The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

Ueno, Hideki

doi:10.1002/eji.201948134

Cited by 25 publications

(11 citation statements)

References 66 publications

(150 reference statements)

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“…29,30 Notably, in autoimmune diseases such as SLE, CD11c + CD21 − CXCR5 − B cells maintain the capacity to respond to BCR stimulation and differentiate into antibody-producing cells, 46,47 whereas CD11c + CD21 − CXCR5 − B cells in chronic infectious diseases are more prone to becoming anergic or exhausted. 49 Thus, Tph cells might promote the differentiation of CD11c + CD21 − CXCR5 − B cells into autoantibody-producing cells outside TLSs and lymphoid aggregates.…”

Section: Similarities Between Tph and Tfh Cellsmentioning

confidence: 99%

Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases

2020

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The interactions of CD4 + T cells and B cells are fundamental for the generation of protective antibody responses, as well as for the development of harmful autoimmune diseases. Recent studies of human tissues and blood samples have established a new subset of CD4 + B helper T cells named peripheral helper T (Tph) cells. Unlike T follicular helper (Tfh) cells, which interact with B cells within lymphoid organs, Tph cells provide help to B cells within inflamed tissues. Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells. The differentiation mechanism is also partly shared between Tph and Tfh cells in humans, and both Tfh and Tph cells can be found within the same tissues, including cancer tissues. However, Tph cells display features distinct from those of Tfh cells, such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio. Unlike that of Tfh cells, current evidence shows that the target of Tph cells is limited to memory B cells. In this review, we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.

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Section: Similarities Between Tph and Tfh Cellsmentioning

confidence: 99%

Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases

2020

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“…We identified several novel as well as known TF-surface protein relationships for each cell type (e.g. EOMES-CD27 ( 27 ), STAT6-CD27 ( 28 ) STAT5-TIGIT ( 29 ), STAT3-ICOS (CD278) ( 30–32 ), SMAD3-CD127, STAT1-CD127 ( 33 , 34 ) in CD8 + T cells; STAT1/STAT4/STAT5-CD27 ( 35–37 ), PRDM1-HLA-DR in B cells ( 38 ); SMAD5-ICOS (CD278) ( 39 ), STAT5-CD27 ( 40 ), MEF2-PD1 ( 41 ) in CD4 + Memory T cells). We next evaluated the known pathway overlap between TF and surface proteins.…”

Section: Resultsmentioning

confidence: 99%

SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators

Somasundaram

et al. 2021

Nucleic Acids Research

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The identity and functions of specialized cell types are dependent on the complex interplay between signaling and transcriptional networks. Recently single-cell technologies have been developed that enable simultaneous quantitative analysis of cell-surface receptor expression with transcriptional states. To date, these datasets have not been used to systematically develop cell-context-specific maps of the interface between signaling and transcriptional regulators orchestrating cellular identity and function. We present SPaRTAN (Single-cell Proteomic and RNA based Transcription factor Activity Network), a computational method to link cell-surface receptors to transcription factors (TFs) by exploiting cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) datasets with cis-regulatory information. SPaRTAN is applied to immune cell types in the blood to predict the coupling of signaling receptors with cell context-specific TFs. Selected predictions are validated by prior knowledge and flow cytometry analyses. SPaRTAN is then used to predict the signaling coupled TF states of tumor infiltrating CD8+ T cells in malignant peritoneal and pleural mesotheliomas. SPaRTAN enhances the utility of CITE-seq datasets to uncover TF and cell-surface receptor relationships in diverse cellular states.

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“…The secondary messengers whose phosphorylation state is modulated by sema3A via the CD72 receptor were all found to be of crucial importance in autoimmune diseases such as SLE. For example, IL-12 induced activation of STAT-4 in B cells contributes to the generation of autoantibodies and the secretion of inflammatory cytokines that play a role in many immunemediated inflammatory diseases (34). In agreement, STAT-4 deficient mice contain increased concentrations of CD4 + Foxp3 + Tregs in their lymph nodes, suggesting that inhibition of STAT-4 expression contributes to Foxp3 + Tregs responses (35).…”

Section: Discussionmentioning

confidence: 95%

CD72-semaphorin3A axis; a possible new player in immune regulation

Eiza

Vadasz

Sabag

et al. 2021

Preprint

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Semaphorin3A (sema3A) inhibits the activity of B and T cells in autoimmune diseases such as Systemic Lupus Erythematosus (SLE). We have now found that CD72 functions as a novel sema3A binding and signal-transducing receptor. These functions of CD72 are independent of the known sema3A receptor neuropilin-1 (NRP-1). We find that sema3A induces the phosphorylation of CD72 on tyrosine residues and the association of CD72 with SHP-1 and SHP-2. In contrast, sema4D/CD100 inhibits these functions. sema3A signals mediated by CD72, inhibit the phosphorylation of STAT-4 and HDAC-1 and induce the phosphorylation of p38-MAPK and PKC-theta in B-cells derived B-lymphoblastoid (BLCL) cells lacking NRP-1 expression, and in primary B-cells isolated from either healthy donors or SLE (Systemic Lupus Erythematosus) patients. We have also generated a modified truncated sema3A (T-sema3A) which cannot signal via NRP-1 yet still activates inhibitory CD72 signaling. We propose that T-sema3A may have potential as a possible therapeutic for autoimmune diseases such as SLE.

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The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

Cited by 25 publications

References 66 publications

Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases

Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases

SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators

CD72-semaphorin3A axis; a possible new player in immune regulation

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