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

Huda, Ruksana; Strait, Richard T.; Tüzün, Erdem; Finkelman, Fred D.; Christadoss, Premkumar

doi:10.1016/j.jneuroim.2015.03.004

Cited by 11 publications

(7 citation statements)

References 26 publications

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“…In line with the above mentioned findings, it has recently been demonstrated that IgG1-deficient mice develop severe autoimmune conditions in different inflammatory autoimmune disease models ( 63 , 64 ) as well as enhanced antigen-dependent IgG3 IC depositions in the kidneys ( 37 ). The autoimmune models used in these studies ( 63 , 64 ), similar to other inflammatory autoimmune models, are apparently dependent on C1q and the complement activation as well as on classical FcγR-mediated immune cell activation ( 21 , 61 , 63 – 69 ). In future studies, it would be important to explore the inhibitory potential of murine IgG1 and its Fc glycosylation status in terms of the complement activation and FcγR-mediated regulation of effector cells using various models of autoimmunity and inflammation.…”

Section: Discussionsupporting

confidence: 71%

Potential of Murine IgG1 and Human IgG4 to Inhibit the Classical Complement and Fcγ Receptor Activation Pathways

et al. 2018

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IgG antibodies (Abs) mediate their effector functions through the interaction with Fcγ receptors (FcγRs) and the complement factors. The main IgG-mediated complement activation pathway is induced through the binding of complement C1q to IgG Abs. This interaction is dependent on antigen-dependent hexamer formation of human IgG1 and IgG3 to increase the affinity for the six-headed C1q molecule. By contrast, human IgG4 fails to bind to C1q. Instead, it has been suggested that human IgG4 can block IgG1 and IgG3 hexamerization required for their binding to C1q and activating the complement. Here, we show that murine IgG1, which functionally resembles human IgG4 by not interacting with C1q, inhibits the binding of IgG2a, IgG2b, and IgG3 to C1q in vitro, and suppresses IgG2a-mediated complement activation in a hemolytic assay in an antigen-dependent and IgG subclass-specific manner. From this perspective, we discuss the potential of murine IgG1 and human IgG4 to block the complement activation as well as suppressive effects of sialylated IgG subclass Abs on FcγR-mediated immune cell activation. Accumulating evidence suggests that both mechanisms seem to be responsible for preventing uncontrolled IgG (auto)Ab-induced inflammation in mice and humans. Distinct IgG subclass distributions and functionally opposite IgG Fc glycosylation patterns might explain different outcomes of IgG-mediated immune responses and provide new therapeutic options through the induction, enrichment, or application of antigen-specific sialylated human IgG4 to prevent complement and FcγR activation as well.

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Section: Discussionsupporting

confidence: 71%

Potential of Murine IgG1 and Human IgG4 to Inhibit the Classical Complement and Fcγ Receptor Activation Pathways

et al. 2018

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“…Serum levels of anti-AChR IgG2b (predominant and pathogenic isotype) in EAMG mice were measured using ELISA 72 h post 3rd treatment using our affinity-purified mouse muscle AChR (coating antigen), rat antimouse IgG2b-HRP (secondary Ab; BD Bioscience, CA), and ABTS (2'azino-bis 3-ethylbenzthiazoline-6-sulfonic acid) (Invitrogen, MA) as substrate ( 33 ). To check if HDAC inhibition - mediated Ab reduction had a time-dependent reversal, EAMG mice were bled at 4 weeks post 3rd (last) treatment.…”

Section: Methodsmentioning

confidence: 99%

“…Functional muscle-AChR content reliably represents the treatment effect on muscle strength of EAMG mice ( 33 ). We standardized a new ELISA method alternative to radioimmunoassay for quantitating the relative abundance of functional AChR in the proximal forelimb muscles that are affected most in EAMG.…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis

et al. 2022

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Myasthenia gravis (MG) is an autoimmune disease characterized by chronic muscle fatigue and weakness caused by autoantibodies and complement-mediated damage at neuromuscular junctions. Histone deacetylases (HDACs) are crucial epigenetic regulators of proinflammatory gene expression; however, it is unclear whether HDACs modulate chronic inflammation or autoantibody production associated with MG pathogenesis. We examined expression profiles and serum levels of key inflammatory cytokines (IL-6 and IL-21) and acetylcholine receptor (AChR)-specific autoantibodies following pharmacological inhibition of key HDAC isoforms in a mouse model of MG. We found that HDAC inhibition significantly reduced the production of IL-6, but not IL-21, in AChR-stimulated PBMCs and splenocytes (n = 5 per group). Trichostatin (pan-HDAC inhibitor) treatment of MG-PBMCs (n = 2) also exhibited reduced production of induced IL-6. Although HDAC1 inhibition lowered IL-6 levels the most, HDAC2 inhibition depleted intracellular IL-6 and markedly reduced serum anti-AChR IgG2b in EAMG mice. The transcriptomic profiling and pathway mapping also revealed that autoimmunity-linked, major cell signaling pathways were differentially altered by HDAC1/2 inhibition. HDAC inhibition-mediated reduction in IL-6 and autoantibody levels also correlated with milder disease and preservation of muscle AChR in the treated mice. Overall, our findings revealed isoform-specific functional variance of HDACs in reducing inflammation and identified HDAC-regulated many genes underlying specific inflammatory and autoantibody pathways in EAMG. Thus, the study provides a rationale for further research to evaluate the HDACs or their gene targets as a potential adjunct treatment for MG.

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“…These results indicated that IgG4 might be involved in the pathogenesis of IgAN. The IgG1 of mice, which cannot activate complement, is similar to human IgG4 in function and Th2-dependency (4,23). Mice deficient in IgG1 were reported as more vulnerable to MG, arthritis, and lethal renal disease under corresponding stimulations, the other IgG isotypes which can activate complement were frequently elevated in these disorders.…”

Section: Decreased Igg4 + B and Th2 Cells In Iganmentioning

confidence: 98%

“…Mice deficient in IgG1 were reported as more vulnerable to MG, arthritis, and lethal renal disease under corresponding stimulations, the other IgG isotypes which can activate complement were frequently elevated in these disorders. Simultaneously, the additional injection of antigen-specific IgG1 was shown to protect mice from diseases through the inhibition of IC formation (23)(24)(25). The effect of mouse IgG1 presumably applies to human IgG4.…”

Section: Decreased Igg4 + B and Th2 Cells In Iganmentioning

confidence: 99%

Low serum IgG4 level: a potential diagnostic biomarker for IgA nephropathy

Tian¹,

Cui²,

Wang³

et al. 2021

Ann Transl Med

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Background: In contrast to intense investigations of galactose-deficient immunoglobulin A (IgA)1 specific immunoglobulin G (IgG), little is known about the IgG subclasses in IgA nephropathy (IgAN). Low IgG4 levels in IgAN were noticed in our preliminary experiment. We aimed to verify the low IgG4 levels and investigate the related immune mechanism in IgAN. Methods: A total of 112 healthy controls (HC) and 112 newly diagnosed IgAN patients were enrolled in this study. Patients with idiopathic membranous nephropathy (IMN), minimal change disease (MCD), or lupus nephritis (LN) were selected as disease controls (DC) (n=122). Serum IgG4 and IgG levels were detected by enzyme-linked immunosorbent assay (ELISA). The IgG4 + B, T helper 1 (Th1), and Th2 cells were measured by flow cytometry. Receiver operating characteristic curves (ROC) were performed to evaluate the diagnostic value of IgG4. Results: Both IgG4 levels and IgG4/IgG in IgAN were lower than HC and DC (all P<0.001). Severe IgAN displayed lower IgG4 levels than mild IgAN (P=0.039). Patients with higher risk of renal progression (>50%) demonstrated lower IgG4 levels than lower-risk (≤15%) patients (P=0.019). The cutoff value of IgG4 in differentiating IgAN from HC and DC was 0.26 mg/mL [sensitivity 98.2%, specificity 82.4%, area under the curve (AUC): 0.941, P<0.0001] and 0.17 mg/mL (sensitivity 90.2%, specificity 85.2%, AUC: 0.937, P<0.0001), respectively. IgG4/IgG displayed similar diagnostic and differential ability. The IgG4 + B/B cells (P<0.0001) and Th2/Th (P=0.042) of IgAN were lower than HC. Conclusions: Serum IgG4 levels were low in IgAN. Lower IgG4 levels indicated more severe disease conditions and higher risk of renal progression. Low serum IgG4 seemed to be a potential diagnostic biomarker for IgAN. Decreased IgG4 + B cells and Th2 cells may contribute to the low IgG4 levels in IgAN.

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

Cited by 11 publications

References 26 publications

Potential of Murine IgG1 and Human IgG4 to Inhibit the Classical Complement and Fcγ Receptor Activation Pathways

Potential of Murine IgG1 and Human IgG4 to Inhibit the Classical Complement and Fcγ Receptor Activation Pathways

Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis

Low serum IgG4 level: a potential diagnostic biomarker for IgA nephropathy

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