Tissue microarray methodology identifies complement pathway activation and dysregulation in progressive multiple sclerosis

Loveless, Samantha; Neal, James; Howell, Owain W.; Harding, Katharine; Sarkies, Patrick; Evans, Rhian; Bevan, Ryan J.; Hakobyan, Svetlana; Harris, Claire L.; Robertson, Neil; Morgan, B. Paul

doi:10.1111/bpa.12546

Cited by 39 publications

(34 citation statements)

References 37 publications

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“…This work confirms that complement activation and dysregulation occur in all cases of MS [11]. In addition, the authors of recent study reported that C3d microglial clusters are present in chronic but not acute MS lesions.…”

Section: Introductionsupporting

confidence: 87%

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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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Section: Introductionsupporting

confidence: 87%

“…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]. In addition C5b-9 deposits were found in macrophages [5], neurons [11] and OLG progenitor cells [12]. …”

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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“…We have previously shown that complement is activated in progressive MS GM neurons and complement activation correlated with severity of GM pathology, whereas others have shown that complement C1q and C3b expression is associated with degenerating synapses in the progressive MS hippocampus . We performed ISH for complement transcripts that encode the recognition fragment C1q and the central complement component C3.…”

Section: Resultsmentioning

confidence: 99%

Meningeal inflammation and cortical demyelination in acute multiple sclerosis

Bevan

Evans

Griffiths

et al. 2018

Annals of Neurology

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114

101

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Objective: Cortical gray matter (GM) pathology, involving demyelination and neurodegeneration, associated with meningeal inflammation, could be important in determining disability progression in multiple sclerosis (MS). However, we need to know more about how cortical demyelination, neurodegeneration, and meningeal inflammation contribute to pathology at early stages of MS to better predict long-term outcome. Methods: Tissue blocks from short disease duration MS (n = 12, median disease duration = 2 years), progressive MS (n = 21, disease duration = 25 years), non-diseased controls (n = 11), and other neurological inflammatory disease controls (n = 6) were quantitatively analyzed by immunohistochemistry, immunofluorescence, and in situ hybridization. Results: Cortical GM demyelination was extensive in some cases of acute MS (range = 1-48% of total cortical GM), and subpial lesions were the most common type (62%). The numbers of activated (CD68 + ) microglia/macrophages were increased in cases with subpial lesions, and the density of neurons was significantly reduced in acute MS normal appearing and lesion GM, compared to controls (p < 0.005). Significant meningeal inflammation and lymphoid-like structures were seen in 4 of 12 acute MS cases. The extent of meningeal inflammation correlated with microglial/macrophage activation (p < 0.05), but not the area of cortical demyelination, reflecting the finding that lymphoid-like structures were seen adjacent to GM lesions as well as areas of partially demyelinated/remyelinated, cortical GM. Interpretation: Our findings demonstrate that cortical demyelination, neuronal loss, and meningeal inflammation are notable pathological hallmarks of acute MS and support the need to identify early biomarkers of this pathology to better predict outcome. ANN NEUROL 2018;84:829-842 M ultiple sclerosis (MS) is a highly variable and lifechanging condition, characterized by inflammation, demyelination, and neurodegeneration. MS typically presents as a relapsing-remitting disease, where bouts of acute inflammation and new, active, demyelinating lesions are associated with neurological impairment. Lesions of the gray matter (GM) occur at all stages of the disease, and the extent of cortical GM pathology predicts conversion to clinically definite MS and associates with cognitive and motor disability, epilepsy, and an earlier transition to the progressive phase. 1 Recent findings suggest that subpial GM lesions of the neocortex, the principal lesion type of the MS cortex, are related, at least in part, to inflammatory activity in the overlying leptomeninges. 2 We and others have shown how the degree of meningeal inflammation correlates with cortical microglial activation, neuritic and neuronal degeneration, and demyelination in primary progressive and View this article online at wileyonlinelibrary.com.

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“…Many of the differentially expressed genes and related biological processes found in each OPC cluster complement emerging literature that indicates non-canonical roles for OPCs during homeostasis, and a more active role of this cell type in multiple diseases. For example, OPC1 expresses high levels of Clusterin, a gene known to be upregulated in both Alzheimer's disease and multiple sclerosis (MS) 61,62 . OPCs have recently been shown to potentially play an active role in the pathology of MS and have been implicated in the progression of Alzheimer's disease 17,20,63 .…”

Section: Discussionmentioning

confidence: 99%

Oligomeric amyloid beta prevents myelination in a clusterin-dependent manner

Beiter

Fernández-Castañeda

Rivet-Noor

et al. 2020

Preprint

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Oligodendrocyte progenitor cells (OPCs) are a mitotically active population of glia that comprise approximately 5% of the adult brain. OPCs maintain their proliferative capacity and ability to differentiate in oligodendrocytes throughout adulthood, but relatively few mature oligodendrocytes are produced following developmental myelination. Recent work has begun to demonstrate that OPCs likely perform multiple functions in both homeostasis and disease, and can significantly impact behavioral phenotypes such as food intake and depressive symptoms. However, the exact mechanisms through which OPCs might influence brain function remains unclear. In this work, we demonstrate that OPCs are transcriptionally diverse and separate into three distinct populations in the homeostatic brain. These three groups show distinct transcriptional signatures and enrichment of biological processes unique to individual OPC populations. We have validated these OPC populations using multiple methods, including multiplex RNA in situ hybridization and RNA flow cytometry. This study provides an important resource that profiles the transcriptome of adult OPCs and will provide a significant foundation for further investigation into novel OPC functions.

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Tissue microarray methodology identifies complement pathway activation and dysregulation in progressive multiple sclerosis

Cited by 39 publications

References 37 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

Meningeal inflammation and cortical demyelination in acute multiple sclerosis

Oligomeric amyloid beta prevents myelination in a clusterin-dependent manner

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