Complement activation in multiple sclerosis plaques: an immunohistochemical analysis

Ingram, Gillian; Loveless, Samantha; Howell, Owain W.; Hakobyan, Svetlana; Dancey, Bethan; Harris, Claire L.; Robertson, Neil; Neal, James; Morgan, B. Paul

doi:10.1186/2051-5960-2-53

Cited by 131 publications

(134 citation statements)

References 34 publications

(37 reference statements)

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…High levels of immunoglobulins and C5b-9 deposition at sites of active myelin destruction are characteristic for pattern II MS lesions and C5–9 deposits are present only in this type of demyelinating lesion [2, 8]. In chronic MS, plaques are found to be consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and inhibitors (factor H, C1-inhibitor, clusterin), suggesting that there is continuing local complement synthesis, activation, and regulation despite the absence of other evidence of ongoing inflammation [9]. An initial heterogeneity of demyelinating lesions in the earliest phase of MS lesion formation [2] may disappear over time as different pathways converge in one general mechanism of demyelination.…”

Section: Introductionmentioning

confidence: 99%

“…C1q staining is present in all plaques, suggesting a dominant role for the classical pathway. Cellular staining for complement components is largely restricted to reactive astrocytes, often adjacent to clusters of microglia that are in close apposition to complement-opsonized myelin and damaged axons [9]. We have previously shown that astrocytes in culture can secrete most of the complement proteins and expression is markedly enhanced by TNFα, IL-1β and IL-8 [10].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…[26][27][28][29][30][31] Regarding reports that oligodendrocyte apoptosis and complementpositive myelin are not seen together in MS lesions but only in tumefactive NMO, 25 in our own studies of prephagocytic and actively demyelinating MS lesions, we have never observed commencing myelin breakdown by macrophages where myelin sheaths are not opsonized by complement or where macrophages stain negatively for complement. Affected sheaths have been observed to stain positively for IgG and kappa and lambda light chains, but this is rare and always difficult to demonstrate.…”

Section: Discussionmentioning

confidence: 70%

Multiple sclerosis: Serum anti-CNS autoantibodies

Prineas

Parratt

2017

Mult Scler

View full text Add to dashboard Cite

Background: It is uncertain whether there are autoantibodies detectable by indirect immunofluorescence in the serum of patients with multiple sclerosis (MS). Objective: To determine whether there are anti-central nervous system (CNS) autoantibodies detectable by indirect immunofluorescence in the serum of MS patients. Methods: Sera and in some cases cerebrospinal fluid from 106 patients with multiple sclerosis, 156 patients with other neurological diseases, and 70 healthy control subjects were examined by indirect immunofluorescence using cryostat sections of rat cerebrum fixed by perfusion with paraformaldehyde. Results: Autoantibodies were detected that recognized more than 30 neuronal, glial, and mesodermal structures in 28 of 106 MS cases. Most were also detected in patients with other related and unrelated neurological diseases and several were also found in healthy controls. Novel anti-CNS autoantibodies recognizing particular sets of interneurons were detected in both normal controls and in subjects with CNS diseases. Interpretation: Serum anti-CNS autoantibodies of diverse specificities are common in MS patients. The same anti-CNS autoantibodies are not uncommon in patients with other neurological diseases. The findings provide no support for the proposition that myelin breakdown in MS is caused by exposure of intact myelin sheaths or oligodendrocytes to a pathogenic serum anti-myelin or anti-oligodendrocyte autoantibody.

show abstract

“…The complement system is a key component of innate immunity [8] and has been implicated in the pathogenesis of inflammatory [9][10][11] and neurodegenerative diseases [12][13][14][15][16], indicating that complement may be a good target to slow, halt or reverse both processes. Notably, a role for complement in MS has been suggested based upon evidence that complement is activated and deposited in the MS brain [17][18][19][20][21][22][23], and it is a critical effector in the acute experimental autoimmune encephalomyelitis model of the disease [24][25][26][27]. However, the extent and nature of complement activation and its contribution to the progressive phase of the disease remain controversial and difficult to investigate in acute models that do not replicate the natural course of the human disease.…”

Section: Introductionmentioning

confidence: 99%

Complement activation and expression during chronic relapsing experimental autoimmune encephalomyelitis in the Biozzi ABH mouse

Ramaglia

Jackson

Hughes

et al. 2015

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryChronic relapsing experimental autoimmune encephalomyelitis (crEAE) in mice recapitulates many of the clinical and histopathological features of human multiple sclerosis (MS), making it a preferred model for the disease. In both, adaptive immunity and anti-myelin T cells responses are thought to be important, while in MS a role for innate immunity and complement has emerged. Here we sought to test whether complement is activated in crEAE and important for disease. Disease was induced in Biozzi ABH mice that were terminated at different stages of the disease to assess complement activation and local complement expression in the central nervous system. Complement activation products were abundant in all spinal cord areas examined in acute disease during relapse and in the progressive phase, but were absent in early disease remission, despite significant residual clinical disease. Local expression of C1q and C3 was increased at all stages of disease, while C9 expression was increased only in acute disease; expression of the complement regulators CD55, complement receptor 1-related gene/protein y (Crry) and CD59a was reduced at all stages of the disease compared to naive controls. These data show that complement is activated in the central nervous system in the model and suggest that it is a suitable candidate for exploring whether anti-complement agents might be of benefit in MS.

show abstract

Complement activation in multiple sclerosis plaques: an immunohistochemical analysis

Cited by 131 publications

References 34 publications

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

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

Multiple sclerosis: Serum anti-CNS autoantibodies

Complement activation and expression during chronic relapsing experimental autoimmune encephalomyelitis in the Biozzi ABH mouse

Contact Info

Product

Resources

About