Biology and function of neuroimmune semaphorins 4A and 4D

Nkyimbeng-Takwi, EusebiusHenry; Chapoval, Svetlana P

doi:10.1007/s12026-010-8201-y

Cited by 58 publications

(78 citation statements)

References 79 publications

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“…Sema4C is therefore the first semaphorin specifically induced on B-lymphocytes under Th2 conditions, yet it is among the least explored semaphorins in immune biology. Related family members such as Sema4D and Sema4A have been studied in B-lymphocytes (8, 10), T-lymphocytes (36, 37), and dendritic cells (8, 38). Mice with a selective KO of Sema4D demonstrated poor recall responses to antigens and impaired immunoglobulin production.…”

Section: Discussionmentioning

confidence: 99%

Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses

et al. 2016

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BackgroundSemaphorins are important molecules in embryonic development and multiple semaphorins have been identified as having key roles in immune regulation. To date, there is little known about Semaphorin 4C (Sema4C) in immune biology. We report for the first time that Sema4C is inducible in human and murine B-cells and may be important for normal B-cell development.MethodsHuman tonsillar B-cells were studied following activation via anti-CD40 antibodies in the presence or absence of representative Th1, Th2, and regulatory cytokines. Murine B-cells from WT and Sema4C−/− mice were similarly stimulated. B-cell phenotyping in WT and Sema4C mutant mice was performed by flow cytometry and lymphoid architecture was studied by immunohistochemistry. Sema4C expression and synapse formation were analyzed by confocal microscopy.ResultsGene array studies performed on human tonsillar B-cells stimulated to produce IgE revealed that Sema4C was among the top genes expressed at 24 h, and the only semaphorin to be increased under Th2 conditions. Validation studies demonstrated that human and murine B-cells expressed Sema4C under similar conditions. Sema4C−/− mice had impaired maturation of B-cell follicles in spleens and associated decreases in follicular and marginal zone B-cells as well as impaired IgG and IgA production. In keeping with a potential role in maturation of B-cells, Sema4C was expressed predominantly on CD27+ human B-cells. Within 72 h of B-cell activation, Sema4C was localized to one pole in a synapse-like structure, in association with F-actin, B-cell receptor, and Plexin-B2. Cell polarization was impaired in Sema4C−/− mice.ConclusionWe have identified a novel immune semaphorin induced in human and murine B-cells under Th2 conditions. Sema4C appears to be a marker for human memory B-cells. It may be important for B-cell polarization and for the formation of normal splenic follicles.

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Section: Discussionmentioning

confidence: 99%

Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses

et al. 2016

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“…[24][25][26][27][28] SEMA-4D is expressed at low levels in resting T cells, B cells, macrophages, NK cells, and dendritic cells, and upon activation of these cells SEMA-4D is up-regulated. 29,30 SEMA-4D shedding is blocked by matrix metalloproteinase (MMP) inhibitors, with ADAM17 and MT1-MMP (membrane-type-1 matrix metalloproteinase) involved. 31,32 Human multipotent neural precursors or primary oligodendrocytes from rat brain exposed to T cells-chronically activated by HTLV-1-expressing sSEMA-4D-induce apoptosis and neurite extension collapse, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…29 Both the increased level of sSEMA-4D released from PBMCs of HAM/TSP patients and the interaction of Tax with this semaphorin suggest that Tax secreted by HTLV-1-infected lymphocytes might play a role in the pathology. The significantly higher levels of sSEMA-4D in PBMC culture medium of HAM/TSP patients can be explained by an increase in matrix metalloproteinase expression/activity.…”

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confidence: 99%

Tax and Semaphorin 4D Released from Lymphocytes Infected with Human Lymphotropic Virus Type 1 and Their Effect on Neurite Growth

Quintremil

Alberti

Medina

et al. 2016

AIDS Research and Human Retroviruses

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Human lymphotropic virus type 1 (HTLV-1) is a retrovirus causing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative central nervous system (CNS) axonopathy. This virus mainly infects CD4 + T lymphocytes without evidence of neuronal infection. Viral Tax, secreted from infected lymphocytes infiltrated in the CNS, is proposed to alter intracellular pathways related to axonal cytoskeleton dynamics, producing neurological damage. Previous reports showed a higher proteolytic release of soluble Semaphorin 4D (sSEMA-4D) from CD4 + T cells infected with HTLV-1. Soluble SEMA-4D binds to its receptor Plexin-B1, activating axonal growth collapse pathways in the CNS. In the current study, an increase was found in both SEMA-4D in CD4+ T cells and sSEMA-4D released to the culture medium of peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients compared to asymptomatic carriers and healthy donors. After a 16-h culture, infected PBMCs showed significantly higher levels of CRMP-2 phosphorylated at Ser 522 . The effect was blocked either with anti-Tax or anti-SEMA-4D antibodies. The interaction of Tax and sSEMA-4D was found in secreted medium of PBMCs in patients, which might be associated with a leading role of Tax with the SEMA-4D-Plexin-B1 signaling pathway. In infected PBMCs, the migratory response after transwell assay showed that sSEMA-4D responding cells were CD4 + Tax + T cells with a high CRMP-2 pSer 522 content. In the present study, the participation of Tax-sSEMA-4D in the reduction in neurite growth in PC12 cells produced by MT2 (HTLV-1-infected cell line) culture medium was observed. These results lead to the participation of plexins in the reported effects of infected lymphocytes on neuronal cells.

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“…This biologic represents a novel therapeutic strategy for cancer, as well as for MS, and other neuroinflammatory/neurodegenerative diseases (for review see 11, 18, 19). Although the mechanism of action differs in each of these therapeutic indications, measurements of the degree of cSEMA4D saturation produce important pharmacodynamic data for each indication.…”

mentioning

confidence: 99%

Saturation monitoring of VX15/2503, a novel semaphorin 4D‐specific antibody, in clinical trials

Fisher

Seils

Reilly

et al. 2015

Cytometry Part B Clinical

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BackgroundReceptor occupancy, or saturation, assays are often utilized in preclinical and clinical development programs to evaluate the binding of a biologic to a cellular target. These assays provide critical information regarding the dose of drug required to “saturate” the target as well as important pharmacodymamic (PD) data. A flow cytometric method was developed to measure the degree of Semaphorin 4D (SEMA4D; CD100) saturation by VX15/2303, an investigational monoclonal antibody specific for SEMA4D.MethodsThe assay detects VX15/2503, a human IgG4 specific for SEMA4D, with an IgG4‐specific monoclonal antibody.ResultsData generated allowed assessment of two related SEMA4D‐specific pharmacodynamic (PD) markers: (1) The measurement of cellular SEMA4D (cSEMA4D) saturation by VX15/2503, and (2) the cell membrane expression levels of cSEMA4D.ConclusionsThis assay specifically and reproducibly measured cSEMA4D saturation and expression levels. Evaluation of the SEMA4D‐specific PD markers were critical in determining the clinical saturation threshold of cSEMA4D by VX15/2503. © 2015 he Authors Cytometry Part B: Clinical Cytometry Published by Wiley Periodicals, Inc.

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Biology and function of neuroimmune semaphorins 4A and 4D

Cited by 58 publications

References 79 publications

Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses

Semaphorin 4C: A Novel Component of B-Cell Polarization in Th2-Driven Immune Responses

Tax and Semaphorin 4D Released from Lymphocytes Infected with Human Lymphotropic Virus Type 1 and Their Effect on Neurite Growth

Saturation monitoring of VX15/2503, a novel semaphorin 4D‐specific antibody, in clinical trials

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