The CD40–CD40L Dyad in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Aarts, Suzanne A. B. M.; Seijkens, Tom; Dorst, Koos J.F. van; Dijkstra, Christine D.; Kooij, Gijs; Lutgens, Esther

doi:10.3389/fimmu.2017.01791

Cited by 56 publications

(57 citation statements)

References 117 publications

(140 reference statements)

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“…These data suggest that genetically-determined modulation of CD40 mRNA expression may promote MS risk via effects of alternatively-spliced transcripts on IL-10 production, although the exact mechanism remains to be clarified. Monoclonal antibodies blocking the interaction between CD40L and CD40 have shown efficacy in rodent and primate EAE 24 .…”

Section: Discussionmentioning

confidence: 99%

“…Early phase II data showed promising efficacy of an anti-CD40L mAb in lupus nephritis 27 . Despite phase I safety of the anti-CD40L antibody, IDEC-131, in MS, the phase II trial was halted due to increased risk of thromboembolic disease caused by inhibition of the thrombusstabilising interaction between CD40L and platelet alpha2,beta3 integrins 24,28 . Subsequently, various strategies have been deployed to overcome this safety concern.…”

Section: Discussionmentioning

confidence: 99%

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Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

Jacobs

Taylor

Awad

et al. 2020

Preprint

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Background:Multiple Sclerosis (MS) is a complex autoimmune disease caused by a combination of genetic and environmental factors. Translation of Genome-Wide Association Study (GWAS) findings in MS into therapeutics and effective preventive strategies has been limited to date. Methods:We used Summary Data-Based Mendelian Randomisation (SMR) to synthesise findings from public expression quantitative trait locus (eQTL; eQTLgen and CAGE), methylation quantitative trait locus (mQTL; Lothian Birth Cohort and Brisbane Systems Genetics Study), and MS GWAS datasets (International Multiple Sclerosis Genetics Consortium). By correlating the effects of methylation on MS (M-2-MS), methylation on expression (M-2-E), and expression on MS susceptibility (E-2-MS), we prioritise genetic loci with strong evidence of causally influencing MS susceptibility. We overlay these findings onto a list of 'druggable' genes, i.e. genes which are currently, or could theoretically, be targeted by therapeutic compounds. We use GeNets and STRING to identify protein-protein interactions and druggable pathways enriched in our results. We extend these findings to a model of Epstein-Barr Virus-infected B cells, Lymphoblastoid Cell Lines (LCLs). We conducted a systematic review of prioritised genes using the Open Targets platform to identify completed and planned trials targeted prioritised genes in MS and related disease areas. Results:Expression of 45 genes in peripheral was strongly associated with MS susceptibility (False discovery rate 0.05). Of these 45 genes, 20 encode a protein which is currently targeted by an existing therapeutic compound. These genes were enriched for Gene Ontology terms pertaining to immune system function and leukocyte signalling. We refined this prioritised gene list by restricting to loci where CpG site methylation was associated with MS susceptibility (M-2-MS), with gene expression (M-2-E), and where expression was associated with MS susceptibility (E-2-MS). This approach yielded a list of 15 prioritised druggable target genes for which there was evidence of a causal pathway linking methylation, expression, and MS. Five of these 15 genes are targeted by existing drugs (CD40, ERBB2, VEGFB, MERTK, and PARP1), and three were replicated in a smaller eQTL dataset (CD40, MERTK, and PARP1). In LCLs, SMR prioritised 7 druggable gene targets, of which only one was priortised by the multi-omic approach in peripheral blood (FCRL3). Systematic review of Open Targets revealed multiple early-phase trials targeting 13/20 prioritised genes in disorders related to MS. Conclusions:We use public datasets and SMR to identify a list of prioritised druggable genetic targets in Multiple Sclerosis. We hope our findings could be translated into effective repurposing of existing drugs to provide novel therapies for MS and, potentially, provide a platform for developing preventive therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

Jacobs

Taylor

Awad

et al. 2020

Preprint

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“…Additionally, CD49d + CD154 + lymphocyte proliferation was accompanied by enhanced concentration of sCD40 in supernatants as a result of negative feedback regulatory loop for CD154-CD40 interaction ( Figure 1C) [26]. RR-MS PBMCs in response to myelin peptides opposite to HC PBMCs produced proinflammatory chemokines: CCL1, 2,7,8,20,21,22,24,25,27,CXCL1,2,5,6,8,9,11,17, proinflammatory cytokines: MIF1, IL-1β, IL-2, and TNF-α (Table 1). Taken together, we demonstrated the induction of autoreactive CD49d + CD154 + lymphocytes in MS patients in PBMCs exposed to myelin peptides and confirmed the role of CD154-CD40 interaction in this process.…”

Section: Cd49d + Cd154 + Lymphocytes Of Rr-ms Patients Proliferate Inmentioning

confidence: 99%

“…In a mouse model of RR-MS, experimental autoimmune encephalomyelitis (EAE), it was demonstrated that CD154 + T cells infiltrate the CNS on the fourth day of postimmunization and their number increases during the acute phase and remains constant in the period of remission [8]. CD154-mediated activation of CD40-expressing cells in the CNS such as monocytes, macrophages, and activated microglia [7] results in the secretion of proinflammatory cytokines/chemokines, which fuel ongoing inflammation [9]. The significance of CD154-CD40 dyad in the disease progression has been demonstrated in the studies with CD154 and CD40 knock-out mice, as well as with the use of neutralizing mAbs anti-CD154 or anti-CD40 in EAE [7,[10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…The single nucleotide polymorphism (SNP) analysis revealed that the variant of CD40 gene (rs1883822C>T) was associated with an increased risk for MS in comparison to healthy individuals about 1.5-fold in heterozygous and 2.5-fold in homozygotes, respectively [15,16]. It was also demonstrated that stimulation of CD40 receptor on B cells of RR-MS patients resulted in significantly higher proliferation than in healthy subjects [17], and application of neutralizing anti-CD154 mAbs (clone IDEC-131) showed promising results in inhibiting the relapses during clinical trials [9,18].…”

Section: Introductionmentioning

confidence: 99%

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Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination

Piatek

Namiecińska

Domowicz

et al. 2019

Cells

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Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d + CD154 + lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d + CD154 + lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d + CD154 + lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d + CD154 + lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d + CD154 + cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG 35-55 ) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d + /CD154 + cells were found to be co-localized with O4 + cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d + CD154 + lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.

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Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis

Aarts

Seijkens

Kusters

et al. 2019

The Journal of Pathology

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The costimulatory CD40L–CD40 dyad plays a major role in multiple sclerosis (MS). CD40 is highly expressed on MHCII + B cells, dendritic cells and macrophages in human MS lesions. Here we investigated the role of the CD40 downstream signaling intermediates TNF receptor‐associated factor 2 (TRAF2) and TRAF6 in MHCII + cells in experimental autoimmune encephalomyelitis (EAE). Both MHCII–CD40–Traf2 −/− and MHCII–CD40–Traf6 −/− mice showed a reduction in clinical signs of EAE and prevented demyelination. However, only MHCII–CD40–Traf6 −/− mice displayed a decrease in myeloid and lymphoid cell infiltration into the CNS that was accompanied by reduced levels of TNF‐α, IL‐6 and IFN‐γ. As CD40–TRAF6 interactions predominantly occur in macrophages, we subjected CD40 flfl LysM cre mice to EAE. This myeloid‐specific deletion of CD40 resulted in a significant reduction in EAE severity, reduced CNS inflammation and demyelination. In conclusion, the CD40–TRAF6 signaling pathway in MHCII + cells plays a key role in neuroinflammation and demyelination during EAE. Concomitant with the fact that CD40–TRAF6 interactions are predominant in macrophages, depletion of myeloid CD40 also reduces neuroinflammation. CD40–TRAF6 interactions thus represent a promising therapeutic target for MS. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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The CD40–CD40L Dyad in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Cited by 56 publications

References 117 publications

Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination

Macrophage CD40 signaling drives experimental autoimmune encephalomyelitis

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