Targeting complement system to treat myasthenia gravis

Huda, Ruksana; Tüzün, Erdem; Christadoss, Premkumar

doi:10.1515/revneuro-2014-0021

Cited by 25 publications

(17 citation statements)

References 51 publications

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“…C5a acts as an anaphylatoxin, playing a critical role in enhancement of inflammation, 33 whereas C5b binds to complement components C6, C7, C8, and C9 to form the membrane attack complex ring. 34 Therapeutic blockage of C5 cleavage has been shown to rescue pathological states characterized by sterile tissue inflammation, such as myasthenia gravis 35 and inflammatory myopathies. 36 Furthermore, it has been shown that specific inhibition of C5a, while sparing C5b, with the Spiegelmer NOX-D20, of which NOX-D21 is a follow-up compound, was enough to improve the phenotype of a murine model of sepsis.…”

Section: Impact Of Inhibition Of C5a On MDX Musclementioning

confidence: 99%

Low-Intensity Training and the C5a Complement Antagonist NOX-D21 Rescue the mdx Phenotype through Modulation of Inflammation

Hyzewicz

Tanihata

Kuraoka

et al. 2017

The American Journal of Pathology

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Inflammatory events occurring in dystrophic muscles contribute to the progression of Duchenne muscular dystrophy (DMD). Low-intensity training (LIT) attenuates the phenotype of mdx mice, an animal model for DMD. Therefore, we postulated that LIT could have anti-inflammatory properties. We assessed levels of inflammatory cytokines and infiltrated immune cells in gastrocnemius muscle of mdx mice after LIT. We detected high levels of complement component C5a, chemokine ligand (CCL) 2, CD68 monocytes/macrophages, and proinflammatory M1 macrophages in muscles of mdx mice. LIT decreased CCL2 levels, increased CD68 cell numbers, and shifted the macrophage population to the regenerative M2 type. We investigated whether inhibition of C5a or CCL2 with L-aptamers could mimic the effects of LIT. Although no effect of CCL2 inhibition was detected, treatment with the C5a inhibitor, NOX-D21, rescued the phenotype of nonexercised mdx mice, but not of exercised ones. In both cases, the level of CD68 cells increased and macrophage populations leaned toward the inflammatory M1 type. In muscles of nonexercised treated mice, the level of IL-1 receptor antagonist increased, damage decreased, and fibers were switched toward the glycolytic fast type; in muscles of exercised mice, fibers were switched to the oxidative slow type. These results reveal the effects of LIT on the inflammatory status of mdx mice and suggest that NOX-D21 could be an anti-inflammatory drug for DMD.

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Section: Impact Of Inhibition Of C5a On MDX Musclementioning

confidence: 99%

Low-Intensity Training and the C5a Complement Antagonist NOX-D21 Rescue the mdx Phenotype through Modulation of Inflammation

Hyzewicz

Tanihata

Kuraoka

et al. 2017

The American Journal of Pathology

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“…Muscle weakness and fatigue in autoimmune myasthenia gravis (MG) is caused by decreased activation of postsynaptic muscle AChR by ACh, due to antibody- and complement-mediated AChR destruction (Ha and Richman, 2015; Huda et al, 2014). A mouse model of experimental autoimmune MG (EAMG), which mimics MG, is induced by immunizing mice 2–3 times with Torpedo AChR in CFA (Christadoss et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

IgG1 deficiency exacerbates experimental autoimmune myasthenia gravis in BALB/c mice

Huda

Strait

Tüzün

et al. 2015

Journal of Neuroimmunology

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Myasthenia gravis is an autoimmune disease characterized by muscle weakness due to neuromuscular junction (NMJ) damage by anti-acetylcholine receptor (AChR) auto-antibodies and complement. In experimental autoimmune myasthenia gravis (EAMG), which is induced by immunization with Torpedo AChR in CFA, anti-AChR IgG2b and IgG1 are the predominant isotypes in the circulation. Complement activation by isotypes such as IgG2b plays a crucial role in EAMG pathogenesis; this suggested the possibility that IgG1, which does not activate complement through the classical pathway, may suppress EAMG. In this study, we show that AChR-immunized BALB/c mice genetically deficient for IgG1 produce higher levels of complement-activating isotypes of anti-AChR, especially IgG3 and IgG2a, and develop increased IgG3/IgG2a deposits at the NMJ, as compared to wild type (WT) BALB/c mice. Consistent with this, AChR-immunized IgG1−/− BALB/c mice lose muscle strength and muscle AChR to a greater extent than AChR-immunized WT mice. These observations demonstrate that IgG1 deficiency leads to increased severity of EAMG associated with an increase in complement activating IgG isotypes. Further studies are needed to dissect the specific role or mechanism of IgG1 in limiting EAMG and that of EAMG exacerbating role of complement activating IgG3 and IgG2a in IgG1 deficiency.

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“…Binding of anti-AChR autoantibodies with AChR in the membrane reduces the availability of the functional receptor to ACh, either by blocking the receptor or leading to its internalization. Subsequent activation of complement cascades by the autoantibody leading to the formation of a "membrane attack complex", also lyses myocytes (15,16). Both MuSK and LRP autoantibodies can disperse postsynaptic AChR clusters and thereby cause AChR deficiency and muscle fatigue (17).…”

Section: Rationale For Mg Therapies Targeting B Cellsmentioning

confidence: 99%

New Approaches to Targeting B Cells for Myasthenia Gravis Therapy

Huda

2020

Front. Immunol.

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Current therapies for myasthenia gravis (MG) are limited, and many investigations have recently focused on target-specific therapies. B cell-targeting monoclonal antibody (mAb) therapies for MG are increasingly attractive due to their specificity and efficacy. The targeted B cell biomarkers are mainly the cluster of differentiation (CD) proteins that mediate maturation, differentiation, or survival of pathogenic B cells. Additional B cell-directed therapies include non-specific peptide inhibitors that preferentially target specific B cell subsets. The primary goals of such therapies are to intercept autoantibodies and prevent the generation of an inflammatory response that contributes to the pathogenesis of MG. Treatment of patients with MG using B cell-directed mAbs, antibody fragments, or selective inhibitors have exhibited moderate to high efficacy in early studies, and some of these therapies appear to be highly promising for further drug development. Numerous other biologics targeting various B cell surface molecules have been approved for the treatment of other conditions or are either in clinical trials or preclinical development stages. These approaches remain to be tested in patients with MG or animal models of the disease. This review article provides an overview of B cell-targeted treatments for MG, including those already available and those still in preclinical and clinical development. We also discuss the potential benefits as well as the shortcomings of these approaches to development of new therapies for MG and future directions in the field.

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Targeting complement system to treat myasthenia gravis

Cited by 25 publications

References 51 publications

Low-Intensity Training and the C5a Complement Antagonist NOX-D21 Rescue the mdx Phenotype through Modulation of Inflammation

Low-Intensity Training and the C5a Complement Antagonist NOX-D21 Rescue the mdx Phenotype through Modulation of Inflammation

IgG1 deficiency exacerbates experimental autoimmune myasthenia gravis in BALB/c mice

New Approaches to Targeting B Cells for Myasthenia Gravis Therapy

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