The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response

Hundgeburth, Lorenz C.; Wunsch, Marie; Rovituso, Damiano M.; Recks, Mascha S.; Addicks, Klaus; Lehmann, Paul; Küerten, Stefanie

doi:10.1016/j.clim.2012.12.007

Cited by 22 publications

(15 citation statements)

References 58 publications

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“…On day 23–30 after immunization when the MP4-induced B cell response had reached its maximum [17] the gut was removed and sections were obtained from the Peyer’s patches of n = 6 conventionally housed and n = 6 SPF mice. In addition, sections were obtained from n = 7 conventionally housed and n = 9 SPF age- and gender-matched control mice.…”

Section: Resultsmentioning

confidence: 99%

Conventional Housing Conditions Attenuate the Development of Experimental Autoimmune Encephalomyelitis

et al. 2014

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BackgroundThe etiology of multiple sclerosis (MS) has remained unclear, but a causative contribution of factors outside the central nervous system (CNS) is conceivable. It was recently suggested that gut bacteria trigger the activation of CNS-reactive T cells and the development of demyelinative disease.MethodsC57BL/6 (B6) mice were kept either under specific pathogen free or conventional housing conditions, immunized with the myelin basic protein (MBP)–proteolipid protein (PLP) fusion protein MP4 and the development of EAE was clinically monitored. The germinal center size of the Peyer’s patches was determined by immunohistochemistry in addition to the level of total IgG secretion which was assessed by ELISPOT. ELISPOT assays were also used to measure MP4-specific T cell and B cell responses in the Peyer’s patches and the spleen. Ear swelling assays were performed to determine the extent of delayed-type hypersensitivity reactions in specific pathogen free and conventionally housed mice.ResultsIn B6 mice that were actively immunized with MP4 and kept under conventional housing conditions clinical disease was significantly attenuated compared to specific pathogen free mice. Conventionally housed mice displayed increased levels of IgG secretion in the Peyer’s patches, while the germinal center formation in the gut and the MP4-specific TH17 response in the spleen were diminished after immunization. Accordingly, these mice displayed an attenuated delayed type hypersensitivity (DTH) reaction in ear swelling assays.ConclusionsThe data corroborate the notion that housing conditions play a substantial role in the induction of murine EAE and suggest that the presence of gut bacteria might be associated with a decreased immune response to antigens of lower affinity. This concept could be of importance for MS and calls for caution when considering the therapeutic approach to treat patients with antibiotics.

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Section: Resultsmentioning

confidence: 99%

Conventional Housing Conditions Attenuate the Development of Experimental Autoimmune Encephalomyelitis

et al. 2014

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“…The function of the complement system in myelinopathies (including demyelination) has been a matter of debate (26). While a protective role of complement in demyelination has been reported (27,28), other authors suggest that the complement does not participate in demyelination (35), or have a role in immune-mediated myelin diseases (29)(30)(31)(32)(33)(34). In the classical pathway of the complement, activated C1 induces the cleavage of C4 to form the anaphylatoxin C4a (75).…”

Section: Discussionmentioning

confidence: 99%

“…The role of the complement system in some demyelinating disorders is an issue of debate and the precise function of complement in such processes remains elusive (26). So, while some reports speak about a protective role of complement in demyelinating processes (27,28), others point to its involvement in immune-mediated myelin diseases (29)(30)(31)(32)(33)(34), or even its lack of participation (35). In neuromyelitis optica, an autoimmune disease of the CNS displaying intramyelinic edema and tissue vacuolation, the complement activation is observed in damaged tissue (36).…”

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Microbial Neuraminidase Induces a Moderate and Transient Myelin Vacuolation Independent of Complement System Activation

et al. 2017

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AimsSome central nervous system pathogens express neuraminidase (NA) on their surfaces. In the rat brain, a single intracerebroventricular (ICV) injection of NA induces myelin vacuolation in axonal tracts. Here, we explore the nature, the time course, and the role of the complement system in this damage.MethodsThe spatiotemporal analysis of myelin vacuolation was performed by optical and electron microscopy. Myelin basic protein-positive area and oligodendrocyte transcription factor (Olig2)-positive cells were quantified in the damaged bundles. Neuronal death in the affected axonal tracts was assessed by Fluoro-Jade B and anti-caspase-3 staining. To evaluate the role of the complement, membrane attack complex (MAC) deposition on damaged bundles was analyzed using anti-C5b9. Rats ICV injected with the anaphylatoxin C5a were studied for myelin damage. In addition, NA-induced vacuolation was studied in rats with different degrees of complement inhibition: normal rats treated with anti-C5-blocking antibody and C6-deficient rats.ResultsThe stria medullaris, the optic chiasm, and the fimbria were the most consistently damaged axonal tracts. Vacuolation peaked 7 days after NA injection and reverted by day 15. Olig2+ cell number in the damaged tracts was unaltered, and neurodegeneration associated with myelin alterations was not detected. MAC was absent on damaged axonal tracts, as revealed by C5b9 immunostaining. Rats ICV injected with the anaphylatoxin C5a displayed no myelin injury. When the complement system was experimentally or constitutively inhibited, NA-induced myelin vacuolation was similar to that observed in normal rats.ConclusionMicrobial NA induces a moderate and transient myelin vacuolation that is not caused either by neuroinflammation or complement system activation.

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“…Transient depletion of complement prior to immunization abrogated disease and demonstrated the pathogenic potential of complement in antibody‐mediated pathology in MP4‐induced EAE. Colocalization of complement factors and demyelination in lesions of the spinal cord and cerebellum also implicate complement in demyelination (Hundgeburth et al, ).…”

Section: Immune Cells and Their Mediators In The Cns: The Drivers Behmentioning

confidence: 99%

“…MS lesions have deposits of antibodies and complement, and complement activation has been hypothesized to contribute to oligodendrocyte and/or myelin damage through the formation of the membrane attack complex and complement-mediated cytolysis(Ingram, Hakobyan, Robertson, & Morgan, 2009). One study introduced MP4 (a fusion protein comprising MBP and three hydrophilic domains of proteolipid protein) to C57BL/6 mice to study the complement system effects on EAE(Hundgeburth et al, 2013). Transient depletion of complement prior to immunization abrogated disease and demonstrated the pathogenic potential of complement in antibody-mediated pathology in MP4-induced EAE.…”

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Modulating inflammation and neuroprotection in multiple sclerosis

Yong

Chartier

Quandt

2017

J of Neuroscience Research

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Multiple sclerosis (MS) is a neurological disorder of the central nervous system with a presentation and disease course that is largely unpredictable. MS can cause loss of balance, impaired vision or speech, weakness and paralysis, fatigue, depression, and cognitive impairment. Immunomodulation is a major target given the appearance of focal demyelinating lesions in myelin-rich white matter, yet progression and an increasing appreciation for gray matter involvement, even during the earliest phases of the disease, highlights the need to afford neuroprotection and limit neurodegenerative processes that correlate with disability. This review summarizes key aspects of MS pathophysiology and histopathology with a focus on neuroimmune interactions in MS, which may facilitate neurodegeneration through both direct and indirect mechanisms. There is a focus on processes thought to influence disease progression and the role of oxidative stress and mitochondrial dysfunction in MS. The goals and efficacy of current disease-modifying therapies and those in the pipeline are discussed, highlighting recent advances in our understanding of pathways mediating disease progression to identify and translate both immunomodulatory and neuroprotective therapeutics from the bench to the clinic.

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The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response

Cited by 22 publications

References 58 publications

Conventional Housing Conditions Attenuate the Development of Experimental Autoimmune Encephalomyelitis

Conventional Housing Conditions Attenuate the Development of Experimental Autoimmune Encephalomyelitis

Microbial Neuraminidase Induces a Moderate and Transient Myelin Vacuolation Independent of Complement System Activation

Modulating inflammation and neuroprotection in multiple sclerosis

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