CD72-semaphorin3A axis: A new regulatory pathway in systemic lupus erythematosus

Eiza, Nasren; Sabag, Adi D.; Kessler, Ofra; Neufeld, Gera; Vadasz, Zahava

doi:10.1016/j.jaut.2022.102960

Cited by 5 publications

(5 citation statements)

References 30 publications

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“…The up regulation of CD72 on B cells (of both normal individuals and patients suffering from SLE) following their co-culture with sema3A was reported in our seminal study ( Vadasz et al, 2014 ), suggesting that sema3A is a ligand for CD72 on B cells. Subsequently, we could definitely show that sema3A binds CD72, resulting in the restoration of B cell homeostasis and self-tolerance ( Eiza et al, 2022 ). With this in mind, the majority of studies do support the idea of Sema3A being a regulatory molecule.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we demonstrated that by binding CD72 the phosphorylation of STAT-4 and HDAC-1 was down-regulated, whereas P38MAPK and PKC-theta phosphorylation was up-regulated. This indicated that sema3A is a potential regulatory molecule able to restore immune-tolerance in SLE patients ( Eiza et al, 2022 ). Considering these regulatory properties, sema3A may become a potential therapeutic agent in restoring self-tolerance.…”

Section: Introductionmentioning

confidence: 99%

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Truncated-semaphorin3A is a potential regulatory molecule to restore immune homeostasis in immune-mediated diseases

et al. 2023

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Regulatory molecules have recently been recognized for their beneficial effects in the treatment of immune-mediated diseases, rather than using cytotoxic immune-suppressing drugs, which are associated with many unwanted side effects. Semaphorin3A (sema3A), a unique regulatory master of the immune system, was shown to be decreased in the serum of systemic lupus erythematosus (SLE) patients, in association with disease severity. Later, we were able to show its extremely beneficial effect in treating lupus nephritis in the NZB/W mice model. The mechanisms by which sema3A maintains its regulatory effect is by binding the regulatory receptor CD72 on B cells, thereby reducing the threshold of BCR signaling on B cells and reducing the production of pro-inflammatory cytokines. The aim of this study was to generate a stable sema3A molecule, easy to produce with a higher binding capacity to CD72 receptor rather than to Neuropilin-1 (NRP-1) receptor, which is expressed in many cell types. Using the crystallographic structure of parental sema3A, we synthesized a new secreted (shorter) sema3A derivative, which we called truncated sema3A (T-sema3A). The new molecule lacked the NRP-1 binding domain (the C-terminal site) and has an artificial dimerization site at position 257 (serine residue was exchanged with a cysteine residue). To facilitate the purification of this molecule we added Histidine epitope tag in frame upstream to a stop codon. This construct was transfected using a viral vector to 293HEK cells to generate cells stably expressing T-sema3A. T-sema3A is shown to be with a higher binding ability to CD72 than to NRP-1 as demonstrated by a homemade ELISA. In addition, T-sema3A was shown to be a regulatory agent which can induce the expression of IL-10 and TGF-β and reduce the secretion of pro-inflammatory cytokines such as IL-6, IFN-γ, and IL-17A from human T and B-lymphocytes. Keeping this in mind, T-sema3A is highly effective in maintaining immune homeostasis, therefore, becoming a potential agent in restoring the regulatory status of the immune system in immune-mediated diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Truncated-semaphorin3A is a potential regulatory molecule to restore immune homeostasis in immune-mediated diseases

et al. 2023

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“…In vivo studies in mice revealed that Sema3A reduces lupus nephritis in NZB/W mice by preventing the deposition of immune complexes in the glomeruli ( Bejar et al, 2018 ). These studies suggest that Sema3A administration restores self-tolerance and thereby reduces the pathogenesis of SLE ( Eiza et al, 2023 ). Moreover, recent studies established the role of class 3 semaphorins like Sema3A, Sema3C, and Sema3F in promoting human DC migration by inducing the F-actin organization ( Curreli et al, 2016 ) ( Table 1 ).…”

Section: Semaphorinsmentioning

confidence: 94%

“…Sema3A treatment enhances CD72 expression on B cells, and CD72 can be used as a biomarker to be followed during the treatment of SLE ( Vadasz et al, 2014 ). Mechanistically, Sema3A binding with CD72 on B cells inhibits the phosphorylation of STAT-4 and HDAC-1 but induces the phosphorylation of p38-MAPK in B cells ( Eiza et al, 2023 ). In vivo studies in mice revealed that Sema3A reduces lupus nephritis in NZB/W mice by preventing the deposition of immune complexes in the glomeruli ( Bejar et al, 2018 ).…”

Section: Semaphorinsmentioning

confidence: 99%