Abstract
IntroductionInflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; however, the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain. This study aims to bring clarity to these questions.ResultsWe describe a detailed immunohistochemical study to localise a strategically selected set of complement proteins, activation products and regulators in brain and spinal cord tissue of 17 patients with progressive multiple sclerosis and 16 control donors, including 9 with central nervous system disease. Active, chronic active and chronic inactive multiple sclerosis plaques (35 in total) and non-plaque areas were examined.Multiple sclerosis plaques were consistently positive for complement proteins (C3, factor B, C1q), activation products (C3b, iC3b, C4d, terminal complement complex) and regulators (factor H, C1-inhibitor, clusterin), suggesting continuing local complement synthesis, activation and regulation despite the absence of other evidence of ongoing inflammation. Complement staining was most apparent in plaque and peri-plaque but also present in normal appearing white matter and cortical areas to a greater extent than in control tissue. C1q staining was present in all plaques suggesting a dominant role for the classical pathway. Cellular staining for complement components was largely restricted to reactive astrocytes, often adjacent to clusters of microglia in close apposition to complement opsonised myelin and damaged axons.ConclusionsThe findings demonstrate the ubiquity of complement involvement in multiple sclerosis, suggest a pathogenic role for complement contributing to cell, axon and myelin damage and make the case for targeting complement for multiple sclerosis monitoring and therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-53) contains supplementary material, which is available to authorized users.
Highlights
Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain
We find that the presence of complement proteins and activation products in and around areas of pathology is a consistent feature of progressive Multiple sclerosis (MS), the extent varies between individuals
In MS white matter (WM) and grey matter (GM), astrocyte cell counts were not significantly different from non-neurological or neurological controls (Figures 2 and 3); microglial cell counts were significantly higher in MS WM than nonneurological control WM, but higher still in the WM and GM of the neurological control group
Summary
Inflammation and complement activation are firmly implicated in the pathology of multiple sclerosis; the extent and nature of their involvement in specific pathological processes such as axonal damage, myelin loss and disease progression remains uncertain. The published studies do not build consensus on whether complement protein immunoreactivity is a consistent feature in MS, which areas of the CNS demonstrate immunoreactivity, or which complement proteins and pathways are involved. This is likely due to studies including tissue from different stages of the disease, limited numbers of patients examined and variability in quality of detection reagents used. A notable exception was a study by Prineas who showed abundant C3d deposition on myelin in areas of pathology and suggested a direct role as an opsonin driving immune response to myelin antigens [9]
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