Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: Implication for disease pathogenesis

Michailidou, Iliana; Naessens, Daphne M. P.; Hametner, Simon; Guldenaar, Willemijn; Kooi, Evert Jan; Geurts, Jeroen J. G.; Baas, Frank; Lassmann, Hans; Ramaglia, Valeria

doi:10.1002/glia.23090

Cited by 57 publications

(46 citation statements)

References 52 publications

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“…Dystrophic SMI32-labeled αRGCs were stained for C3d, while most αRGCs with healthy morphology had dim or Page 9 undetectable C3d staining. We did not observe C3d deposition on microglia of naïve or treated retinas (Figure S1B), unlike reports of C3d localization to brain microglia in patients with multiple sclerosis and other neurodegenerative conditions [61][62][63] . We did detect C3d on GFAP+ parenchymal astrocytes in some naïve retinas aged 10 months (data not shown).…”

Section: Intravitreal Aav2cr2-crry Limits the Deposition Of C3d On Rgcscontrasting

confidence: 93%

Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

Bosco

Anderson

Breen

et al. 2018

Preprint

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Dysregulation of the complement system is implicated in neurodegeneration, including human and animal glaucoma. Optic nerve and retinal damage in glaucoma is preceded by local complement upregulation and activation, but whether targeting this early innate immune response could have therapeutic benefit remains undefined. Because complement signals through three pathways that intersect at complement C3 activation, here we targeted this step to restore complement balance in the glaucomatous retina, and to determine its contribution to degeneration onset and/or progression. To achieve this, we combined adeno-associated viral retinal gene therapy with the targeted C3 inhibitor CR2-Crry. We show that intravitreal injection of AAV2.CR2-Crry produced sustained Crry overexpression in the retina, and reduced deposition of the activation product complement C3d on retinal ganglion cells and the inner retina of DBA/2J mice.This resulted in neuroprotection of retinal ganglion cell axons and somata despite continued intraocular pressure elevation, suggesting a direct restriction of neurodegeneration onset and progression, and significant delay to terminal disease stages. Our study uncovers a damaging effect of complement C3 or downstream complement activation in glaucoma and establishes AAV2.CR2-Crry as a viable therapeutic strategy to target pathogenic C3-mediated complement activation in the glaucomatous retina.

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Section: Intravitreal Aav2cr2-crry Limits the Deposition Of C3d On Rgcscontrasting

confidence: 93%

Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

Bosco

Anderson

Breen

et al. 2018

Preprint

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“…Instead, they are linked to slowly expanding lesions, localized on axons with impaired transport and associated with neuronal C3 production. C3d microglial clusters are not specific to MS, since they are also found in stroke [13]. The authors of this recent study also concluded that C3d microglial clusters in MS are not part of an acute attack against myelinated axons.…”

Section: Introductionmentioning

confidence: 93%

“…The authors of this recent study also concluded that C3d microglial clusters in MS are not part of an acute attack against myelinated axons. Therefore, it is unlikely that they drive the formation of new lesions, but they could represent a physiological mechanism to remove irreversibly damaged axons in chronic disease [13]. …”

Section: Introductionmentioning

confidence: 99%

The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

et al. 2017

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Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The complement system has an established role in the pathogenesis of MS, and evidence suggests that its components can be used as biomarkers of disease-state activity and response to treatment in MS. Plasma C4a levels have been found to be significantly elevated in patients with active relapsing-remitting MS (RRMS), as compared to both controls and patients with stable RRMS. C3 levels are also significantly elevated in the cerebrospinal fluid (CSF) of patients with RRMS, and C3 levels are correlated with clinical disability. Furthermore, increased levels of factor H can predict the transition from relapsing to progressive disease, since factor H levels have been found to increase progressively with disease progression over a 2-year period in patients transitioning from RRMS to secondary progressive (SP) MS. In addition, elevations in C3 are seen in primary progressive (PP) MS. Complement components can also differentiate RRMS from neuromyelitis optica. Response gene to complement (RGC)-32, a novel molecule induced by complement activation, is a possible biomarker of relapse and response to glatiramer acetate (GA) therapy, since RGC-32 mRNA expression is significantly decreased during relapse and increased in responders to GA treatment. The predictive accuracy of RGC-32 as a potential biomarker (by ROC analysis) is 90% for detecting relapses and 85% for detecting a response to GA treatment. Thus, complement components can serve as biomarkers of disease activity to differentiate MS subtypes and to measure response to therapy.

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“…The initial step in the development of lesions in this disease is the formation of microglia nodules with inflammasome activation, which precedes the CNS infiltration by T‐cells (Tröscher et al, ). Interestingly, such microglia nodules are also abundant in the normal appearing white matter adjacent to active lesions in MS (Michailidou et al, ; Peferoen et al, ; Singh et al, ; van der Valk & Amor, , Figure ). The early inflammasome activation of microglia appears to be an important general mechanism of infection control in the CNS.…”

Section: Microglia and Macrophages In Inflammatory Diseases In Humansmentioning

confidence: 99%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an‐anti‐inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.

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Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: Implication for disease pathogenesis

Cited by 57 publications

References 52 publications

Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

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