[The proportion of CD19+CD25+ Bregs in peripheral blood and the expression of PD-1 and PD-L1 on cell surface in patients with systemic lupus erythematosus and their correlation with clinical indicators].

Objective To investigate the expression and clinical significance of PD-1 and its ligand PD-L1 in peripheral blood CD19+CD25+ regulatory B cells (Bregs) in patients with systemic lupus erythematosus (SLE). Methods Peripheral blood samples were collected from 50 patients and 41 healthy controls (HCs). The proportion of CD19+CD25+Bregs in peripheral blood as well as the expression of PD-1+B and PD-L1+B cells on CD19+CD25+/-B cells, were detected by flow cytometry. At the same time, clinical information, such as clinical manifestations and laboratory indexes, was collected from patients. CD4+T cells and CD19+B cells were isolated by immunomagnetic beads and co-cultured in vitro to detect the differentiation of Bregs. Results The proportion of CD19+CD25+Bregs in the peripheral blood of SLE patients was lower than that in HC, while the expression of PD-1 and PD-L1 on Bregs was higher than that in HCs. SLE patients with pleural effusion, arthritis, and elevated CRP had a higher frequency of Bregs compared to the corresponding negative group. SLE patients with decreased immunoglobulin M (IgM) and positive anti-ribonuclear protein (RNP) antibodies had a lower frequency of Bregs compared to the corresponding negative group. SLE patients with infection, fever, arthritis, and elevated immunoglobulin A (IgA) had a higher frequency of CD19+CD25+PD-1+ cells compared to the corresponding negative group. SLE patients with infection, fever, and elevated IgA had a higher frequency of CD19+CD25+PD-L1+ cells compared to the corresponding negative group. And activated CD4+T cells were beneficial to the expression of CD25 on CD19+B cells. Conclusion The peripheral blood CD19+CD25+ Bregs are decreased in SLE patients, while the expression of PD-1 and PD-L1 on cell surface is increased, which is correlated with clinical manifestations and laboratory parameters. Activation of CD4+T cells promotes the differentiation of Bregs.

Effect of curcumin on regulatory B cells in chronic colitis mice involving TLR/MyD88 signaling pathway.

Curcumin (Cur) is a natural active phenolic compound extracted from the root of Curcuma Longa L. It has anti-inflammatory, anti-tumor and other pharmacological activities, and is commonly used to treat ulcerative colitis (UC). However, it is not clear whether curcumin regulates the function and differentiation of Breg cells to treat UC. In this study, mice with chronic colitis were induced by dextran sulfate sodium (DSS), and treated with curcumin for 12 days. Curcumin effectively improved the body weight, colonic weight, colonic length, decreased colonic weight index and pathological injury score under colonoscopy in mice with chronic colitis, and significantly inhibited the production of IL-1ß, IL-6, IL-33, CCL-2, IFN-γ, TNF-α, and promoted the secretion of IL-4, IL-10, IL-13 and IgA. Importantly, curcumin markedly upregulated CD3- CD19+ CD1d+ , CD3- CD19+ CD25+ , CD3- CD19+ Foxp3+ Breg cells level and significantly down-regulated CD3- CD19+ PD-L1+ , CD3- CD19+ tim-1+ , CD3- CD19+ CD27+ Breg cells level. In addition, our results also showed that curcumin observably inhibited TLR2, TLR4, TLR5, MyD88, IRAK4, p-IRAK4, NF-κB P65, IRAK1, TRAF6, TAB1, TAB2, TAK1, MKK3, MKK6, p38MAPK, p-p38MAPK and CREB expression in TLR/MyD88 signaling pathway. These results suggest that curcumin can regulate the differentiation and function of Breg cell to alleviate DSS-induced colitis, which may be realized by inhibiting TLR/MyD88 pathway.

Mesenchymal stem cells moderate experimental autoimmune uveitis by dynamic regulating Th17 and Breg cells response.

Mesenchymal stem cells (MSCs) are adult stem cells from mesoderm with multi potential differentiation, and are being widely studied as a promising treatment for autoimmune diseases. The main inflammatory factors of experimental autoimmune uveitis (EAU) are T helper type 1 (Th1) and Th17. Regulatory B cells (Bregs) are a newly designated B cell subgroup, which has been proved to play a key role in regulating inflammation, autoimmunity and cancer. In this regard, we establish the EAU model by injecting interphotoreceptor retinoid-binding protein combined with complete Freund's adjuvant into the tail vein and bilateral thighs of rats, and inject MSCs or equal volume of phosphate buffer saline intraperitoneally on the day of immunization. Dynamic changes of cell subsets and cytokine expression are tested at different time periods to explore the relationship between MSCs treatment and disease prognosis during EAU course. Our results suggest that compared with the model control group, MSCs treatment can significantly reduce the production of Th1 and Th17 cytokines during EAU, while the production of regulatory B cells (Bregs) cytokines is significantly increased. At the same time, MSCs can reduce the proportion of Th17 in lymphocytes while the proportion of Bregs is elevated, thus inhibiting the differentiation and activity of interleukin in EAU rats. All this results provide more powerful evidence for cell therapy of autoimmune uveitis.

Short-Chain Fatty Acids Promote Immunotherapy by Modulating Immune Regulatory Property in B Cells.

The dysfunction of regulatory B cells (Breg) may result in immune inflammation such as allergic rhinitis (AR); the underlying mechanism is not fully understood yet. Short-chain fatty acids, such as propionic acid (PA), have immune regulatory functions. This study is aimed at testing a hypothesis that modulates PA production alleviating airway allergy through maintaining Breg functions. B cells were isolated from the blood obtained from AR patients and healthy control (HC) subjects. The stabilization of IL-10 mRNA in B cells was tested with RT-qPCR. An AR mouse model was developed to test the role of PA in stabilizing the IL-10 expression in B cells. We found that the serum PA levels were negatively correlated with the serum Th2 cytokine levels in AR patients. Serum PA levels were positively associated with peripheral CD5+ B cell frequency in AR patients; the CD5+ B cells were also IL-10+. The spontaneous IL-10 mRNA decay was observed in B cells, which was prevented by the presence of PA through activating GPR43. PA counteracted the effects of Tristetraprolin (TTP) on inducing IL-10 mRNA decay in B cells through the AKT/T-bet/granzyme B pathway. Administration of Yupinfeng San, a Chinese traditional medical formula, or indole-3-PA, induced PA production by intestinal bacteria to stabilize the IL-10 expression in B cells, which promoted the allergen specific immunotherapy, and efficiently alleviated experimental AR. In summary, the data show that CD5+ B cells produce IL-10. The serum lower PA levels are associated with the lower frequency of CD5+ B cells in AR patients. Administration with Yupinfeng San or indole-3-PA can improve Breg functions and alleviate experimental AR.

Partially hydrolyzed whey proteins prevent clinical symptoms in a cow's milk allergy mouse model and enhance regulatory T and B cell frequencies.

SCOPE: Partially hydrolyzed cow's milk proteins are used to prevent cow's milk allergy in children. Here we studied the immunomodulatory mechanisms of partial cow's milk hydrolysates in vivo. METHODS AND RESULTS: Mice were sensitized with whey or partially hydrolyzed whey using cholera toxin. Whey-specific IgE levels were measured to determine sensitization and immune cell populations from spleen, mesenteric lymph nodes and Peyer's patches after oral whey administration were measured by flowcytometry. Whey-specific IgE and IgG1 levels in partial whey hydrolysate sensitized animals were enhanced, but challenge did not induce clinical symptoms. This immunomodulatory effect of partial whey hydrolysate was associated with increased regulatory B and T cells in the spleen, together with a prevention of IgM-IgA class switching in the mesenteric lymph nodes and an increased Th1 and activated Th17 in the Peyer's patches. CONCLUSION: Partial hydrolysate sensitization did not induce whey-induced clinical symptoms, even though sensitization was established. Increased regulatory cell populations in the systemic immune system and a prevention of increased total Th1 and activated Th17 in the intestinal immune organs could contribute to the suppression of allergic symptoms. This knowledge is important for a better understanding of the beneficial effects of hydrolysates.