Impact of complement activation on clinical outcomes in multiple sclerosis.
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ABSTRACT:
SUBMITTER: Keller CW
PROVIDER: S-EPMC8045986 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
Publications
Impact of complement activation on clinical outcomes in multiple sclerosis.
Keller Christian W CW Oechtering Johanna J Wiendl Heinz H Kappos Ludwig L Kuhle Jens J Lünemann Jan D JD
Annals of clinical and translational neurology 20210301 4
We determined activation profiles of the classical and alternative complement pathway in 39 treatment-naïve patients with early relapse-onset MS. Plasma concentrations of complement fragments were unchanged in MS compared to 32 patients with non-inflammatory neurological diseases. Profiles in patients experiencing clinical exacerbations did not differ from patients with stable disease and did not correlate with baseline EDSS, numbers of T2 lesions and time to second relapse. Long-term EDSS outco ...[more]
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Project description: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.
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Project description:Psoriasis was found to ameliorate multiple sclerosis (MS) outcomes when it MS onset. However, the molecular basis for this observation remains unclear. Herein, we compared the blood mononuclear cell transcriptome of psoriasis and MS comorbide (P/MS) patients with that of patients with either psoriasis or MS to understand the clinical observation.
2020-12-11 | GSE141804 | GEO
Project description:IntroductionMultiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis. Innate immunity, in addition to the adaptive immune system, plays a relevant role in MS pathogenesis. It represents the immediate non-specific defense against infections through the intrinsic effector mechanism "immunothrombosis" linking inflammation and coagulation. Moreover, decreased cerebral blood volume (CBV), cerebral blood flow (CBF), and prolonged mean transit time (MTT) have been widely demonstrated by MRI in MS patients. We hypothesized that coagulation/complement and platelet activation during MS relapse, likely during viral infections, could be related to CBF decrease. Our specific aims are to evaluate whether there are differences in serum/plasma levels of coagulation/complement factors between relapsing-remitting (RR) MS patients (RRMS) in relapse and those in remission and healthy controls as well as to assess whether brain hemodynamic changes detected by MRI occur in relapse compared with remission. This will allow us to correlate coagulation status with perfusion and demographic/clinical features in MS patients.Materials and methodsThis is a multi-center, prospective, controlled study. RRMS patients (1° group: 30 patients in relapse; 2° group: 30 patients in remission) and age/sex-matched controls (3° group: 30 subjects) will be enrolled in the study. Patients and controls will be tested for either coagulation/complement (C3, C4, C4a, C9, PT, aPTT, fibrinogen, factor II, VIII, and X, D-dimer, antithrombin, protein C, protein S, von-Willebrand factor), soluble markers of endothelial damage (thrombomodulin, Endothelial Protein C Receptor), antiphospholipid antibodies, lupus anticoagulant, complete blood count, viral serological assays, or microRNA microarray. Patients will undergo dynamic susceptibility contrast-enhanced MRI using a 3.0-T scanner to evaluate CBF, CBV, MTT, lesion number, and volume.Statistical analysisANOVA and unpaired t-tests will be used. The level of significance was set at p ≤ 0.05.DiscussionIdentifying a link between activation of coagulation/complement system and cerebral hypoperfusion could improve the identification of novel molecular and/or imaging biomarkers and targets, leading to the development of new effective therapeutic strategies in MS.Clinical trial registrationClinicaltrials.gov, identifier NCT04380220.
| S-EPMC7655134 | biostudies-literature
Project description:Multiple sclerosis (MS) is a neurological disease featuring neuroinflammation and neurodegeneration in young adults. So far, most research has focused on the peripheral immune system, which appears to be the driver of acute relapses. Concurrently, the mechanisms underlying neurodegeneration in the progressive forms of the disease remain unclear. The complement system, a molecular component of the innate immunity, has been recently implicated in several neurological disorders, including MS. However, it is still unknown if the complement proteins detected in the central nervous system (CNS) are actively involved in perpetuating chronic inflammation and neurodegeneration. To address this knowledge gap, we compared two clinically distinct mouse models of MS: 1) proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (rEAE) resembling a relapsing-remitting disease course, and 2) Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) resembling a progressive disease. Real-time PCR was performed in the spinal cord of rEAE mice, TMEV-IDD mice and age-matched sham controls to quantify gene expression for a broad range of complement components. In both experimental models, we found significantly increased expression of complement factors, such as C1q, C3, CfB, and C3aR. We showed that the complement system, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of C1q, C3 and C3aR1 were all significantly correlated to a worse disease outcome (all P≤0.0168). In line with this finding, C1q and C3 deposition was observed in the spinal cord of TMEV-IDD mice. Furthermore, C1q deposition was detected in spinal cord regions characterized by inflammation, demyelination, and axonal damage. Conversely, activation of the classical complement cascade seemed to result in protection from rEAE (C1q: P=0.0307). Interestingly, the alternative pathway related to a worse disease outcome in rEAE (CFb: P=0.0006). Overall, these results indicate potential divergent roles for the complement system in MS. The chronic-progressive disease form is more reliant on the activation of the classic complement pathway, while protecting from acute relapses. Conversely, relapsing MS appears more likely affected by the alternative pathway. Understanding the functions of the complement system in MS is critical and can lead to better, more targeted therapies in the future.
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Project description:The complement pathway has potential contributions to both white (WM) and grey matter (GM) pathology in Multiple Sclerosis (MS). A quantitative assessment of complement involvement is lacking. Here we describe the use of Tissue MicroArray (TMA) methodology in conjunction with immunohistochemistry to investigate the localization of complement pathway proteins in progressive MS cortical GM and subcortical WM. Antibodies targeting complement proteins C1q, C3b, regulatory proteins C1 inhibitor (C1INH, complement receptor 1 (CR1), clusterin, factor H (FH) and the C5a anaphylatoxin receptor (C5aR) were utilised alongside standard markers of tissue pathology. All stained slides were digitised for quantitative analysis. We found that numbers of cells immunolabelled for HLA-DR, GFAP, C5aR, C1q and C3b were increased in WM lesions (WML) and GM lesions (GML) compared to normal appearing WM (NAWM) and GM (NAGM), respectively. The complement regulators C1INH, CR1, FH and clusterin were more abundant in WM lesions, while the number of C1q+ neurons were increased and the number of C1INH+, clusterin+, FH+ and CR1+ neurons decreased in GM lesions. The number of complement component positive cells (C1q, C3b) correlated with complement regulator expression in WM, but there was no statistical association between complement activation and regulator expression in the GM. We conclude that TMA methodology and quantitative analysis provides evidence of complement dysregulation in MS GML, including an association of the numerical density of C1q+ cells with tissue lesions. Our work confirms that complement activation and dysregulation occur in all cases of progressive MS and suggest that complement may provide potential biomarkers of the disease.
| S-EPMC8028318 | biostudies-literature
Project description:The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post-mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p < 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = -0.58, p = 0.009) and age of death (Spearman r = -0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS.
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Project description:Multiple Sclerosis (MS) pathology is complex and includes inflammatory processes, neurodegeneration, and demyelination. While multiple drugs have been developed to tackle MS-related inflammation, to date there is scant evidence regarding which therapeutic approach, if any, could be used to reverse demyelination, foster tissue repair, and thus positively impact on chronic disability. Here, we reviewed the current structural and functional markers (magnetic resonance imaging, positron emission tomography, optical coherence tomography, and visual evoked potentials) which could be used in phase II clinical trials of new compounds aimed to foster tissue repair in MS. Magnetic transfer ratio recovery in newly formed lesions currently represents the most widely used biomarker of tissue repair in MS, even if other markers, such as optical coherence tomography and positron emission tomography hold great promise to complement magnetic transfer ratio in tissue repair clinical trials. Future studies are needed to better characterize the different possible biomarkers to study tissue repair in MS, especially regarding their pathological specificity, sensitivity to change, and their relationship with disease activity.
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Project description:BackgroundTo examine whether lower neighborhood-level and individual-level indicators of socioeconomic status (SES) are associated with subsequently worse neurological disability in people with MS (pwMS).MethodsIn a multi-center study using prospectively collected data from discovery cohorts (University of Pittsburgh, N=1316) and replication cohorts (Columbia University, N=488), we calculated a neighborhood SES indicator, area deprivation index (ADI), based on participants' residence at enrollment, and we derived an individual SES indicator based on participants' household income. Patient-reported neurological outcomes included the Multiple Sclerosis Rating Scale-Revised (MSRS-R), Patient-Determined Disease Steps (PDDS), and Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function scores from 2018 to 2020. We performed covariate-adjusted regression analyses in each cohort and then random-effects meta-analyses.ResultsHigher ADI (lower SES) in 2015 was associated with subsequently worse neurological outcomes during 2018-2020 (discovery: MSRS-R, β=0.62, 95%CI [0.36,0.89], p<0.001; PDDS, β=0.11, 95%CI [0.02,0.20], p=0.02 | replication: MSRS-R, β=0.46, 95%CI [0.21,0.72], p<0.001; PDDS, β=0.12, 95%CI [0.03,0.21], p=0.009, PROMIS, β=-0.60, 95%CI [-1.12,-0.08], p=0.025). Lower neighborhood percent with college education (MSRS-R, β=-7.31, 95%CI [-8.99,-5.64], p<0.001; PDDS, β=-1.62, 95%CI [-2.20,-1.05], p<0.001; PROMIS, β=9.31, 95%CI [5.73,12.89], p<0.001), neighborhood median household income (MSRS-R, β=-3.80e-05, 95%CI [-5.05e-05,-2.56e-05], p<0.001; PDDS, β=-8.58e-06, 95%CI [-1.28e-05,-4.32e-06], p<0.001; PROMIS, β=2.55e-05, 95%CI [5.96e-07,5.05e-05], p=0.045), and neighborhood median home value (MSRS-R, β=-6.50e-06, 95%CI [-8.16e-06,-4.84e-06], p<0.001; PDDS, β=-1.54e-06, 95%CI [-2.11e-06,-9.65e-07], p<0.001; PROMIS, β=4.98e-06, 95%CI [1.81e-06,8.14e-06], p=0.002) drove the association between higher ADI and subsequently worse neurological disability (in joint analyses). Neighborhood percent of population with Medicaid, but not private insurance, significantly mediated the observed covariate-adjusted associations. Higher individual-level household income bracket was associated with better neurological outcomes in joint analyses (MSRS-R: R=-0.39, p<0.001; PDDS: R=-0.35, p<0.001; PROMIS: R=0.37, p<0.001), independent of ADI.ConclusionsLower neighborhood SES is associated with subsequently worse neurological outcomes in pwMS. Future testing of targeted intervention through public policies that improve SES are warranted.
| S-EPMC9444968 | biostudies-literature
Project description:Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.
| S-EPMC4383591 | biostudies-literature