Myeloid-derived suppressor cells (MDSCs) contribute to the pathogenesis of systemic lupus erythematosus (SLE), in part due to promoting the survival of plasma cells. FoxO1 expression in monocytic MDSCs (M-MDSCs) exhibits a negative correlation with the SLE Disease Activity Index score. This study aimed to investigate the hypothesis that M-MDSC-specific FoxO1 deficiency enhances aberrant B cell function in aggressive SLE.

We used GEO data sets and clinical cohorts to verify the clinical significance of FoxO1 expression and circulating M-MDSCs. Using Cre-LoxP technology, we generated myeloid FoxO1 deficiency mice (mFoxO1-/-) to establish murine lupus-prone models. The transcriptional stage was assessed by integrating chromatin immunoprecipitation (ChIP)-sequencing with transcriptomic analysis, luciferase reporter assay, and ChIP-quantitative polymerase chain reaction. Methylated RNA immunoprecipitation sequencing, RNA sequencing, and CRISPR-dCas9 were used to identify N6-adenosine methylation (m6A) modification. In vitro B cell coculture experiments, capmatinib intragastric administration, m6A-modulated MDSCs adoptive transfer, and sample validation of patients with SLE were performed to determine the role of FoxO1 on M-MDSCs dysregulation during B cell autoreacted with SLE.

We present evidence that low FoxO1 is predominantly expressed in M-MDSCs in both patients with SLE and lupus mice, and mice with myeloid FoxO1 deficiency (mFoxO1-/-) are more prone to B cell dysfunction. Mechanically, FoxO1 inhibits mesenchymal-epithelial transition factor protein (Met) transcription by binding to the promoter region. M-MDSCs FoxO1 deficiency blocks the Met/cyclooxygenase2/prostaglandin E2 secretion pathway, promoting B cell proliferation and hyperactivation. The Met antagonist capmatinib effectively mitigates lupus exacerbation. Furthermore, alkB homolog 5 (ALKBH5) targeting catalyzes m6A modification on FoxO1 messenger RNA in coding sequences and 3' untranslated regions. The up-regulation of FoxO1 mediated by ALKBH5 overexpression in M-MDSCs improves lupus progression. Finally, these correlations were confirmed in untreated patients with SLE.

Our findings indicate that effective inhibition of B cells mediated by the ALKBH5/FoxO1/Met axis in M-MDSCs could offer a novel therapeutic approach to manage SLE.

B-1 cells are a distinct lineage of tissue-resident B cells with crucial roles in innate immunity and tissue homeostasis. Mature B-1 cell pools are mostly maintained by self-renewal in their peripheral niches, in a process that is largely uncharacterized. Here, we investigated the role of the transcription repressor Bach2 in maintaining the B-1 cell pool. We found that B-1 cell numbers and antibody responses were dramatically reduced in adult mice bearing a B cell-specific Bach2 deletion, although the proportions of B-1 progenitors in early neonatal life were unaffected. Cells taken from the fetal liver or bone marrow of Bach2-deleted mice were defective in reconstituting the B-1 cell pool in the peritonea of Rag2-/- hosts, and peritoneal B-1 cell transplants from adult Bach2-deleted mice failed to sustain their numbers in the host's peritoneum. The mutant B-1 cells proliferated normally in vivo but were more apoptotic. They also expressed the reduced level of the self-renewal factor Bmi1. These results indicate that Bach2 deficiency does not affect the development of B-1 progenitors in fetal liver and bone marrow but impairs the self-renewal of mature B-1 cells in peripheral tissues, which is caused by increased apoptosis. Thus, this study suggests that a cell-autonomous function of Bach2 is crucial for maintaining a stable population size of B-1 cells in their peripheral niches.

Persistent alloantigens derived from allograft tissues can be recognized by the host's alloreactive immune system. This process enables cognate B cells to differentiate into plasma cells, which secrete donor-specific antibodies that are key drivers of antibody-mediated allograft rejection. A subset of these plasma cells can survive for extended periods in a suitable survival niche and mature into long-lived plasma cells (LLPCs), which are a cellular component of humoral memory. The current understanding of LLPCs is limited due to their scarcity, heterogeneity, and absence of unique markers. However, accumulating evidence indicates that LLPCs, unlike conventional short-lived plasma cells, can respond to extrinsic signals from their survival niches and can resist cell death associated with intracellular stress through cell-intrinsic mechanisms. Notably, they are refractory to traditional immunosuppressants and B cell depletion therapies. This resistance, coupled with their longevity, may explain why current treatments targeting antibody-mediated rejection are often ineffective. This review offers insights into the biology of LLPCs and discusses ongoing therapeutic trials that target LLPCs in the context of antibody-mediated allograft rejection.

FOXP3 is a transcription factor that regulates the development and function of Treg, playing an essential role in preventing autoimmune diseases. Variation in FOXP3 can impair the function of Treg cells, thus destroying their inhibitory capacity and leading to autoimmune diseases. This paper investigated whether the three SNPs in the FOXP3 gene (-3279 C/A, -924 A/G and -6054 del/ATT) are associated with systemic lupus erythematosus (SLE) susceptibility in the Han Chinese population.

The study cohort comprised 122 SLE patients and 268 healthy controls. Genotyping was performed by polymerase chain reaction sequence-specific primer (PCR-SSP). Furthermore, we examined the potential clinical manifestations associated with FOXP3 polymorphisms in SLE patients.

The results showed that the -3279 (C > A) was significantly associated with the SLE risk in a homozygote (OR = 3.24, 95% CI = 1.23-8.52, p = .013, AA vs. CC), dominant (OR = 1.68, 95% CI = 1.07-2.65, p = .025, AC + AA vs. CC), recessive (OR = 2.90, 95% CI = 1.12-7.55, p = .023, AA vs. AC + CC) and allelic (OR = 1.72, 95% CI = 1.18-2.53, p = .005, A vs. C) models. In addition, -924 (A > G) was positively associated with SLE risk in the heterozygote (OR = 1.66, 95% CI = 1.04-2.66, p = .033, AG vs. AA) and dominant (OR = 1.59, 95% CI = 1.01-2.49, p = .042, AG + GG vs. AA) models, whereas -6054 (del > ATT) was not associated with SLE. Moreover, the immunological index analysis suggested that decreased complement C4 occurred more frequently in SLE patients carrying the minor allele (A) -3279 (C > A) than those not (p = .005).

We demonstrated that -3279 (C > A) and -924 (A > G) were associated with an increased risk of SLE and the immunological index, indicating that the FOXP3 variation is potentially related to the occurrence and development of SLE.

The transcription repressor Bach2 plays a crucial role in shaping humoral immunity, but its cell-autonomous function remains elusive. Here, we reveal the mechanism by which Bach2 regulates effector cell maturation in peripheral B cells. In response to Toll-like receptor (TLR) agonists, Bach2 deficiency promotes the differentiation of follicular, but not marginal zone, B cells into effector cells, producing interleukin (IL)-6 and antibodies. This phenomenon is associated with changes in lipid metabolism, such as increases in CD36 expression, lipid influx, and fatty acid oxidation. Consistent with this, Bach2-deficient B cells exhibit elevated levels of mitochondrial oxidative stress, lipid peroxidation, and p38 activation. Mechanistically, Bach2 acts as a repressor of Cd36, and inhibition of CD36 or fatty acid oxidation reduces the differentiation of naive B cells into IL-6- and antibody-secreting cells. These results indicate Bach2 as a key metabolic checkpoint regulator crucial for maintaining a functionally quiescent state of follicular B cells.

Understanding phenotype-to-genotype relationships is a grand challenge of 21st century biology with translational implications. The recently proposed "omnigenic" model postulates that effects of genetic variation on traits are mediated by core-genes and -proteins whose activities mechanistically influence the phenotype, whereas peripheral genes encode a regulatory network that indirectly affects phenotypes via core gene products. Here, we develop a positive-unlabeled graph representation-learning ensemble-approach based on a nested cross-validation to predict core-like genes for diverse diseases using Mendelian disorder genes for training. Employing mouse knockout phenotypes for external validations, we demonstrate that core-like genes display several key properties of core genes: Mouse knockouts of genes corresponding to our most confident predictions give rise to relevant mouse phenotypes at rates on par with the Mendelian disorder genes, and all candidates exhibit core gene properties like transcriptional deregulation in disease and loss-of-function intolerance. Moreover, as predicted for core genes, our candidates are enriched for drug targets and druggable proteins. In contrast to Mendelian disorder genes the new core-like genes are enriched for druggable yet untargeted gene products, which are therefore attractive targets for drug development. Interpretation of the underlying deep learning model suggests plausible explanations for our core gene predictions in form of molecular mechanisms and physical interactions. Our results demonstrate the potential of graph representation learning for the interpretation of biological complexity and pave the way for studying core gene properties and future drug development.

Although various studies have been performed on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in RA, the results were conflicting. Here we were trying to clarify the role of PMN-MDSCs in the pathogenesis of RA and its specific mechanisms. We detected the frequencies and counts of PMN-MDSCs, TNF-α+ B cells and Ki67+ B cells in spleen and inflamed joints of collagen-induced arthritis (CIA) mice using flow cytometry. The pathological role of PMN-MDSCs was examined by anti-Ly6G neutralizing antibodies against PMN-MDSCs or adoptive transfer of PMN-MDSCs. And the modulation of PMN-MDSCs on B cells was conducted by coculture assays, RNA-Seq, RT-qPCR, and so on. The mechanism of BAFF regulating B cells was verified through western blot and flow cytometry. PMN-MDSCs accumulated in the spleen and joints of CIA mice. PMN-MDSCs depletion could alleviate the arthritis severity, which was accompanied by decreased TNF-α secretion and proliferation of B cells. And its adoptive transfer also facilitated disease progress. Furthermore, PMN-MDSCs from CIA mice had higher expression level of BAFF, which regulated TNF-α expression, proliferation and apoptosis of B cells in vitro. What's more, BAFF promoted phosphorylation of BTK/NF-κB signalling pathway. And Ibrutinib (BTK inhibitor) could reverse the effect of BAFF on TNF-α expression of B cells. Our study suggested that PMN-MDSCs enhanced disease severity of CIA and manipulated TNF-α expression, proliferation and apoptosis of B cells via BAFF, furthermore, BAFF promoted TNF-α expression through BTK/NF-κB signalling pathway, which demonstrated a novel pathogenesis of PMN-MDSCs in CIA.

Autoimmune hemolytic anemia (AIHA) is a rare, very heterogeneous, and sometimes life-threatening acquired hematologic disease characterized by increased red blood cell (RBC) destruction by autoantibodies (autoAbs), either with or without complement involvement. Recent studies have shown that the involvement of T- and B-cell dysregulation and an imbalance of T-helper 2 (Th2) and Th17 phenotypes play major roles in the pathogenesis of AIHA. AIHA can be primary (idiopathic) but is more often secondary, triggered by infections or drug use or as a part of other diseases. As the location of origin of autoAbs and the location of autoAb-mediated RBC clearance, as well as the location of extramedullary hematopoiesis, the spleen is crucially involved in all the steps of AIHA pathobiology. Splenectomy, which was the established second-line therapeutic option in corticosteroid-resistant AIHA patients for decades, has become less common due to increasing knowledge of immunopathogenesis and the introduction of targeted therapy. This article provides a comprehensive overview of current knowledge regarding the place of the spleen in the immunological background of AIHA and the rapidly growing spectrum of novel therapeutic approaches. Furthermore, this review emphasizes the still-existing expediency of laparoscopic splenectomy with appropriate perioperative thromboprophylaxis and the prevention of infection as a safe and reliable therapeutic option in the context of the limited availability of rituximab and other novel therapies.