CD40L-Stimulated B Lymphocytes Are Polarized toward APC Functions after Exposure to IL-4 and IL-21

Interleukins 4 (IL-4) and 21 (IL-21) belong to the common gamma chain cytokine family which are highly involved in the progression of autoimmune diseases. While IL-4 is well known to be involved in the suppression of apoptosis of autoreactive B cells, the role played by IL-21 remains unclear. In the current study, we activated the human Burkitt’s lymphoma Ramos B cells with anti-IgM to mimic B cell hyperactivation observed in patients of autoimmune diseases. Consistent with other reported findings, anti-IgM led to the downregulation of proteins involved in B cell survival and proliferation, as well as the activation of caspase 3 activity and DNA damage, resulting in apoptotic cell death after 48-hour treatment. Although both IL-4 and IL-21 reversed anti-IgM-induced apoptosis and cell cycle arrest, they did so via different mechanisms: while IL-4 could directly suppress anti-IgM-induced caspase 3 activation and marker indicative of DNA damage, IL-21 could induce B cell proliferation in the presence of anti-IgM. Importantly, IL-21 also suppressed activation induced cell death in human primary B cells. Pre-treatment with clinically validated JAK inhibitors completely reversed the effects of IL-4 and IL-21 to rescue anti-IgM induced cell death and DNA damage. The results indicate the underlying mechanisms of how IL-4 and IL-21 differentially promote survival of hyperactivated B cells and provide hints to treat autoimmune diseases.

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Il-4 and Il-21 Rescued Ramos Cells Through Differential Mech...mentioning

confidence: 96%

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Interleukins 4 and 21 Protect Anti-IgM Induced Cell Death in Ramos B Cells: Implication for Autoimmune Diseases

Hui¹,

Wu²,

Leung³

2022

“…Also, COCH is regulated at the time of embryo implantation by leukemic inhibitory factor in the uterus (34). CD40LG, expressed on the T-cell surface, can regulate B-cell functions by engaging CD40 on the B-cell surface (35)(36)(37). CD40LG has been identified as a prognostic biomarker that regulates TME via immune processes in breast cancer (38).…”

Section: Discussionmentioning

confidence: 99%

A TP53 Related Immune Prognostic Model for the Prediction of Clinical Outcomes and Therapeutic Responses in Lung Adenocarcinoma

Zhang

Min²,

Yang³

et al. 2022

TP53 is the most frequently mutated gene in lung adenocarcinoma (LUAD). The tumor immune microenvironment (TIM) is considered a vital factor that influences tumor progression and survival rate. The influence of TP53 mutation on TIM in LUAD has not been fully studied. Here we systematically investigated the relationship and potential mechanisms between TP53 mutation status and immune response in LUAD. We constructed an immune prognostic model (IPM) using immune associated genes, which were expressed differentially between the TP53 mutant and wild type LUAD patients. We discovered that TP53 mutations were significantly associated with 5 immune related biological processes. Thirty-six immune genes were expressed differentially between TP53 mutant and wild type LUAD patients. An IPM was constructed using 3 immune genes to differentiate the prognostic survival in LUAD. The high-risk LUAD group displayed significantly higher proportions of dendritic cell resting, T cell CD4 memory resting and mast cell resting, and significantly low proportions of dendritic cell activated, T cell CD4 memory activated, and mast cell activated. Moreover, IPM was found to be an independent clinical feature and can be used to predict immunotherapy responses. In summary, we constructed and validated an IPM using 3 immune related genes, which provides a better understanding of the mechanism from an immunological perspectives.

“…B cells were only recently observed to act as natural APCs for T cells, promoting their activation and proliferation when B cells were exposed to T follicular helper (Tfh) cell CD40L and IL4 signaling in contrast to IL21 signaling ( 105 , 106 ). Colocalization at the T cell-B cell border of lymph nodes or within B cell follicles represent opportunities for B cell antigen presentation to T cells, facilitating T helper functions, B cell activation and clonal expansion.…”

Section: Functional Diversity In Antibodies and B Cellsmentioning

confidence: 99%

Leveraging Antibody, B Cell and Fc Receptor Interactions to Understand Heterogeneous Immune Responses in Tuberculosis

Carpenter

2022

Despite over a century of research, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to kill 1.5 million people annually. Though less than 10% of infected individuals develop active disease, the specific host immune responses that lead to Mtb transmission and death, as well as those that are protective, are not yet fully defined. Recent immune correlative studies demonstrate that the spectrum of infection and disease is more heterogenous than has been classically defined. Moreover, emerging translational and animal model data attribute a diverse immune repertoire to TB outcomes. Thus, protective and detrimental immune responses to Mtb likely encompass a framework that is broader than T helper type 1 (Th1) immunity. Antibodies, Fc receptor interactions and B cells are underexplored host responses to Mtb. Poised at the interface of initial bacterial host interactions and in granulomatous lesions, antibodies and Fc receptors expressed on macrophages, neutrophils, dendritic cells, natural killer cells, T and B cells have the potential to influence local and systemic adaptive immune responses. Broadening the paradigm of protective immunity will offer new paths to improve diagnostics and vaccines to reduce the morbidity and mortality of TB.