Coming of age:the formation and function of age-associated B cells

B cells are generated in the bone marrow during ontogeny and migrate to peripheral lymphoid organs,where they encounter antigens to elicit humoral immunity.During the past decade,many novel B-cell subsets with distinct phenotypes and functions have been identified,and among these subsets,age-associated B cells(ABCs)were first characterized as a B-cell subset that accumulates with age[1].

Aryl hydrocarbon receptor activation drives polymorphonuclear myeloid-derived suppressor cell response and efficiently attenuates experimental Sjögren’s syndrome

Myeloid-derived suppressor cells(MDSCs)comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction.We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome(pSS)and mice with experimental SS(ESS).However,the molecular mechanisms underlying MDSC dysfunction remain largely unclear.In this study,we first found that aryl hydrocarbon receptor(AhR)was highly expressed by human and murine polymorphonuclear MDSCs(PMN-MDSCs).Indole-3-propionic acid(IPA),a natural AhR ligand produced from dietary tryptophan,significantly promoted PMN-MDSC differentiation and suppressive function on CD4^(+)T cells.In contrast,feeding a tryptophan-free diet resulted in a decreased PMN-MDSC response,a phenotype that could be reversed by IPA supplementation.The functional importance of PMN-MDSCs was demonstrated in ESS mice by using a cell-depletion approach.Notably,AhR expression was reduced in PMN-MDSCs during ESS development,while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells,which could be phenocopied by a tryptophan-free diet.Interferon regulatory factor 4(IRF4),a repressive transcription factor,was upregulated in PMN-MDSCs during ESS progression.Chromatin immunoprecipitation analysis revealed that IRF4 could bind to the promoter region of AhR,while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses.Furthermore,dietary supplementation with IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function.Together,our results identify a novel function of AhR in modulating the PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

B cells play a pivotal role in the pathogenesis of autoimmune diseases.Although previous studies have shown many genetic polymorphisms associated with B-cell activation in patients with various autoimmune disorders,progress in epigenetic research has revealed new mechanisms leading to B-cell hyperactivation.Epigenetic mechanisms,including those involving histone modifications,DNA methylation,and noncoding RNAs,regulate B-cell responses,and their dysregulation can contribute to the pathogenesis of autoimmune diseases.Patients with autoimmune diseases show epigenetic alterations that lead to the initiation and perpetuation of autoimmune inflammation.Moreover,many clinical and animal model studies have shown the promising potential of epigenetic therapies for patients.In this review,we present an up-to-date overview of epigenetic mechanisms with a focus on their roles in regulating functional B-cell subsets.Furthermore,we discuss epigenetic dysregulation in B cells and highlight its contribution to the development of autoimmune diseases.Based on clinical and preclinical evidence,we discuss novel epigenetic biomarkers and therapies for patients with autoimmune disorders.

New insights into the functions of MDSCs in autoimmune pathogenesis

Myeloid-derived suppressor cells(MDSCs)are a heterogeneous population of immature myeloid cells with immunosuppressive effects that are expanded under pathological conditions.In the past decade,MDSCs have generated significant research interest and increased attention.Recently,clinical observations and animal model studies have shown that MDSCs accumulate during the development of various autoimmune diseases,including primary Sjogren's syndrome(psS).psS is a common systemic autoimmune disease characterized by lymphocyte infiltration and tissue inflammation in the salivary glands(SG)and lacrimal glands,resulting in dry mouth and dry eyes.Here,we review the latest evidence and provide new insights into the roles of MDSCs in the pathogenesis of autoimmune diseases,focusing on the functional changes in MDSCs and their therapeutic potential in autoimmune diseases.