T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell–Cell Contact Mediated through SLAMF6 and SAP

Radomir, Lihi; Cohen, Sivan; Kramer, Matthias P.; Bakos, Eszter; Lewinsky, Hadas; Barak, Avital; Porat, Ziv; Bucala, Richard; Stepensky, Polina; Becker-Herman, Shirly; Shachar, Idit

doi:10.4049/jimmunol.1700557

Cited by 25 publications

(19 citation statements)

References 47 publications

(73 reference statements)

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“…B cells in CD74‐deficient mice revealed an arrest at the transitional stage and a reduced lifespan . Consistently, decreased CD74 expression impaired B‐cell maturation in patients with X‐linked lymphoproliferative disease . Both cell autonomous and nonautonomous roles of CD74 could explain these defects in B‐cell development.…”

Section: Discussionmentioning

confidence: 72%

The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis

et al. 2018

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In MS, B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the underlying molecular mechanisms are relatively underexplored. In mice, the MIF pathway controls B‐cell development and the induction of EAE. Here, we found that MIF and MIF receptor CD74 are downregulated, while MIF receptor CXCR4 is upregulated in B cells from early onset MS patients. B cells were identified as the main immune subset in blood expressing MIF. Blocking of MIF and CD74 signaling in B cells triggered CXCR4 expression, and vice versa, with separate effects on their proinflammatory activity, proliferation, and sensitivity to Fas‐mediated apoptosis. This study reveals a new reciprocal negative regulation loop between CD74 and CXCR4 in human B cells. The disturbance of this loop during MS onset provides further insights into how pathogenic B cells survive peripheral tolerance checkpoints to mediate disease activity in MS.

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Section: Discussionmentioning

confidence: 72%

The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis

et al. 2018

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“…Thus, this finding was the first hint of a connection between MIF-B-cell interactions and atherogenesis. This link was further insinuated by previous observations showing that MIF promotes B-cell survival (25,26) and chemotaxis in vitro (27).…”

Section: Discussionmentioning

confidence: 88%

“…MIF supports B-cell survival by activation of the CD74-CD44 receptor complex (25,26) and was found to promote B-cell chemotaxis through its receptors CXCR4 and CD74 (27,28). However, B-cell subtype-specific effects of MIF have not been explored, and the interactions between MIF and B cells in atherogenesis are unknown.…”

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confidence: 99%

Mif ‐deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis

et al. 2018

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The inflammatory cytokine macrophage migration-inhibitory factor (MIF) promotes atherosclerosis via lesional monocyte and T-cell recruitment. B cells have emerged as important components in atherogenesis, but the interaction between MIF and B cells in atherogenesis is unknown. Here, we investigated the atherosclerotic phenotype of Mif-gene deletion in Apoe mice. Apoe Mif mice fed a Western diet exhibited strongly reduced atherosclerotic lesions in brachiocephalic artery (BC) and abdominal aorta compared with controls. This phenotype was accompanied by reduced circulating B cells. Flow cytometry revealed a B-cell developmental defect with increased premature and immature B-cell counts in bone marrow (BM) of Apoe Mif mice and diminished B-cell numbers in spleen. This finding was linked with a decreased expression of Baff-R and differentiation-driving transcription factors at the immature B-cell stage, whereas peritoneal B cells exhibited unchanged CD80 and CD86 expression but vastly decreased CD9 and elevated CD23 levels, indicating that the developmental block favors the generation of immature, egressing, and reactive B cells. Mif deficiency did not affect absolute B-cell numbers in the vessel wall but favored a relative increase of B cells in the atheroprone BC region and the appearance of periadventitial B-cell-rich clusters. Of note, Mif mice exhibited a significant increase in oxidized low-density lipoprotein (oxLDL)-specific antibodies after the injection of oxLDL, indicating that Mif deficiency is associated with higher sensitivity of B cells against natural-occurring antigens such as oxLDL. Importantly, Apoe mice adoptively transplanted with ApoeMif BM showed reduced peripheral B cells compared with Apoe BM transplantation but no atheroprotection in the BC; also, whereas there was a selective increase in atheroprotective IgM-anti-oxLDL-antibodies in global Mif deficiency, BM-specific Mif deficiency also led to elevated proatherogenic anti-oxLDL-IgG. Together, these findings reveal a novel link between MIF and B cells in atherogenesis. Protection from atherosclerosis by Mif deficiency is associated with enhanced B-cell hypersensitivity, which in global but not BM-restricted Mif deficiency favors an atheroprotective autoantibody profile in atherosclerotic mice. Targeting MIF may induce protective B-cell responses in atherosclerosis.-Schmitz, C., Noels, H., El Bounkari, O., Straussfeld, E., Megens, R. T. A., Sternkopf, M., Alampour-Rajabi, S., Krammer, C., Tilstam, P. V., Gerdes, N., Bürger, C., Kapurniotu, A., Bucala, R., Jankowski, J., Weber, C., Bernhagen, J. Mif-deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis.

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“…SLAMF6 is a member of superfamily immunoglobulin (Ig) domain-containing molecules that are involved in haemophilic interactions between naive B and T cells. 41 SLAMF6 acts as a costimulatory molecule on the surface of T lymphocytes to increase T-cell adhesiveness by activating the small GTPase Rap1, promoting the TCR downstream signal transduction and the differentiation to Th17 cells expressing IL-17A. 42 SLAMF members including SLAMF6 have been proposed as potential therapeutic targets for inflammatory and autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis

et al. 2020

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ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population.MethodsWe newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.ResultsWe identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta<5×10−8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.ConclusionThis study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

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T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell–Cell Contact Mediated through SLAMF6 and SAP

Cited by 25 publications

References 47 publications

The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis

The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis

Mif ‐deficiency favors an atheroprotective autoantibody phenotype in atherosclerosis

Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis

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