IL-21 enhances STAT3/Blimp-1 signaling pathway in B cells and contributes to plasma cell differentiation in newly diagnosed patients with myasthenia gravis

Xu, Yanan; Huang, Xiaoyu; Li, Fengzhan; Liu, Tan; Yang, Tingting; Chen, Fei; Zhu, Jie; Pan, Meng; Wang, Yu‐Zhong; Fu, Lei; Xiao, Chengshan; Geng, Deqin

doi:10.1007/s12026-020-09164-2

Cited by 5 publications

(4 citation statements)

References 49 publications

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“…In addition, the increase in TLS in tumor tissue after neoadjuvant chemoimmunotherapy may provide an ideal site for tumor-specific T-B cell interactions and collaboration. Published studies have confirmed that IL-21 can induce class switching of naive B cells to IgG [ 40 , 41 ], and IL-21 stimulation up-regulated STAT3 phosphorylation, increased Blimp-1 expression in B cells, and promoted plasma cell differentiation. The dominant IgG1 and IgG3 antibodies can bind to the Fcγ receptor (FcγR) and trigger ADCC and antibody-mediated phagocytosis and mediate complement-based cytotoxicity to kill tumor cells [ 42 ].…”

Section: Discussionmentioning

confidence: 97%

Single-cell profiling of immune cells after neoadjuvant pembrolizumab and chemotherapy in IIIA non-small cell lung cancer (NSCLC)

et al. 2022

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The combination of immune checkpoint inhibitors (ICIs) with chemotherapy (chemoimmunotherapy) in the neoadjuvant setting have achieved favorable clinical benefits in non-small cell lung cancer (NSCLC), but the mechanism of clinical responses remain unclear. We provide a rich resource of 186,477 individual immune cells from 48 samples of four treatment-naive and eight neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients (responders versus non-responders) by single-cell RNA-seq and TCR-seq. We observed the synergistic increase of B cells and CD4+ T cells were associated with a positive therapeutic response of neoadjuvant chemoimmunotherapy. B cell IgG subclasses IgG1 and IgG3 played a critical role in anti-tumor immune response in tumor lesions, and this process was driven by increased IL-21 secreted by infiltrated T follicular helper (Tfh) cells after neoadjuvant chemoimmunotherapy. Furthermore, we uncovered several critical events for positive clinical outcomes, including the diminished activated TNFRSF4+ regulatory T cells (Tregs), increased LAMP3+ dendritic cells (DCs), and the expansion of intratumoral CD4+ T clones and peripheral C3-Cytotoxic CD8+ T clones. A validation cohort of 26 treatment-naive and 30 neoadjuvant chemoimmunotherapy treated IIIA/ IIIB NSCLC patients verified these findings. In total, our comprehensive study of the single-cell profile of immune cells provides insights into mechanisms underlying anti-PD-1-based therapies and identified potential predictive factors and therapeutic targets for improving the efficiency of neoadjuvant chemoimmunotherapy in NSCLC.

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Section: Discussionmentioning

confidence: 97%

Single-cell profiling of immune cells after neoadjuvant pembrolizumab and chemotherapy in IIIA non-small cell lung cancer (NSCLC)

et al. 2022

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“…Our group and others have also demonstrated that IL-6-deficient mice are resistant to MG, and that anti-IL-6 Ab treatment reduces autoAb levels and suppresses the disease in a rat model of MG ( 11 , 12 ). Therapeutic Abs against IL-6 or IL-6 receptors have been developed and shown to be beneficial for patients with refractory MG ( 13 ), further providing the evidence that IL-6 play a pivotal role in MG. IL-6-mediated upregulation of IL-21 and the role of IL-21 in MG pathogenesis have recently been demonstrated ( 14 , 15 ). Elevated serum levels of IL-21 secreted from follicular T-helper cells have been shown to correlate with enhanced Ab production from B cells in MG patients ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis

et al. 2022

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Myasthenia gravis (MG) is an autoimmune disease characterized by chronic muscle fatigue and weakness caused by autoantibodies and complement-mediated damage at neuromuscular junctions. Histone deacetylases (HDACs) are crucial epigenetic regulators of proinflammatory gene expression; however, it is unclear whether HDACs modulate chronic inflammation or autoantibody production associated with MG pathogenesis. We examined expression profiles and serum levels of key inflammatory cytokines (IL-6 and IL-21) and acetylcholine receptor (AChR)-specific autoantibodies following pharmacological inhibition of key HDAC isoforms in a mouse model of MG. We found that HDAC inhibition significantly reduced the production of IL-6, but not IL-21, in AChR-stimulated PBMCs and splenocytes (n = 5 per group). Trichostatin (pan-HDAC inhibitor) treatment of MG-PBMCs (n = 2) also exhibited reduced production of induced IL-6. Although HDAC1 inhibition lowered IL-6 levels the most, HDAC2 inhibition depleted intracellular IL-6 and markedly reduced serum anti-AChR IgG2b in EAMG mice. The transcriptomic profiling and pathway mapping also revealed that autoimmunity-linked, major cell signaling pathways were differentially altered by HDAC1/2 inhibition. HDAC inhibition-mediated reduction in IL-6 and autoantibody levels also correlated with milder disease and preservation of muscle AChR in the treated mice. Overall, our findings revealed isoform-specific functional variance of HDACs in reducing inflammation and identified HDAC-regulated many genes underlying specific inflammatory and autoantibody pathways in EAMG. Thus, the study provides a rationale for further research to evaluate the HDACs or their gene targets as a potential adjunct treatment for MG.

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“…Very hypothetically, these findings could indicate an oncogenic interaction of 6q deletion and BCL2 translocation. PRDM1 ( BLIMP1 ) that has been described to be involved in plasma cell differentiation 32 is affected by the 6q deletion. The interplay of a PRDM1 -deletion in SFL, that more frequently harbor BCL2 translocations, might support the germinal center (GC) differentiation of B-cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular Cytogenetic Profiling Reveals Similarities and Differences Between Localized Nodal and Systemic Follicular Lymphomas

Horn¹,

Jurinović²,

Leich³

et al. 2022

HemaSphere

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Recently, we have developed novel highly promising gene expression (GE) classifiers discriminating localized nodal (LFL) from systemic follicular lymphoma (SFL) with prognostic impact. However, few data are available in LFL especially concerning hotspot genetic alterations that are associated with the pathogenesis and prognosis of SFL. A total of 144 LFL and 527 SFL, enrolled in prospective clinical trials of the German Low Grade Lymphoma Study Group, were analyzed by fluorescence in situ hybridization to detect deletions in chromosomes 1p, 6q, and 17p as well as BCL2 translocations to determine their impact on clinical outcome of LFL patients. The frequency of chromosomal deletions in 1p and 17p was comparable between LFL and SFL, while 6q deletions and BCL2 translocations more frequently occurred in SFL. A higher proportion of 1p deletions was seen in BCL2 -translocation–positive LFL, compared with BCL2 -translocation–negative LFL. Deletions in chromosomes 1p, 6q, and 17p predicted clinical outcome of patients with SFL in the entire cohort, while only deletions in chromosome 1p retained its negative prognostic impact in R-CHOP–treated SFL. In contrast, no deletions in one of the investigated genetic loci predicted clinical outcome in LFL. Likewise, the presence or absence of BCL2 translocations had no prognostic impact in LFL. Despite representing a genetic portfolio closely resembling SFL, LFL showed some differences in deletion frequencies. BCL2 translocation and 6q deletion frequency differs between LFL and SFL and might contribute to distinct genetic profiles in LFL and SFL.

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IL-21 enhances STAT3/Blimp-1 signaling pathway in B cells and contributes to plasma cell differentiation in newly diagnosed patients with myasthenia gravis

Cited by 5 publications

References 49 publications

Single-cell profiling of immune cells after neoadjuvant pembrolizumab and chemotherapy in IIIA non-small cell lung cancer (NSCLC)

Single-cell profiling of immune cells after neoadjuvant pembrolizumab and chemotherapy in IIIA non-small cell lung cancer (NSCLC)

Histone Deacetylase Isoforms Differentially Modulate Inflammatory and Autoantibody Responses in a Mouse Model of Myasthenia Gravis

Molecular Cytogenetic Profiling Reveals Similarities and Differences Between Localized Nodal and Systemic Follicular Lymphomas

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