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Autoimmune diseases are heterogeneous disorders believed to stem from the immune system’s inability to distinguish between auto- and foreign- antigens. B lymphocytes serve a crucial role in humoral immunity as they generate antibodies and present antigens. Dysregulation of B cell function induce the onset of autoimmune disorders by generating autoantibodies and pro-inflammatory cytokines, resulting in an imbalance in immune regulation. New research in immunometabolism shows that cellular metabolism plays an essential role in controlling B lymphocytes immune reactions by providing the energy and substrates for B lymphocytes activation, differentiation, and function. However, dysregulated immunometabolism lead to autoimmune diseases by disrupting self-tolerance mechanisms. This review summarizes the latest research on metabolic reprogramming of B lymphocytes in autoimmune diseases, identifying crucial pathways and regulatory factors. Moreover, we consider the potential of metabolic interventions as a promising therapeutic strategy. Understanding the metabolic mechanisms of B cells brings us closer to developing novel therapies for autoimmune disorders.

Background and PurposeWhite blood cell count to mean platelet volume ratio (WMR) is increasingly recognized as a promising biomarker. However, its predictive capability for acute ischemic stroke (AIS) patients is relatively less researched. The primary aim of this study is to explore its prognostic value in AIS patients after reperfusion regarding 3-month poor functional outcome.MethodsA total of 549 AIS patients who had undergone vascular reperfusion procedure with complete 3-month follow-up were retrospectively recruited in this study. White blood cell count, mean platelet volume at 24 h of admission were recorded. Stroke severity had been estimated using the National Institutes of Health Stroke Scale (NIHSS) and poor outcome was defined as modified Rankin Scale (mRS) 3–6 at 3 months.ResultsAIS patients with poor functional outcome at 3 months displayed higher WMR. A positive correlation between WMR and NIHSS score was found (r = 0.334, p < 0.001). After adjusting potential confounders, WMR was still an independent risk factor for poor prognosis at 3 months (OR = 2.257, 95% CI [1.117-4.564], p = 0.023) in multivariate logistic regression model. Subgroup analyses further suggested a significant association between WMR and poor outcome in high baseline NIHSS (per 0.1-point increase: OR = 1.153, 95% CI [1.014-1.312], p = 0.030) group. Receiver operating characteristic (ROC) curves analysis was utilized to assess the predictive ability of WMR, indicating a cut-off value of 0.86. A nomogram that includes age, sex, NIHSS on admission, high WMR for predicting 1-year all-cause survival was also developed (C-index = 0.628).ConclusionsWMR is significantly correlated with stroke severity on admission and is proved to be an important prognostic indicator for AIS outcomes, especially in high NIHSS on admission group. Additionally, the developed nomogram that includes high WMR for predicting 1-year survival provides us with an effective visualization tool.

T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.

EZH2 inhibitors (EZH2i), a class of small-molecule inhibitors that target EZH2 to exert anti-tumor functions, have just been approved by the US Food and Drug Administration (FDA) in treatment of adults and adolescents with locally advanced or metastatic epithelioid sarcoma. The application of EZH2i in several solid tumors is still in different stages of clinical trials and needs to be further validated. As a key epigenetic regulator, besides its role in controlling the proliferation of tumor cells, EZH2 has been implicated in the regulation of various immune cells including macrophages. But there are still controversial research results at present. Colorectal cancer (CRC) is a common malignant tumor that highly expresses EZH2, which has the third highest incidence and is the second leading cause of cancer-related death worldwide. Studies have shown that the numbers of M2-type tumor-associated macrophages (TAMs) are highly associated with the progression and metastasis of CRC. In the current study, we aim to investigate how EZH2 modulates the polarization of macrophages in the tumor microenvironment (TME) of CRC, and compare the role of two different EZH2 inhibitors, EPZ6438 and GSK126. We applied a 3D culture method to demonstrate that EZH2i did indeed suppress the proliferation of CRC cells in vitro. In vivo, we found that the percentage of CD206+ macrophages of the TME was decreased under the treatment of EPZ6438, but it increased upon GSK126 treatment. Besides, in the co-culture system of macrophages and CRC cells, EPZ6438 led to significant elevation of M1 markers and reduction of M2 markers. Furthermore, mechanistic studies validated by ChIP-qPCR demonstrated that EZH2i inhibit EZH2-mediated H3K27me3 levels on the promoters of STAT3, an essential transcription factor for M1 macrophage polarization. Therefore, our data suggested that EZH2i not only suppress CRC cell proliferation directly, but also regulate macrophage by skewing M2 into effector M1 macrophage to exert a tumor suppressive effect. Moreover, our study provided new insight for better understanding of the role of two kinds of EZH2i: EPZ6438 and GSK126, which may pave the way in treating CRC by targeting cancer cells and immune cells via this epigenetic approach in the future.

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2), which regulates downstream gene expression by trimethylation of lysine 27 in histone H3 (H3K27me3). EZH2 mutations or overexpressions are associated with many types of cancer. As inhibition of EZH2 activity could upregulate the expression of tumor suppressor genes, EZH2 has recently become an interesting therapeutic target for cancer therapy. Moreover, accumulating evidence has shown that EZH2 may contribute to the regulation of immune cells, especially T cells. EZH2 regulates T cell development, differentiation, and function, suggesting that EZH2 also regulates immune homeostasis in addition to tumor suppressor genes. Moreover, EZH2 can regulate T cell fate by targeting non-T cell factors such as metabolism, cytokines, and myeloid-derived suppressor cells. The role of EZH2 in this process has not been fully addressed. This review discusses up-to-date research on EZH2-mediated regulation of immunological function and the progress of immunological therapeutic strategies based on this regulation.

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a poor prognosis and limited therapeutic options. Alpha-fetoprotein (AFP), an established clinical biomarker of HCC, has been employed as an attractive target for T cell-based immunotherapy against this disease given its high expression in the tumor and restricted expression in normal tissues. We have identified a number of T cell receptors (TCRs) recognizing the HLA-A*02:01 restricted AFP158−166 peptide FMNKFIYEI, providing a TCR candidate pool for identifying TCRs with optimal clinical benefit. To select the ideal AFP TCR for clinical use, we evaluated the efficacy and safety profile of 7 TCRs by testing their potency toward AFP-expressing HCC cells and their specificity based upon reactivity to normal and transformed cells covering a wide variety of primary cell types and HLA serotypes. Furthermore, we assessed their cross-reactivity to potential protein candidates in the human genome by an extensive alanine scan (X-scan). We first selected three TCR candidates based on the in vitro anti-tumor activity. Next we eliminated two potential cross-reactive TCRs based on their reactivity against normal and transformed cells covering a variety of primary cell types and HLA serotypes, respectively. We then excluded the potential cross-reactivity of the selected TCR with a protein candidate identified by X-scan. At present we have selected an AFP TCR with the optimal affinity, function, and safety profile, bearing properties that are expected to allow AFP TCR redirected T cells to specifically differentiate between AFP levels on tumor and normal tissues. An early phase clinical trial using T cells transduced with this TCR to treat HCC patients (NCT03971747) has been initiated.