Abstract
Antibody-induced complement activation may cause injury of the neuromuscular junction (NMJ) and is thus considered as a primary pathogenic factor in human myasthenia gravis (MG) and animal models of experimental autoimmune myasthenia gravis (EAMG). In this study, we tested whether CRIg/FH, a targeted complement inhibitor, could attenuate NMJ injury in rat MG models. We first demonstrated that CRIg/FH could inhibit complement-dependent cytotoxicity on human rhabdomyosarcoma TE671 cells induced by MG patient-derived IgG in vitro. Furthermore, we investigated the therapeutic effect of CRIg/FH in a passive and an active EAMG rodent model. In both models, administration of CRIg/FH could significantly reduce the complement-mediated end-plate damage and suppress the development of EAMG. In the active EAMG model, we also found that CRIg/FH treatment remarkably reduced the serum concentration of autoantibodies and of the cytokines including IFN-γ, IL-2, IL-6, and IL-17, and upregulated the percentage of Treg cells in the spleen, which was further verified in vitro. Therefore, our findings indicate that CRIg/FH may hold the potential for the treatment of MG via immune modulation.
Highlights
The complement system is a major component of innate immunity and plays a crucial role in the pathogenesis of several inflammatory and autoimmune diseases [1]
We examined the ability of Complement receptor of the immunoglobulin superfamily (CRIg)/factor H (FH) to inhibit complement activation induced by MG patient serum IgG in vitro, evaluated the in vivo therapeutic effect of CRIg/FH in both passive transfer myasthenia gravis (PTMG) and active experimental autoimmune myasthenia gravis (EAMG) models, and investigated possible humoral and cellular mechanisms involved in this effect
We further explored the protective effect of CRIg/FH on TE671 cells by detecting MAC deposition on the cell membrane using Immunocytochemistry assay stained by C5b-9n antibody after incubation with the gMG patient-derived IgG and normal human sera
Summary
The complement system is a major component of innate immunity and plays a crucial role in the pathogenesis of several inflammatory and autoimmune diseases [1]. The complement cascade is composed of more than 30 soluble and membrane-bound proteins, which could be initiated through three pathways, i.e., classical pathway (CP), alternative pathway (AP), and lectin pathway (LP) [2]. Complement receptor of the immunoglobulin superfamily (CRIg) is exclusively expressed on tissue-resident macrophages and binds to C3b/iC3b/C3c to inhibit AP and mediate opsonophagocytosis [6, 7]. Based on their functions, a C3b/iC3b-targeted complement inhibitor, termed CRIg/ FH, is developed by linking the extracellular functional domains of CRIg with the inhibitory domain of FH SCR1-5 [8]. The therapeutic role of CRIg/FH has been verified in several inflammatory disorder models, including paroxysmal nocturnal hemoglobinuria (PNH) [8], mesangioproliferative glomerulonephritis [8], renal ischemia reperfusion injury [9], and lupus nephritis [10]
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