Aberrant Expression of a Proliferation-Inducing Ligand Underlies Autoimmune Mechanisms in Immune Thrombocytopenia

Abstract Background: Immunological thrombocytopenia (ITP) is an antibody-mediated autoimmune disease characterized by accelerated platelet destruction and suboptimal platelet production. The proliferation-inducing ligand (APRIL or TNFSF13), a member of the TNF superfamily, is structurally and functionally related to the TNF family of B cell activating factors (BAFF, TNFSF13b) and has been shown to regulate lymphocyte survival by interacting with its receptors. And activation. Transmembrane activators and calcium regulate cyclophilin ligand interactors (TACI) and B cell mature antigens (BCMA). APRIL is secreted by various cells as soluble factors, including inactive B cells, T cells, monocytes, neutrophils, macrophages and dendritic cells, as well as epithelial cells, osteoclasts and megakaryocytes. Recent studies have shown that APRIL not only participates in normal immune responses, but also plays an important role in the establishment and/or maintenance of autoimmune and inflammatory diseases. Aims: Based on the relationship between APRIL, which promotes proliferation and regulates immunity, and the development of autoimmunity, we hypothesize that APRIL may play a role in the pathogenesis of ITP. Methods:1. The EDTA anticoagulated whole blood was collected, and peripheral blood mononuclear cells (PBMC) were separated by Ficoll density gradient centrifugation. The APRIL levels on the surface of T cells, B cells, DC cells and platelets were detected by flow cytometry.Detection of plasma APRIL levels in patients with ITP by ELISA.Real time quantitative PCR were used for detecting the level of APRIL and its receptors BCMA and TACI from PBMC of healthy controls and ITP patients.Use soluble APRIL or BLyS protein and APRIL inhibitors to examine the effect of APRIL inhibition on IL-10 secretion by B cells. Flow cytometry and intracellular staining were used to evaluate B10 cells. Resoult: 1. The APRIL on the platelet surface of patients with ITP was significantly lower than that of the normal control group (p<0.01). In the ITP patients of 10 patients with complete remission, the content of APRIL on the platelet surface was significantly increased after treatment (p=0.02), and there was no significant change in the treatment-ineffective group. . The levels of APRIL and its receptors BCMA and TACI on B cells and DC cells in ITP patients were higher than those in normal controls, and the difference was statistically significant. APRIL is not expressed on CD4 + T cells, CD8 + T cells.The expression of APRIL mRNA in PBMNCs was significantly higher in ITP patients than in the normal control group (p <0.01). There was no difference in BCMA and TACI expression in PBMNC of ITP patients compared to normal controls.Plasma APRIL levels were significantly higher in ITP patients than in the normal control group, p = 0.04, and negatively correlated with platelet count, p = 0.029.In 10 patients with ITP, the percentage of CD19 + B cells remained similar between patients, and the results showed that the amount of B10 cells in the medium supplemented with APRIL was greater than that of B10 cells containing BLyS and control medium (p<0.01; p= 0.01), and the use of APRIL inhibitors resulted in a decrease in B10 cells. Conclusion: Our study shows that aberrant expression of APRIL is involved in the autoimmune response of ITP, and the effect of treatment can be assessed by measuring changes in the level of APRIL on the platelet surface. We also speculate that APRIL inhibits, rather than promotes, an immune-mediated inflammatory response in the pathogenesis of ITP. Our current observations support that the immunomodulatory effects of APRIL may be due, at least in part, to stimulation of IL-10 producing B cells. Disclosures No relevant conflicts of interest to declare.

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ACTH4-10 protects the ADR-injuried podocytes by stimulating B lymphocytes to secrete IL-10

10.21203/rs.2.23007/v1 ◽

2020 ◽

Author(s):

Kun Wang ◽

Huaping Du ◽

Zhen Chen ◽

Dong Xue

Keyword(s):

B Cells ◽

Protein Expression ◽

B Lymphocytes ◽

Normal Control ◽

Normal Control Group ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Apoptosis Detection ◽

Mrna And Protein Expression ◽

Cell Supernatant

Abstract Background: In the present study, we aimed to assess whether adrenocorticotropic hormone (ACTH) could protect the podocytes from adriamycin (ADR)-induced injury by stimulating B lymphocytes to secrete the associated cytokines.Methods: The supernatant of B lymphocytes was respectively collected after B lymphocytes were intervened by phorbol myristate acetate (PMA) or ACTH4-10 (1 µg/L, 10 µg/L and 100 µg/L). Podocytes were randomly divided into the groups as follows: normal control group, adriamycin (ADR) group, the supernatant (1 µg/L, 10 µg/L, or 100 µg/L ACTH4-10)+ADR groups, ACTH4-10 (10 µg/L)+ADR group, and the supernatant (10 µg/L ACTH4-10)+anti-IL-10R+ADR group. Proliferation assay was used to assess the proliferation and activity of podocytes. Enzyme-linked immunosorbent assay was used to examine the secretion of IL-10 and IL-4. TUNEL apoptosis detection kit was used to detect podocyte apoptosis.Real-time PCR and western blotting were used to examine the mRNA and protein expression of nephrin and podocin.Results: Compared with the normal control group, the podocyte proliferation of ADR group was significantly inhibited. However, compared with the ADR group, the podocyte proliferation of the supernatant (1 µg/L, 10 µg/L or 100 µg/L ACTH4-10)+ADR groups was generally increased, and the proliferation effect of the supernatant containing 10 µg/L ACTH4-10 was the highest. Moreover, we found that after B lymphocytes were intervened by 10 µg/L ACTH4-10, the IL-10 level in the cell supernatant was significantly elevated (p <0.05). When anti-IL-10R was added, the podocyte proliferation of the supernatant (10 µg/L ACTH4-10)+ADR group was significantly inhibited. Furthermore, the supernatant of B cells stimulated with 10 µg/L ACTH4-10 could better decrease the apotosis rate of injuried podocytes and increase the mRNA and protein expression of nephrin and podocin by elevating the secretion of IL-10.Conclusions: Compared with ACTH4-10, the supernatant of B cells stimulated with ACTH4-10 could better protect the podocytes from ADR-induced injury by elevating the secretion of IL-10.

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Analysis on the Clinical Characteristics of 36 Cases of Novel Coronavirus Pneumonia in Kunming

10.1101/2020.02.28.20029173 ◽

2020 ◽

Cited By ~ 5

Author(s):

Haiyan Fu ◽

Hongjuan Li ◽

Xiaoqing Tang ◽

Xiang Li ◽

Jie Shen ◽

...

Keyword(s):

T Cells ◽

Normal Control ◽

Cd8 T Cells ◽

Clinical Characteristics ◽

Normal Control Group ◽

Control Group ◽

C Reactive Protein ◽

Reactive Protein ◽

Hs Crp ◽

Novel Coronavirus

AbstractObjectiveTo analyze the clinical characteristics of patients with novel coronavirus pneumonia in Kunming City, and to study the correlation between nutritional status and immune function.MethodsClinical data of 36 patients with novel coronavirus pneumonia in isolation area of Kunming Third People’s Hospital from January 31 to February 15, 2020 were collected, and the basic situation, clinical characteristics, laboratory examination and CT imaging characteristics were analyzed. Serum albumin (ALB), prealbumin (PAB), hypersensitive c-reactive protein (hs-crp), CD3T cells, CD4T cells, CD8T cells and normal control group were analyzed. A simple linear regression analysis of the relationship between proalbumin and T cell subpopulation counts in the blood of patients.Results(1) The patients with new coronavirus pneumonia in Kunming were mainly of common type. (2) 50% of the patients’ first symptoms were fever and cough; (3) The total number of white blood cells in peripheral blood was normal or decreased in 23 cases (79%), and the lymphocyte count decreased in 5 cases (13.89%), without anemia. Hypersensitive c-reactive protein increased in 19 (52.78%) cases, and procalcitonin increased in 1 case. Albumin decreased in 5 cases (13.89%), proalbumin decreased in 15 cases (41.67%), alanine transaminase increased slightly in 4 cases (11.11%), alanine transaminase increased slightly in 4 cases (11.11%), total bilirubin increased slightly in 11 cases (30.56%), and renal function and blood coagulation were normal. Absolute value of CD3+T cells is with a decrease in 21 cases (58.3%), CD4+T in 28 cases (77.8%), CD8+T in 17 cases (47.2%), and CD4+/ CD8+ inverse in 6 cases (16.7%). (4) The prealbumin, CD3 T cells, CD4 T cells and CD8 T cells in the new coronavirus pneumonia group were significantly lower than those in the normal control group, and the hypersensitive c-reactive protein was higher than that in the normal control group. (5) The levels of PAB in the serum of the patients were linearly correlated with hs-crp, CD3 T cells, CD4 T cells and CD8 T cells, and the correlation coefficients were −0.474, 0.558, 0.467 and 0.613, respectively, showing statistical differences.ConclusionThe clinical characteristics of the novel coronavirus pneumonia in Kunming are different from those in Wuhan. The changes of serum proalbumin and T cell subsets are relatively obvious. Changes in serum proalbumin may contribute to the early warning of novel coronavirus pneumonia. The nutritional status of patients with common and mild pneumonia should be considered.

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Roles of 1,25(OH)2D3 and Vitamin D Receptor in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus by Regulating the Activation of CD4+ T Cells and the PKCδ/ERK Signaling Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000453135 ◽

2016 ◽

Vol 40 (3-4) ◽

pp. 743-756 ◽

Cited By ~ 18

Author(s):

Xiao-Jie He ◽

Yan Ding ◽

Wei Xiang ◽

Xi-Qiang Dang

Keyword(s):

Dna Methylation ◽

T Cells ◽

Mrna Expression ◽

Normal Control ◽

Lupus Erythematosus ◽

Cd4 T Cells ◽

Normal Control Group ◽

Erk Signaling ◽

Control Group ◽

Sirna Group

Background/Aims: The study aims to elucidate the roles of 1,25(OH)2D3 and vitamin D receptor (VDR) in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) by regulating the activation of CD4+ T cells and the PKCδ/ERK signaling pathway. Methods: From January 2013 to December 2015, a total of 130 SLE patients, 137 RA patients and 130 healthy controls were selected in this study. Serum levels of 1,25(OH)2D3 and VDR mRNA expression were detected by ELISA and real-time fluorescence quantitative PCR (RT-qPCR). Density gradient centrifugation was performed to separate peripheral blood mononuclear cells (PBMCs). CD4+ T cells were separated using magnetic activated cell sorting (MACS). CD4+T cells in logarithmic growth phase were collected and assigned into 9 groups: the normal control group, the normal negative control (NC) group, the VDR siRNA group, the RA control group, the RA NC group, the VDR over-expressed RA group, the SLE control group, the SLE NC group, and the VDR over-expressed SLE group. The mRNA and protein expressions of VDR, PKCδ, ERK1/2, CD11a, CD70 and CD40L were detected by RT-qPCR and Western blotting. Bisulfite genomic sequencing was conducted to monitor the methylation status of CD11a, CD70 and CD40L. Results: Compared with healthy controls, serum 1,25(OH)2D3 level and VDR mRNA expression in peripheral blood were decreased in SLE patients and RA patients. With the increase of concentrations of 1,25(OH)2D3 treatment, the VDR mRNA expression and DNA methylation levels of CD11a, CD70 and CD40L were declined, while the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L were elevated in SLE, RA and normal CD4+T cells. Compared with the SLE contro, RA control, SLE NC and RA NC groups, the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L decreased but DNA methylation levels of CD11a, CD70 and CD40L increased in the VDR over-expressed SLE group and VDR over-expressed RA group. However, compared with the normal control and normal NC groups, the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L increased, but DNA methylation levels of CD11a, CD70 and CD40L decreased in the VDR siRNA group. Compared with the normal control group, the expressions of PKCδ, ERK1/2, CD11a, CD70 and CD40L increased, but DNA methylation levels of CD11a, CD70 and CD40L decreased in the SLE control and RA control groups. Conclusion: Our study provide evidence that 1,25(OH)2D3 and VDR could inhibit the activation of CD4+ T cells and suppress the immune response of SLE and RA through inhibiting PKCδ/ERK pathway and promoting DNA methylation of CD11a, CD70 and CD40L.

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Evaluation of Donor CD4+CD25+Foxp3+ Regulatory T Cells and CD3-CD56+ NK Cells on Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-112735 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5726-5726

Author(s):

Fumihito Tajima ◽

Koji Adachi ◽

Takaya Nishio ◽

Toshio Kawatani ◽

Junji Suzumiya

Keyword(s):

T Cells ◽

Nk Cells ◽

Normal Control ◽

Cd8 T Cells ◽

Research Funding ◽

Absolute Number ◽

Treg Cells ◽

Normal Control Group ◽

Control Group ◽

The Absolute

Abstract Background: It is important to determine the changes in both donor T cells and B cells on immune reconstitution following allogeneic hematopoietic stem cell transplantation (HCT). It is well-known that Treg cells play important roles in the prevention of T-cell-mediated graft-versus-host disease (GVHD) and in promoting tumor escape from T-cell-dependent immunosurveillance. However, very little is known about the number and function of both CD4+CD25+Foxp3+ regulatory T (Treg) cells and CD3-CD56+ natural killer (NK) cells and about NK activity during immune reconstitution. In this study, we examined changes in the number of circulating Treg and NK cells in the peripheral blood (PB) and the NK activity of HCT patients at various times after HCT, and we evaluated the clinical significance of these findings relative to patient survival. Patients and Methods: We evaluated 29 consecutive patients (ages >18) without GVHD who underwent HCT for different hematologic diseases between December 2008 and April 2017. Treg and NK cells were characterized and quantified by flow cytometry from these 29 patients and 15 healthy controls. Evaluated variables included recipient and donor characteristics, transplant-related factors, including conditioning regimen (myeloablative conditioning or reduced-intensity conditioning), donor type (matched sibling donor, unrelated donor, other relative (haploidentical), or cord blood transplant), degree of match (8/8, 7/8, 6/8, or haploidentical), and GVHD prophylaxis. Patients who were followed up for more than 12 months were enrolled in the study. After obtaining informed consent, blood was drawn from all patients on the day of engraftment and at day 100 and at 12-month intervals thereafter. CD4+CD25+Foxp3+ Treg cells, CD3+CD4+T cells, CD3+CD8+ T cells, and CD3-CD56+ NK cells were analyzed using flow cytometry, and the absolute numbers of these cells were calculated. The NK activity was measured by the standard 51Cr release assay at an effector: target (E: T) ratio of 20:1. Results: The median patient age was 58 years (range: 19-71 years), and 21 out of 29 of the patients were male. At 100 days, the percentage of B cells (2.5±6.0%) and absolute numbers of CD8+ T cells (269.7±284.8/μL), CD4+T (22.83±292.4/μL) cells and NK cells (248.3±229.1/μL) were significantly lower than those at 2 years (20.9±11.6%, 747.2±648.4/μL, 588.0±607.3/μL, 558.1±336.2/μL, p<0.01, p<0.01, p<0.01, p=0.027, respectively) ,and at 3 years (18.2±11.2%, 554.1±343.3/μL, 488.1±210.3/μL, 500.1±451.3/μL, p<0.01, p=0.020, p=0.017, p=0.043, respectively). The changes in Treg% values in peripheral lymphocytes within 100 days to 3 years after HCT significantly decreased from 11.57 ±11.39 to 3.65 ±2.59% (p=0,039). The % of NK cells in the PB at 1 year after HCT (13.95±10.34%) was significantly lower than that within 100 days after HCT (27.1±16.8%, p=0.01). However, the absolute number of NK cells did not differ. In comparison with the normal control group, significant difference was observed in the Treg cells. Both percentage and absolute number of Treg cells (0.70±0.29%, 40.2±17.3/μL) in the normal control group were significantly higher than those at 1 year (0.33±0.16%, 20.6±15.4/μL, p<0.01, p<0.01, respectively), at 2 years (0.44±0.16/%, 25.1±15.4/μL, p=0.35, p<0.01, respectively), and at 3 years (0.29±0.23%, 15.5±11.8/μL, p<0.01, p<0.01, respectively). In contrast, the absolute number of CD8+ T cells (380.3±128.5/μL) in the normal control group were significantly lower than those at 1 year (935.1±648.4/μL, p<0.01), at 2 years (747.2±648.4/μL, p<0.01), and then did not differ at 3 years (554.1±343.3/μL). Conclusion: The percentage and the absolute number of Treg cells in HCT patients were significantly lower than those in the normal control group, whereas CD8+ T cells was significantly higher in the patients within 2 years after HCT than that in the normal control group. The % Treg cells did not recover even at 3 years after HCT, rather it tended to be somewhat lower. In contrast, there was no change in the NK cells. These results suggest that the immunological reconstitution has not been achieved even at 3 years after transplantation and that the immunological consequences of GVHD are maintained. The antitumor effect is also maintained. On the other hand, NK cells recover at an early stage. The roles of these different immune cells after HCT require further investigation. Disclosures Suzumiya: Eisai: Research Funding, Speakers Bureau; Pfizer: Research Funding; Celltrion: Research Funding; Taiho: Research Funding, Speakers Bureau; Sumitomo Dainioppon: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SymBio: Research Funding; Bristol Myers Squibb: Speakers Bureau; Toyama Chemical: Research Funding; Chugai-Roche: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Zenyaku Kogyo: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Ono: Speakers Bureau; Ohtsuka: Speakers Bureau; Shire Japan: Speakers Bureau.

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Regulatory B Cells and Their Cytokine Profile in HCV-Related Hepatocellular Carcinoma: Association with Regulatory T Cells and Disease Progression

Vaccines ◽

10.3390/vaccines8030380 ◽

2020 ◽

Vol 8 (3) ◽

pp. 380 ◽

Cited By ~ 3

Author(s):

Helal F. Hetta ◽

Mohamed A. Mekky ◽

Asmaa M. Zahran ◽

Mohamed O. Abdel-Malek ◽

Haidi K. Ramadan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

B Cell ◽

Disease Progression ◽

System Analysis ◽

Control Group ◽

Regulatory B Cells ◽

B Cell Activating Factor

Although regulatory B cells (Bregs) have been proven to play a suppressive role in autoimmune diseases, infections and different tumors, little is known regarding hepatocellular carcinoma (HCC), especially in hepatitis C-related settings. Herein, we analyzed the frequency of circulating Bregs, serum levels of IL-10, IL-35 and B-cell activating factor (BAFF) and investigated their association with regulatory T cells (Tregs) and disease progression in HCV-related HCC. For comparative purposes, four groups were enrolled; chronic HCV (CHC group, n = 35), HCV-related liver cirrhosis (HCV-LC group, n = 35), HCV-related HCC (HCV-HCC group, n = 60) and an apparently healthy control (Control-group, n = 20). HCC diagnosis and staging were in concordance with the Barcelona Clinic Liver Cancer (BCLC) staging system. Analysis of the percentage of Breg cells and peripheral lymphocyte subsets (Treg) was performed by flow cytometry. Serum cytokine levels of IL-10, IL-35 and B-cell activating factor (BAFF) were measured by ELISA. The frequency of Bregs was significantly higher in the HCV-HCC group compared to the other groups and controls. A significant increase was noted in late-HCC versus those in the early stages. The frequency of Bregs was positively correlated with Tregs, serum IL-10, IL-35 and BAFF. In conclusion, Peripheral Bregs were positively correlated with the frequency of Tregs, IL-10, IL-35 and BAFF, and may be associated with HCV-related HCC progression.

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Clinical Significance of Free Circulating CD3 and CD5 in Patients with Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v108.11.4947.4947 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4947-4947

Author(s):

Menna Hodge ◽

Susan O’Brien ◽

Adam Abdool ◽

Michael Keating ◽

Iman Jilani ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Normal Control ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Β2 Microglobulin ◽

Control Subjects

Abstract </DEL> CD5, a transmembrane protein expressed in T-cells, few B-cells, and chronic lymphocytic leukemia (CLL) B-cells, is the ligand for CD72 and may play a role in B-cell-T-cell communication. CD5 is part of the T-cell receptor (TCR)-CD3 complex in T-cells as well as the B-cell receptor (BCR) complex and serves as substrate for induction of tyrosine kinase activity. Since leukemic cells have high turnover and pour their protein, RNA, and DNA into the circulation, we speculated that free circulating CD3 (cCD3) and CD5 (cCD5) could be detected in the plasma of patients with CLL. We have developed a bead-based sandwich immunoassay to measure cCD3 and cCD5 in the plasma. Using this assay, we assessed the value of cCD5 measurement, alone and after normalization to cCD3 levels, as a tumor marker in CLL. Plasma levels of cCD3 and cCD5 were measured in 85 patients with CLL and 51 normal control subjects. cCD3 and cCD5 levels were significantly higher in patients with CLL (median, 7,465 and 55,806 U/μl, respectively) than in normal control subjects (median, 830 and 1,671 U/μl, respectively). Patients with CLL had significantly higher cCD5:cCD3 ratios (median, 5.28; range, 0–161) than did normal controls (median, 1.70; range, 0–8.06) (P <0.0001). Levels of cCD5, but not cCD3, correlated positively with WBC count, β2-microglobulin level, splenomegaly, and Rai stage (all P <0.01). The cCD5:cCD3 ratio also correlated with Rai stage (P = 0.04) and β2-microglobulin level (P = 0.03). cCD5 levels and the cCD5:cCD3 ratio both correlated with survival (P = 0.03). These findings confirm that free circulating surface markers can be detected in the circulation of patients with CLL, most likely reflect the tumor load, and can be used as tumor markers. The biological and therapeutic relevance of these free circulating proteins should be considered in pharmacokinetic and pharmacodynamic studies.

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Therapeutic targeting of the BCR-associated protein CD79b in a TCR-based approach is hampered by aberrant expression of CD79b

Blood ◽

10.1182/blood-2014-07-587840 ◽

2015 ◽

Vol 125 (6) ◽

pp. 949-958 ◽

Cited By ~ 10

Author(s):

Lorenz Jahn ◽

Pleun Hombrink ◽

Chopie Hassan ◽

Michel G. D. Kester ◽

Dirk M. van der Steen ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

B Cell Malignancies ◽

Aberrant Expression ◽

Therapeutic Targeting ◽

High Affinity ◽

Key Points

Key Points B-cell malignancies were efficiently recognized by T cells expressing high-affinity alloHLA-restricted TCRs specific for CD79b. Aberrant expression of CD79b in non–B cells caused unwanted reactivity, rendering CD79b unsuitable for TCR-based immunotherapies.

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Cocapture of cognate and bystander antigens can activate autoreactive B cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1614472114 ◽

2017 ◽

Vol 114 (4) ◽

pp. 734-739 ◽

Cited By ~ 23

Author(s):

Nicholas S. R. Sanderson ◽

Maria Zimmermann ◽

Luca Eilinger ◽

Céline Gubser ◽

Nicole Schaeren-Wiemers ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Cell Membranes ◽

Cell Receptor ◽

Acute Disseminated Encephalomyelitis ◽

Autoimmune Response ◽

Influenza Hemagglutinin ◽

Mog Antibodies

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) are associated with autoimmune central nervous system diseases like acute disseminated encephalomyelitis (ADEM). For ADEM, it is speculated that a preceding infection is the trigger of the autoimmune response, but the mechanism connecting the infection to the production of MOG antibodies remains a mystery. We reasoned that the ability of B cells to capture cognate antigen from cell membranes, along with small quantities of coexpressed “bystander” antigens, might enable B-cell escape from tolerance. We tested this hypothesis using influenza hemagglutinin as a model viral antigen and transgenic, MOG-specific B cells. Using flow cytometry and live and fixed cell microscopy, we show that MOG-specific B cells take up large amounts of MOG from cell membranes. Uptake of the antigen from the membrane leads to a strong activation of the capturing B cell. When influenza hemagglutinin is also present in the membrane of the target cell, it can be cocaptured with MOG by MOG-specific B cells via the B-cell receptor. Hemagglutinin and MOG are both presented to T cells, which in turn are activated and proliferate. As a consequence, MOG-specific B cells get help from hemagglutinin-specific T cells to produce anti-MOG antibodies. In vivo, the transfer of MOG-specific B cells into recipient mice after the cocapture of MOG and hemagglutinin leads to the production of class-switched anti-MOG antibodies, dependent on the presence of hemagglutinin-specific T cells. This mechanism offers a link between infection and autoimmunity.

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Changes of Peripheral Blood Lymphocyte Subsets and Cytokines in Patients with Multiple Myeloma and Their Clinical Significance

Blood ◽

10.1182/blood-2020-142759 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 38-38

Author(s):

Li Fei

Keyword(s):

T Cells ◽

Normal Control ◽

Cd4 T Cells ◽

Lymphocyte Subsets ◽

Risk Group ◽

Normal Control Group ◽

Control Group ◽

Newly Diagnosed ◽

Significant Difference ◽

The Difference

Objective: Accumulating evidence have indicated that immune response play an essential role in development of multiple myeloma (MM),To evaluate the immune function of patients with MM by detecting the levels of lymphocyte subsets and cytokines, and to analyze the correlation between the immune function and prognosis of patients. Methods: we examined 50 patients with newly diagnosed MM, 20 patients with Relapse / refractory MM and 30 healthy volunteers. the levels of T lymphocyte subsets, activated T cells subtypes, Treg and cytokines in peripheral blood were detected by flow cytometry (FCM).Results: ① compared with healthy control group, CD3 + CD4 + T cells of newly diagnosed MM patients were significantly decreased (P = 0.04), There was no significant difference in CD3+CD8+T and CD4/CD8 of newly diagnosed MM patients with normal controls (P=0.14).The percentage of CD16 + cd56dim NK cells of newly diagnosed MM was significantly lower than that of the normal control group (P = 0.01); There was no significant difference in frequencies of CD3+CD4+T cells, CD4/CD8, CD16+CD56dimNK (P=0.34, P=0.561, P=0.88) between newly treated MM patients and relapsed/refractory MM; HLA-DR-CD8+ activated TS cells of newly diagnosed MM was significantly higher than the normal control group (P = 0.04).② The proportion of CD4 + CD25 + CD127dim T cells(treg) in total CD4 + T cells in of newly diagnosed MM was higher than that in normal control group (P < 0.05). The CD4 + CD25 +CD127dim T cells of MM patients with relapse / refractory MM was higher than that of newly treated patients, but the difference was not statistically significant (P > 0.05). Further analysis showed that CD4 + CD25 + CD127dim T cells in mSMART stratified high-risk group were higher than those in low-risk group (P = 0.03). The number of CD4 + CD25 + CD127dim T cells in patients without PR after 2 courses of PAD was higher than that in patients with≥ PR, but the difference was not statistically significant (P > 0.05). ③ The levels of IL-6, IL-8, TNF - α of newly diagnosed MM were significantly higher than normal control group, and were positively correlated with ISS stage (r=0.61, r=0.67, r=0.59, P均<0.05).④ The levels of IL-6 and IL-8 of newly diagnosed MM with renal injury were significantly higher than those in patients with normal renal function (P < 0.05). Further studies showed that the level of IL-8 was negatively correlated with the proportion of CD16 + CD56dimNK cells (r=-0.65, P<0.05).Conclusion: the abnormal expression of lymphocyte subsets and cytokine levels in MM patients may be related to the tumor load, disease progression and prognosis. Disclosures No relevant conflicts of interest to declare.

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Dopaminergic stimulation leads B-cell infiltration into the central nervous system upon autoimmunity

10.21203/rs.3.rs-41605/v2 ◽

2021 ◽

Author(s):

Carolina Prado ◽

Francisco Osorio-Barrios ◽

Alexandra Espinoza ◽

Juan J Saez ◽

María I Yuseff ◽

...

Keyword(s):

Central Nervous System ◽

T Cells ◽

Nervous System ◽

T Cell ◽

B Cells ◽

B Cell ◽

T Cell Response ◽

Autoimmune Response ◽

Cns Autoimmunity ◽

Anti Inflammatory

Abstract Multiple sclerosis (MS) involves a CD4+ T-cell-driven autoimmune response to central nervous system (CNS) derived antigens. Previous evidence has suggested that B-cells play a fundamental role as antigen-presenting cells (APC) in mouse models of MS re-stimulating CD4+ T-cells in the CNS as well as regulating the T-cell response by mean of inflammatory or anti-inflammatory cytokines. Despite an important dopaminergic regulation of T-cells has been previously described in MS, the effects of dopaminergic signalling in B-cells in this pathology remains unexplored. Here we addressed the role of the dopamine receptor D3 (DRD3), which display the highest affinity for dopamine, in B-cells in animal models of MS. Experimental autoimmune encephalomyelitis (EAE) was induced in mice harbouring Drd3-deficient or Drd3-suficient B-cells. Our data shows that, by promoting the expression of the chemokine receptor CXCR3 in autoreactive B-cells, DRD3-stimulation favours the CNS-tropism in a subset of B-cells that act as APC in the CNS, which is fundamental for disease development. Furthermore, we found that DRD3-stimulation induced the expression of the CNS-homing molecule CD49d in a B-cell subset with anti-inflammatory features, thus attenuating EAE manifestation in a CNS-autoimmunity model independent of the APC function of B-cells. Our findings demonstrate that DRD3-stimulation in B-cells exerts a dual role in CNS-autoimmunity, favouring CNS-tropism of pro-inflammatory B-cells with APC function, and also promoting CNS-homing of B-cells with anti-inflammatory features. Thus, these results show DRD3-stimulation in B-cells as a key regulator of CNS-autoimmunity.

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