population involved. Excessive Th1 and Th17 responses have been shown to be involved in the development of MG and EAMG ( 32 – 37 ). Consistent with these findings, we observed that the enhanced susceptibility of Vav1 R63W KI mice to EAMG was associated with an increased frequency of autoreactive CD4 + T cells producing Th1 and Th17 cytokines.…”

Section: Discussionmentioning

confidence: 99%

A Natural Variant of the Signaling Molecule Vav1 Enhances Susceptibility to Myasthenia Gravis and Influences the T Cell Receptor Repertoire

et al. 2018

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The guanine nucleotide exchange factor Vav1 is essential for transducing T cell receptor (TCR) signals and plays an important role in T cell development and activation. Previous genetic studies identified a natural variant of Vav1 characterized by the substitution of an arginine (R) residue by a tryptophane (W) at position 63 (Vav1R63W). This variant impacts Vav1 adaptor functions and controls susceptibility to T cell-mediated neuroinflammation. To assess the implication of this Vav1 variant on the susceptibility to antibody-mediated diseases, we used the animal model of myasthenia gravis, experimental autoimmune myasthenia gravis (EAMG). To this end, we generated a knock-in (KI) mouse model bearing a R to W substitution in the Vav1 gene (Vav1R63W) and immunized it with either torpedo acetylcholine receptor (tAChR) or the α146-162 immunodominant peptide. We observed that the Vav1R63W conferred increased susceptibility to EAMG, revealed by a higher AChR loss together with an increased production of effector cytokines (IFN-γ, IL-17A, GM-CSF) by antigen-specific CD4+ T cells, as well as an increased frequency of antigen-specific CD4+ T cells. This correlated with the emergence of a dominant antigen-specific T cell clone in KI mice that was not present in wild-type mice, suggesting an impact on thymic selection and/or a different clonal selection threshold following antigen encounter. Our results highlight the key role of Vav1 in the pathophysiology of EAMG and this was associated with an impact on the TCR repertoire of AChR reactive T lymphocytes.

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Section: Discussionmentioning

confidence: 99%

A Natural Variant of the Signaling Molecule Vav1 Enhances Susceptibility to Myasthenia Gravis and Influences the T Cell Receptor Repertoire

et al. 2018

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“…A247), and all experimental outcomes are reported using the quality assurance guidelines set by the National Institute of Neurological Disorders and Stroke. Using methods previously described for EAMG induction (14), 27 female C57BL/6J mice were injected with Torpedo AChR (tAChR) in CFA (catalog no. F5881; Sigma-Aldrich) on day 0 and were boosted with tAChR in IFA (catalog no.…”

Section: Eamg Induction and Treatmentmentioning

confidence: 99%

The Presence of Survivin on B Cells from Myasthenia Gravis Patients and the Potential of an Antibody to a Modified Survivin Peptide to Alleviate Weakness in an Animal Model

Zhang

Ciesielski

Fenstermaker

et al. 2020

The Journal of Immunology

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Myasthenia gravis (MG) is an autoimmune disease in which Abs target neuromuscular junction proteins, in particular the acetylcholine receptor. We previously identified the antiapoptotic protein survivin in the autoreactive B cells and plasma cells of MG patients. To further define the role of survivin in MG, we have assessed PBMCs from 29 patients with MG and 15 controls. We confirmed the increased expression of survivin in CD20 + lymphocytes from MG patients compared with controls. Furthermore, the CD20 + population of cells from MG patients contained a higher percentage of extracellular survivin compared with controls. The analysis of CD4 + cells showed an increased percentage of intracellular survivin in MG patients compared with controls, whereas the extracellular survivin CD4 + percentage was unaffected. In an experimental mouse model of MG, we assessed the therapeutic potential of an Ab raised to a modified survivin peptide but cross-reactive to survivin. Ab treatment reduced disease severity, lowered acetylcholine receptor-specific Abs, and decreased CD19 + survivin + splenocytes. The ability to target survivin through Ab recognition of autoreactive cells offers the potential for a highly specific therapeutic agent for MG.

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“…EAMG studies with knockout (KO) mice have shown that cytokines related to the T H 17 pathway play critical roles in the development of EAMG. For instance, IL‐6 and IL‐17 gene KO mice present a lower EAMG incidence and less severe clinical symptoms than their respective wild‐type (WT) mice . Additionally, in both models, there is a reduction of the level of the anti‐AChR antibodies, especially the IgG 2 b isotype, and a decreased GC area in the spleen of EAMG KO mice compared with controls .…”

Section: Cytokines Related To Th17 Cells and Experimental Autoimmune mentioning

confidence: 99%

“…For instance, IL‐6 and IL‐17 gene KO mice present a lower EAMG incidence and less severe clinical symptoms than their respective wild‐type (WT) mice . Additionally, in both models, there is a reduction of the level of the anti‐AChR antibodies, especially the IgG 2 b isotype, and a decreased GC area in the spleen of EAMG KO mice compared with controls . Moreover, in vitro analyses showed decreased production of IFN‐γ in AChR‐stimulated lymphocytes from Il6 –/– mice but not from IL‐17–deficient ( Il17a –/– ) mice, suggesting that IL‐6 may have a wider impact on the inflammatory process than IL‐17.…”

Section: Cytokines Related To Th17 Cells and Experimental Autoimmune mentioning

confidence: 99%

An imbalance between regulatory T cells and T helper 17 cells in acetylcholine receptor–positive myasthenia gravis patients

Villegas

Wassenhove

Panse

et al. 2018

Annals of the New York Academy of Sciences

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A chronic autoimmune disease, myasthenia gravis (MG) is characterized in 85% of patients by antibodies directed against the acetylcholine receptor (AChR) located at the neuromuscular junction. The functional and effective balance between regulatory T cells (T cells) and effector T cells (T cells) is lost in the hyperplastic thymus of MG patients with antibodies specific for the AChR (AChR MG patients). The objective of this review is to describe how T cells and inflammatory T cells participate in this imbalance and contribute to induce a chronic inflammatory state in the MG thymus. We discuss the origins and characteristics of T cells and their reported dysfunctions in AChR MG patients. We also review the inflammatory condition observed in MG thymus, including overexpression of interleukin (IL)-1β, IL-6, and IL-23, cytokines that promote the differentiation of T helper 17 (T 17) cells and the expression of IL-17. We summarize the preclinical models used to determine the implication of expression of cytokines, such as IL-6, IL-12 (IL-23 subunit), IL-17, and interferon γ to the development of experimental autoimmune MG. Finally, we suggest that biological agents, such as humanized monoclonal antibodies that target the IL-23/T 17 pathway, should be investigated in the context of MG, as they have proven efficiency in other autoimmune diseases.

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Ablation of IL-17 expression moderates experimental autoimmune myasthenia gravis disease severity

Cited by 23 publications

References 26 publications

A Natural Variant of the Signaling Molecule Vav1 Enhances Susceptibility to Myasthenia Gravis and Influences the T Cell Receptor Repertoire

A Natural Variant of the Signaling Molecule Vav1 Enhances Susceptibility to Myasthenia Gravis and Influences the T Cell Receptor Repertoire

The Presence of Survivin on B Cells from Myasthenia Gravis Patients and the Potential of an Antibody to a Modified Survivin Peptide to Alleviate Weakness in an Animal Model

An imbalance between regulatory T cells and T helper 17 cells in acetylcholine receptor–positive myasthenia gravis patients

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