Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors

Urich, Eduard; Gutcher, Ilona; Prinz, Marco

doi:10.1073/pnas.0607283103

Cited by 61 publications

(53 citation statements)

References 73 publications

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“…al. [32] showed that reconstitution of common c chain-deficient mice with wildtype leukocytes (DC, monocytes and granulocytes) makes them susceptible to EAE, even though lymphocytes remained common c chain-deficient. Consistently with these previous findings, we observed an increased susceptibility to develop EAE in FccRIIb -/-C57BL/6 mice, and for the first time show significantly greater T cell activation and IFN-c secretion in response to MOG, as well as reduced numbers of Foxp3 + T cells in these mice.…”

Section: Discussionmentioning

confidence: 99%

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Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

et al. 2008

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The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although FccR have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (FccRIII) and inhibitory (FccRIIb) FccR can modulate myelin-specific T cell response, as well as the susceptibility to develop EAE in mice. While FccRIIb -/-mice showed a significant increase in EAE severity, an FccRIII deficiency protected mice from disease. In addition, FccRIIb -/-mice showed enhanced activation of myelin-specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild-type mice. In contrast, FccRIII -/-mice showed a significantly reduced activation of myelin-specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for FccRIII -/-mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory FccR signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression.

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Section: Discussionmentioning

confidence: 99%

“…Previous studies performed in various FccR-knockout strains have suggested a role of FccR in EAE pathogenesis [28][29][30][31][32], but these studies have not revealed conclusively the exact nature of the contribution of FccR to EAE susceptibility, reporting in some cases opposing findings [28][29][30][31][32].…”

Section: Introductionmentioning

confidence: 94%

Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

et al. 2008

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“…C1q is known to play an important role in immune complex diseases, such as systemic lupus erythematosus, Arthus reaction, autoantibody-induced arthritis, glomerulonephritis, and experimental autoimmune encephalitis. 11,[64][65][66] In addition, mast cells have been associated with these diseases. 36,[67][68][69][70] Our findings provide a molecular mechanism linking C1q and activation of these inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between the α2β1 integrin and c-met/HGF-R regulates innate immunity

McCall-Culbreath¹,

Li²,

Zutter

2008

Blood

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Data from several investigators suggest that the ␣2␤1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1, endorepellin, and several viruses, is required for innate immunity and regulation of autoimmune/ allergic disorders. We demonstrated that the innate immune response to Listeria monocytogenes required ␣2␤1 integrin expression by peritoneal mast cells (PMCs). Ligation of the ␣2␤1 integrin by C1q contained in immune complexes comprised of Listeria and antibody was required for PMC activation in vitro and in vivo. However, ligation of the ␣2␤1 integrin alone was insufficient to activate cytokine secretion, suggesting that one or more additional signals emanating from a coreceptor were required for PMC activation. Here, we demonstrate that C1q, but neither other complement proteins nor FcR␥, is required for early innate immune response to Listeria. IntroductionThe role of the ␣2␤1 integrin in the innate and acquired immune response has been an area of active investigation. We initially reported that the ␣2␤1 integrin-deficient mice exhibited markedly diminished inflammatory responses to Listeria monocytogenes because of a requirement for ␣2␤1 integrin expression on peritoneal mast cells (PMCs) for mast-cell activation and cytokine release in vivo. 1 Although the ␣2␤1 integrin serves as a receptor for several matrix and nonmatrix ligands, the ligand for the integrin during the PMC response to infection was unknown. 2,3 We demonstrated that C1q complement protein and collectin family members, including mannose binding lectin and surfactant protein A, all served as ligands for the integrin. 4 In addition, the ␣2␤1 integrin was required for mast-cell activation in vitro in response to Listeria. However, ligation of the ␣2␤1 integrin alone was insufficient to activate cytokine secretion because mast-cell adhesion to collagen or C1q alone failed to support cytokine secretion. 4 We hypothesized that one or more additional signals emanating from an additional receptor was required to activate mast-cell cytokine secretion in response to immune complexes. At that time, we presented 2 alternative models by which ␣2␤1 integrin-ligand interactions may stimulate mast-cell activation and cytokine secretion. Our first model proposed that ligation of the ␣2␤1 integrin simultaneously with a second, costimulatory receptor elicited mast-cell activation, in a manner reminiscent of the role proposed for the ␣2␤1 integrin and the glycoprotein VI/Fc receptor common ␥ chain (FcR␥) during platelet adhesion to collagen. 5,6 In our second model, binding of the ␣2␤1 integrin to an immune complex containing C1q may directly activate the complement cascade, resulting in the deposition of C3b or iC3b and generation of complement byproducts, such as C3a or C5a, which would subsequently stimulate mast cell activation. [7][8][9] We now report that neither the FcR␥ nor components of the complement cascade are required in ␣2␤1 integrin-dependent mast-cell activation. Instead, we describe a novel coreceptor...

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“…These studies suggest that FcgRs can be induced in the brain where they can play an important role in controlling Ab-mediated neuroinflammation. However, some studies do not support a key effector function of FcgRs in neuroinflammation and suggest a key role of complement activation instead (48).…”

Section: The Role Of Fcgrs In Chronic Neurodegenerationmentioning

confidence: 99%

Systemic Inflammation Modulates Fc Receptor Expression on Microglia during Chronic Neurodegeneration

Lunnon

Teeling

Tutt

et al. 2011

The Journal of Immunology

112

105

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Chronic neurodegeneration is a major worldwide health problem, and it has been suggested that systemic inflammation can accelerate the onset and progression of clinical symptoms. A possible explanation is that systemic inflammation “switches” the phenotype of microglia from a relatively benign to a highly aggressive and tissue-damaging phenotype. The current study investigated the molecular mechanism underlying this microglia phenotype “switching.” We show in mice with chronic neurodegeneration (ME7 prion model) that there is increased expression of receptors that have a key role in macrophage activation and associated signaling pathways, including TREM-2, Siglec-F, CD200R, and FcγRs. Systemic inflammation induced by LPS further increased protein levels of the activating FcγRIII and FcγRIV, but not of other microglial receptors, including the inhibitory FcγRII. In addition to these changes in receptor expression, IgG levels in the brain parenchyma were increased during chronic neurodegeneration, and these IgG levels further increased after systemic inflammation. γ-Chain–deficient mice show modified proinflammatory cytokine expression in the brain after systemic inflammation. We conclude that systemic inflammation during chronic neurodegeneration increases the expression levels of activating FcγR on microglia and thereby lowers the signaling threshold for Ab-mediated cell activation. At the same time, IgG influx into the brain could provide a cross-linking ligand resulting in excessive microglia activation that is detrimental to neurons already under threat by misfolded protein.

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Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors

Cited by 61 publications

References 73 publications

Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

Crosstalk between the α2β1 integrin and c-met/HGF-R regulates innate immunity

Systemic Inflammation Modulates Fc Receptor Expression on Microglia during Chronic Neurodegeneration

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