Altered Tim-1 and IL-10 Expression in Regulatory B Cell Subsets in Type 1 Diabetes

BackgroundType 1 diabetes (T1D) is an autoimmune disease with a complex aetiology. B cells play an important role in the pathogenesis of T1D. Regulatory B cells (Bregs) are a subset of B cells that produce and secrete the inhibitory factor interleukin-10 (IL-10), thereby exerting an anti-inflammatory effect. It was recently discovered that T-cell immunoglobulin mucin domain 1 (Tim-1) is essential for maintaining Bregs function related to immune tolerance. However, the detailed understanding of Tim-1+ Bregs and IL-10+ Bregs in T1D patients is lacking. This study aimed to characterize the profile of B cell subsets in T1D patients compared with that in controls and determine whether Tim-1+ Bregs and IL-10+ Bregs play roles in T1D.Materials and MethodsA total of 47 patients with T1D, 30 patients with type 2 diabetes (T2D) and 24 healthy controls were recruited in this study. Flow cytometry was used to measure the levels of different B cell subsets (including B cells, plasmablasts, and Bregs) in the peripheral blood. Radiobinding assays were performed to detect the antibody titres of T1D patients. In addition, the correlations between different B cell subsets and patient parameters were investigated.ResultsCompared with healthy controls, differences in frequency of Tim-1+ Bregs were significantly decreased in patients with T1D (36.53 ± 6.51 vs. 42.25 ± 6.83, P=0.02*), and frequency of IL-10+ Bregs were lower than healthy controls (17.64 ± 7.21vs. 24.52 ± 11.69, P=0.009**), the frequency of total Bregs in PBMC was also decreased in patients with T1D (1.42 ± 0.53vs. 1.99 ± 0.93, P=0.002.**). We analyzed whether these alterations in B cells subsets were associated with clinical features. The frequencies of Tim-1+ Bregs and IL-10+ Bregs were negatively related to fasting blood glucose (FBG) (r=-0.25 and -0.22; P=0.01* and 0.03*, respectively). The frequencies of Tim-1+ Bregs and IL-10+ Bregs are positively correlated with fast C-peptide (FCP) (r=0.23 and 0.37; P=0.02* and 0.0001***, respectively). In addition, the frequency of IL-10+ Breg was also negatively related to glycosylated haemoglobin (HbA1c) (r=-0.20, P=0.04*). The frequencies of Tim-1+ Bregs, IL-10+ Bregs and Bregs in T2D patients were reduced, but no statistically significant difference was found between other groups. Interestingly, there was positive correlation between the frequencies of Tim-1+ Bregs and IL-10+ Bregs in T1D (r=0.37, P=0.01*). Of note, it is worth noting that our study did not observe any correlations between B cell subsets and autoantibody titres.ConclusionsOur study showed altered Tim-1 and IL-10 expression in regulatory B cell in T1D patients. Tim-1, as suggested by the present study, is associated with islet function and blood glucose levels. These findings indicate that Tim-1+ Bregs and IL-10+ Bregs were involved in the pathogenesis of T1D.

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Altered Regulatory B Cell Subsets in Children with Type 1 Diabetes Mellitus

Journal of Immunology Research ◽

10.1155/2020/8935694 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Mohamed A. El-Mokhtar ◽

Nahla M. Elsherbiny ◽

Douaa Sayed ◽

Duaa M. Raafat ◽

Eman Askar ◽

...

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

B Cells ◽

B Cell ◽

Fasting Blood Glucose ◽

Interleukin 10 ◽

Peripheral Tolerance ◽

Regulatory B Cell ◽

B Cell Subsets

B regulatory cells (Breg) refer to characteristic subsets of B cells that generally exert anti-inflammatory functions and maintain peripheral tolerance mainly through their ability to secrete interleukin-10 (IL10). Dysregulation in the function of Breg cells was reported in several autoimmune diseases. However, the relation between Breg and children with type 1 diabetes (T1D) is poorly understood. Thus, this study is aimed at determining whether Breg cells play a role in T1D in children or not, so we hypothesized that an altered phenotype of B cell subsets is associated with T1D in children. Children with T1D (n=29) and control children with normal blood glucose levels (n=14) were recruited. The percentages of different circulating IL10-producing Breg subsets, including B10, immature transitional, and plasmablasts were determined using flow cytometry analysis. Furthermore, the association between different IL10-producing B cells and patient parameters was investigated. The percentage of circulating IL10+CD24hiCD27+ (B10) and IL10+CD24hiCD38hi (immature transitional) subsets of Breg cells was significantly lower in T1D patients than in healthy controls. Moreover, these cells were also negatively correlated with fasting blood glucose and HbA1c levels. Breg cells did not correlate with autoantibody levels in the serum. These findings suggest that certain Breg subsets are numerically deficient in children with T1D. This alteration in frequency is associated with deficient islet function and glycemia. These findings suggest that Breg cells may be involved in the loss of auto-tolerance and consequent destruction of pancreatic cells and could, therefore, be a potential target for immunotherapy.

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The Expression of BTK/p-BTK Is Different between CD5+ and CD5- B Lymphocyte from Autoimmune Hemolytic Anemia/Evans Syndromes

Blood ◽

10.1182/blood-2018-99-114339 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4886-4886

Author(s):

Limin Xing ◽

Yingying Qu ◽

Ningning Duan ◽

Zonghong Shao

Keyword(s):

B Cells ◽

Tyrosine Kinase ◽

B Cell ◽

B Lymphocytes ◽

Autoimmune Hemolytic Anemia ◽

Bruton’S Tyrosine Kinase ◽

Healthy Controls ◽

Bruton's Tyrosine Kinase ◽

Significant Difference ◽

B Cell Subsets

Abstract Objective To investigate the expression level of Bruton's tyrosine kinase (Btk) on CD19+B lymphocytes in peripheral blood (PB) of autoimmune hemolytic anemia (AIHA)/Evans patients. Methods The expression of Btk and Phosphorylated Btk(p-Btk) on CD5+CD19+B and CD5-CD19+B lymphocytes were detected using flow cytometry in AIHA/ Evans patients with different disease states, healthy controls (HC) and chronic lymphocytic leukemia (CLL) patients and analyzed its correlation with clinical parameters. Results 36 AIHA/ES patients (16 hemolytic, 20 remission), 11 CLL patients and 15 healthy controls (HC) were enrolled in this study. The expression of Btk and p-Btk on CD5+B lymphocytes in AIHA/Evans patients were higher than those in HCs and CLL patients, the latter two groups had no significant difference, and were positively correlated with the quantity of IgE. The ratio of p-Btk to Btk on CD5+B lymphocytes of hemolytic group and remission group was obviously higher than that on CD5-B lymphocytes [(74.62±6.42)%, (29.63±10.19)%, P=0.001], [(77.95±9.57)%, (26.29±6.86)%, P=0.006]. The ratio of p-BTK to BTK on CD5+B lymphocytes [(54.89±9.56)%] and CD5-B lymphocytes [(30.86±12.47)%, P=0.109)] showed no significant difference in HCs. There was no significant difference of Btk on CD5+B and CD5- B lymphocytes in AIHA/Evans patients, but the expression of p-Btk on CD5+B lymphocytes significantly higher than that on CD5-B lymphocytes in AIHA/Evans patients. Conclusion The expression levels of p-BTK in different B cell subsets of AIHA/Evans patients were significantly different, the expression levels of p-BTK in CD5+B cells were obviously higher than that in CD5-B cells, and higher than that in CD5+ B cells in CLL patients, and positively correlated with the number of serum IgE. Key words: anemia hemolytic autoimmune; Bruton's tyrosine kinase, Phosphorylated Bruton's tyrosine kinase; B cell subsets Disclosures No relevant conflicts of interest to declare.

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SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00749-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Yukai Jing ◽

Li Luo ◽

Ying Chen ◽

Lisa S. Westerberg ◽

Peng Zhou ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Immune Regulation ◽

Cell Metabolism ◽

Healthy Controls ◽

Bcr Signaling ◽

Before And After ◽

B Cell Subsets ◽

Almost All ◽

Cd19 Expression

AbstractThe SARS-CoV-2 infection causes severe immune disruption. However, it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients. In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients, and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation, but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation. However, the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. Interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. Moreover, the BCR signaling and early B-cell response were disrupted upon BCR stimulation. Mechanistically, we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism. In conclusion, we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, which may provide a new intervention target to cure COVID-19.

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Marginating transitional B cells modulate neutrophils in the lung during inflammation and pneumonia

Journal of Experimental Medicine ◽

10.1084/jem.20210409 ◽

2021 ◽

Vol 218 (9) ◽

Author(s):

John Podstawka ◽

Sarthak Sinha ◽

Carlos H. Hiroki ◽

Nicole Sarden ◽

Elise Granton ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Regulatory Networks ◽

Vascular Inflammation ◽

Transitional B Cells ◽

Pulmonary Capillaries ◽

Life Threatening ◽

B Cell Subsets

Pulmonary innate immunity is required for host defense; however, excessive neutrophil inflammation can cause life-threatening acute lung injury. B lymphocytes can be regulatory, yet little is known about peripheral transitional IgM+ B cells in terms of regulatory properties. Using single-cell RNA sequencing, we discovered eight IgM+ B cell subsets with unique gene regulatory networks in the lung circulation dominated by transitional type 1 B and type 2 B (T2B) cells. Lung intravital confocal microscopy revealed that T2B cells marginate in the pulmonary capillaries via CD49e and require CXCL13 and CXCR5. During lung inflammation, marginated T2B cells dampened excessive neutrophil vascular inflammation via the specialized proresolving molecule lipoxin A4 (LXA4). Exogenous CXCL13 dampened excessive neutrophilic inflammation by increasing marginated B cells, and LXA4 recapitulated neutrophil regulation in B cell–deficient mice during inflammation and fungal pneumonia. Thus, the lung microvasculature is enriched in multiple IgM+ B cell subsets with marginating capillary T2B cells that dampen neutrophil responses.

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Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto’s thyroiditis or Addison’s disease in the German population

Acta Endocrinologica ◽

10.1530/eje.1.02035 ◽

2005 ◽

Vol 153 (6) ◽

pp. 895-899 ◽

Cited By ~ 74

Author(s):

Heinrich Kahles ◽

Elizabeth Ramos-Lopez ◽

Britta Lange ◽

Oliver Zwermann ◽

Martin Reincke ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Hashimoto’S Thyroiditis ◽

Addison’S Disease ◽

Hashimoto's Thyroiditis ◽

Addison's Disease ◽

Healthy Controls ◽

Significant Difference

Background: Endocrine autoimmune disorders share genetic susceptibility loci, causing a disordered T-cell activation and homeostasis (HLA class II genes, CTLA-4). Recent studies showed a genetic variation within the PTPN22 gene to be an additional risk factor. Materials and Methods: Patients with type 1 diabetes (n = 220), Hashimoto’s thyroiditis (n = 94), Addison’s disease (n = 121) and healthy controls (n = 239) were genotyped for the gene polymorphism PTPN22 1858 C/T. Results: Our study confirms a significant association between allelic variation of the PTPN22 1858 C/T polymorphism and type 1 diabetes mellitus (T1D). 1858T was observed more frequently in T1D patients (19.3% vs 11.3%, P = 0.0009; odds ratio for allele T = 1.88, 95% confidence interval [1.3–2.7]). Furthermore, we found a strong association in female patients with T1D (P = 0.0003), whereas there was no significant difference between male patients with type 1 diabetes and male controls. No significant difference was observed between the distribution of PTPN22 C/T in patients with Hashimoto’s thyroiditis or Addison’s disease and healthy controls. Conclusion: The PTPN22 polymorphism 1858 C/T may be involved in the pathogenesis of type 1 diabetes mellitus by a sex-specific mechanism that contributes to susceptibility in females.

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Fasting Blood Glucose-A Missing Variable for GFR-Estimation in Type 1 Diabetes?

PLoS ONE ◽

10.1371/journal.pone.0096264 ◽

2014 ◽

Vol 9 (4) ◽

pp. e96264 ◽

Cited By ~ 11

Author(s):

Petter Bjornstad ◽

R. Brett McQueen ◽

Janet K. Snell-Bergeon ◽

David Cherney ◽

Laura Pyle ◽

...

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Fasting Blood Glucose ◽

Gfr Estimation

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Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus

International Journal of Molecular Sciences ◽

10.3390/ijms20236021 ◽

2019 ◽

Vol 20 (23) ◽

pp. 6021 ◽

Cited By ~ 3

Author(s):

Kongyang Ma ◽

Wenhan Du ◽

Xiaohui Wang ◽

Shiwen Yuan ◽

Xiaoyan Cai ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

B Cell ◽

Lupus Erythematosus ◽

Therapeutic Interventions ◽

Systemic Lupus ◽

Autoantibody Production ◽

Regulatory B Cell ◽

Functional Features ◽

B Cell Subsets

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and multi-organ involvement. Although the etiology of SLE still remains unclear, recent studies have characterized several pathogenic B cell subsets and regulatory B cell subsets involved in the pathogenesis of SLE. Among pathogenic B cell subsets, age-associated B cells (ABCs) are a newly identified subset of autoreactive B cells with T-bet-dependent transcriptional programs and unique functional features in SLE. Accumulation of T-bet+ CD11c+ ABCs has been observed in SLE patients and lupus mouse models. In addition, innate-like B cells with the autoreactive B cell receptor (BCR) expression and long-lived plasma cells with persistent autoantibody production contribute to the development of SLE. Moreover, several regulatory B cell subsets with immune suppressive functions have been identified, while the impaired inhibitory effects of regulatory B cells have been indicated in SLE. Thus, further elucidation on the functional features of B cell subsets will provide new insights in understanding lupus pathogenesis and lead to novel therapeutic interventions in the treatment of SLE.

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Proportions of B-cell subsets are altered in incomplete systemic lupus erythematosus and correlate with interferon score and IgG levels

Rheumatology ◽

10.1093/rheumatology/keaa114 ◽

2020 ◽

Vol 59 (9) ◽

pp. 2616-2624

Author(s):

Svenja Henning ◽

Wietske M Lambers ◽

Berber Doornbos-van der Meer ◽

Wayel H Abdulahad ◽

Frans G M Kroese ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Lupus Erythematosus ◽

Cell Subset ◽

Cross Sectional Study ◽

Type I ◽

Healthy Controls ◽

Sectional Study ◽

Cross Sectional ◽

B Cell Subsets

Abstract Objectives Incomplete SLE (iSLE) patients display symptoms typical for SLE but have insufficient criteria to fulfil the diagnosis. Biomarkers are needed to identify iSLE patients that will progress to SLE. IFN type I activation, B-cell-activating factor (BAFF) and B-cell subset distortions play an important role in the pathogenesis of SLE. The aim of this cross-sectional study was to investigate whether B-cell subsets are altered in iSLE patients, and whether these alterations correlate with IFN scores and BAFF levels. Methods iSLE patients (n = 34), SLE patients (n = 41) with quiescent disease (SLEDAI ≤4) and healthy controls (n = 22) were included. Proportions of B-cell subsets were measured with flow cytometry, IFN scores with RT-PCR and BAFF levels with ELISA. Results Proportions of age-associated B-cells were elevated in iSLE patients compared with healthy controls and correlated with IgG levels. In iSLE patients, IFN scores and BAFF levels were significantly increased compared with healthy controls. Also, IFN scores correlated with proportions of switched memory B-cells, plasma cells and IgG levels, and correlated negatively with complement levels in iSLE patients. Conclusion In this cross-sectional study, distortions in B-cell subsets were observed in iSLE patients and were correlated with IFN scores and IgG levels. Since these factors play an important role in the pathogenesis of SLE, iSLE patients with these distortions, high IFN scores, and high levels of IgG and BAFF may be at risk for progression to SLE.

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Metabolic impacts of cordycepin on hepatic proteomic expression in streptozotocin-induced type 1 diabetic mice

PLoS ONE ◽

10.1371/journal.pone.0256140 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0256140

Author(s):

Kongphop Parunyakul ◽

Krittika Srisuksai ◽

Sawanya Charoenlappanit ◽

Narumon Phaonakrop ◽

Sittiruk Roytrakul ◽

...

Keyword(s):

Body Weight ◽

Blood Glucose ◽

Signaling Pathway ◽

Tricarboxylic Acid Cycle ◽

Fasting Blood Glucose ◽

Protein Profiling ◽

Diabetic Mice ◽

Final Body Weight ◽

Significant Difference

Type 1 Diabetes mellitus (T1DM) is associated with abnormal liver function, but the exact mechanism is unclear. Cordycepin improves hepatic metabolic pathways leading to recovery from liver damage. We investigated the effects of cordycepin in streptozotocin-induced T1DM mice via the expression of liver proteins. Twenty-four mice were divided into four equal groups: normal (N), normal mice treated with cordycepin (N+COR), diabetic mice (DM), and diabetic mice treated with cordycepin (DM+COR). Mice in each treatment group were intraperitoneally injection of cordycepin at dose 24 mg/kg for 14 consecutive days. Body weight, blood glucose, and the tricarboxylic acid cycle intermediates were measured. Liver tissue protein profiling was performed using shotgun proteomics, while protein function and protein-protein interaction were predicted using PANTHER and STITCH v.5.0 software, respectively. No significant difference was observed in fasting blood glucose levels between DM and DM+COR for all time intervals. However, a significant decrease in final body weight, food intake, and water intake in DM+COR was found. Hepatic oxaloacetate and citrate levels were significantly increased in DM+COR compared to DM. Furthermore, 11 and 36 proteins were only expressed by the N+COR and DM+COR groups, respectively. Three unique proteins in DM+COR, namely, Nfat3, Flcn, and Psma3 were correlated with the production of ATP, AMPK signaling pathway, and ubiquitin proteasome system (UPS), respectively. Interestingly, a protein detected in N+COR and DM+COR (Gli3) was linked with the insulin signaling pathway. In conclusion, cordycepin might help in preventing hepatic metabolism by regulating the expression of energy-related protein and UPS to maintain cell survival. Further work on predicting the performance of metabolic mechanisms regarding the therapeutic applications of cordycepin will be performed in future.

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Metabolic phenotype of B cells from young and elderly HIV individuals

Immunity & Ageing ◽

10.1186/s12979-021-00245-w ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Daniela Frasca ◽

Suresh Pallikkuth ◽

Savita Pahwa

Keyword(s):

B Cells ◽

B Cell ◽

Cell Function ◽

Metabolic Phenotype ◽

Healthy Controls ◽

Metabolic Abnormalities ◽

Metabolic Markers ◽

Extracellular Flux ◽

Cell Pool ◽

B Cell Subsets

Abstract Background HIV infection induces inflammaging and chronic immune activation (IA), which are negatively associated with protective humoral immunity. Similar to HIV, aging is also associated with increased inflammaging and IA. The metabolic requirements of B cell responses in HIV infected (HIV+) individuals are not known, although metabolic abnormalities have been reported in these individuals. How these metabolic abnormalities are exacerbated by aging is also not known. Methods B cells were isolated by magnetic sorting from the blood of young and elderly HIV + individuals, as well as from the blood of age-matched healthy controls. We evaluated the composition of the B cell pool by flow cytometry, the expression of RNA for pro-inflammatory and metabolic markers by qPCR and their metabolic status using a Seahorse XFp extracellular flux analyzer. Results In this study we have evaluated for the first time the metabolic phenotype of B cells from young and elderly HIV + individuals as compared to those obtained from age-matched healthy controls. Results show that the B cell pool of HIV + individuals is enriched in pro-inflammatory B cell subsets, expresses higher levels of RNA for pro-inflammatory markers and is hyper-metabolic, as compared to healthy controls, and more in elderly versus young HIV + individuals, suggesting that this higher metabolic phenotype of B cells is needed to support B cell IA. We have identified the subset of Double Negative (DN) B cells as the subset mainly responsible for this hyper-inflammatory and hyper-metabolic profile. Conclusions Our results identify a relationship between intrinsic B cell inflammation and metabolism in HIV + individuals and suggest that metabolic pathways in B cells from HIV + individuals may be targeted to reduce inflammaging and IA and improve B cell function and antibody responses.

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