Impact of exercise on markers of B cell-related immunity:A systematic review

Background:B cells represent a crucial component of adaptive immunity that ensures long-term protection from infection by generating pathogen-specific immunoglobulins.Exercise alters B cell counts and immunoglobulin levels,but evidence-based conclusions on potential benefits for adaptive immunity are lacking.This systematic review assessed current literatures on the impact of acute exercise and exercise training on B cells,immunoglobulins,and markers of secretory immunity in human biofluids.Methods:According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)guidelines,MEDLINE,Web of Science,and Embase were searched on March 8,2023.Non-randomized controlled trials and crossover trials investigating the impact of acute exercise or exercise training on B cell counts and proportions,immunoglobulin levels,salivary flow rate,or secretory immunoglobulin A secretion rate were included.Quality and reporting of exercise training studies were assessed using the Tool for the Assessment of Study Quality and reporting in Exercise.Study characteristics,outcome measures,and statistically significant changes were summarized tabularly.Results:Of the 67 eligible studies,22 applied acute exercise and 45 applied exercise training.All included outcomes revealed significant alterations over time in acute exercise and exercise training context,but only a few investigations showed significant differences compared to control conditions.Secretory and plasma immunoglobulin A levels were most consistently increased in response to exercise training.Conclusion:B cell-related outcomes are altered by acute exercise and exercise training,but evidence-based conclusions cannot be drawn with high confidence due to the large heterogeneity in populations and exercise modalities.Well-designed trials with large sample sizes are needed to clarify how exercise shapes B cell-related immunity.

Identification of the epitopes on HCV core protein recognized by HLA-A2 restricted cytotoxic T lymphocytes

AIM: To identify hepatitis C virus(HCV) core protein epitopes recognized by HLA-A2 restricted cytotoxic T lymphocyte (CTL). METHODS: Utilizing the method of computer prediction followed by a 4h(51)Cr release assay confirmation. RESULTS: The results showed that peripheral blood mononuclear cells (PBMC) obtained from two HLA-A2 positive donors who were infected with HCV could lyse autologous target cells labeled with peptide "ALAHGVRAL (core 150-158)". The rates of specific lysis of the cells from the two donors were 37.5% and 15.8%, respectively. Blocking of the CTL response with anti-CD4 mAb caused no significant decrease of the specific lysis. But blocking of CTL response with anti-CD8 mAb could abolish the lysis. CONCLUSION: The peptide (core 150-158) is the candidate epitope recognized by HLAA2 restricted CTL.

Hepatitis C virus in human B lymphocytes transformed by Epstein-Barr virus in vitro by in situ reverse transcriptase-polymerase chain reaction

AIM: To study persistence and replication of hepatitis C virus (HCV) in patients' peripheral blood mononuclear cells (PBMC) cultured in vitro. METHODS: Epstein Barr virus (EBV) was used to transform the hepatitis C virus from a HCV positive patient to permanent lymphoblastoid cell lines (LCL). Positive and negative HCV RNA strands of the cultured cells and growth media were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) each month. Core and NS5 proteins of HCV were further tested using immunohistochemical SP method and in situ RT-PCR. RESULTS: HCV RNA positive strands were consistently detected the cultured cells for one year. The negative-strand RNA in LCL cells and the positive-strand RNA in supernatants were observed intermittently. Immunohistochemical results medicated expression of HCV NS3 and C proteins in LCL cytoplasm mostly. The positive signal of PCR product was dark blue and mainly localized to the LCL cytoplasm. The RT-PCR signal was eliminated by overnight RNase digestion but not DNase digestion. CONCLUSION: HCV may exist and remain functional in a cultured cell line for a long period.

B-cell clonality in the liver of hepatitis C virus-infected patients

AIM:The association of hepatitis C virus(HCV) infection with typeⅡmixed cryoglobulinemia is well established,but the role of HCV in B-cell lymphoma remains controversial.In patients with HCV infection,B-cell clonal expansions have been detected in peripheral blood and bone marrow,and a high prevalence of B-cell non-Hodgkin's lymphomas has been documented.Liver biopsies in chronic HCV infection frequently show portal lymphoid infiltrates with features of B follicles,whose clonality has not yet been investigated.The object of this study was to determine the frequency of liver-infiltrating monoclonal B-cells in 40 patients with HCV infection.METHODS:Eight hundred and forty-eight patients were studied prospectively,including 40 HCV-positive patients and 808 patients with chronic hepatitis B virus(HBV)infection.Immunohistochemical study for B-and T-cell markers was performed on the paraffin-embedded liver tissue sections.The clonality of lymphoid B-cells was tested using a polymerase chain reaction(PCR)approach designed to identify immunoglobulin heavy chain gene(IgH) rearrangements.RESULTS:Liver-infiltrating monoclonal B-cells were detected in the liver for 4(10%)of 40 HCV-positive patients but were present in only 3(0.37%)of 808 liver biopsy specimens with chronic HBV infection.Chi-square testing showed that the monoclonal B-cells infiltration in the liver was more frequent in the HCV-infected patients(P=0.000).A clonal IgH rearrangement was detected in 5(71.4%)of 7 liver biopsy specimens with monoclonal B-cells infiltration.In 2 of 5 patients with both a clonal B-cell expansion and monoclonal B-cells infiltration in the liver,a definite B-cell malignancy was finally diagnosed.CONCLUSION:Liver-infiltrating monoclonal B-cells are detected in the liver of patients with chronic HCV and HBV infection.A high percentage of patients with monoclonal B-cells infiltration and B-cell clonality in the liver were finally diagnosed as having a definite B-cell malignancy.

Rituximab for the Treatment of Multiple Sclerosis: A Retrospective Observational Cohort in Morocco

Background: RITUXIMAB (RTX) is a chimeric anti-CD20 monoclonal antibody that has initially demonstrated efficacy in patients with B-cell lymphoma. Then, over time, it has demonstrated its efficacy in systemic inflammatory diseases and recently in neurological diseases such as multiple sclerosis (MS). Here we describe our experience with rituximab from one MS center from MOROCCO. Objectives: To investigate the safety and efficacy of Rituximab in MS in a Moroccan population. Methods: A retrospective uncontrolled observational single-center study from January 2017 to July 2020, was including all off-label Rituximab-treated patients with MS with at least 6 months of follow-up. Outcome data were collected and evaluated relapse rate, EDSS score, and adverse events (AEs) from the medical charts. Adverse events grade according to the Common Terminology Criteria for Adverse Events. Results: A total of 63 MS patients were treated with RTX, 47 patients were included, while 12 cases had just initiated treatment and 4 cases were lost to follow-up. The mean age of the patients was 39 ± 12 years with a female predominance (F/M: 1.6). All forms of MS were included, 83% of whom had relapsing-remitting MS. The duration of disease progression was 8 ± 5 years. Median EDSS before RTX initiation was 5.5 (0 - 7). 51% of patients were treated with RTX as second-line therapy after failure of other disease-modifying therapies, whereas 34% received it as first-line therapy. The annualized relapse rates decreased from 0.8 to 0.2 after RTX treatment. The Median EDSS remained unchanged at 71%. Radiological stability was noted in 83.7%, while 13.5% had a single new T2 lesion. Infusion-related AEs occurred during 27.6% of infusions and most were mild. Simple infection grades ≤ 2 were noted in 19%. Abortion occurred in only one patient. Conclusion: Our study confirms the usability of rituximab treatment for MS in the MOROCCO healthcare environment.

Value of the peripheral blood B-cells subsets in patients with ankylosing spondylitis

Background The role of B-cell remains an enigma in the pathogenesis of ankylosing spondylitis （AS）. This study aimed to investigate the distributions of B-cells and subsets in peripheral blood of AS patients and observe their changes in etanercept-treated AS patents. Methods We detected the proportions of CD19^＋ B-cell, naive B-cell （CD19^＋CD27）, memory B-cell （CD19^＋CD27dim） and plasmablast （CD19^＋CD27high） in peripheral blood of 66 patients with AS （39 at active stage, 27 at stable stage; 35 patients with peripheral joint involvement, 31 patients with axial involvement alone）, 30 patients with rheumatoid arthritis （RA） and 30 healthy volunteers using flow cytometry. And then we observed the changes of the above indexes of 39 active AS patients treated with etanercept in a randomized, double-blind, placebo-controlled trial. Results （1） Percentages of CD19^＋ B-cells in active or peripheral joint involvement AS patients increased more obviously than those in stable or axial involvement alone AS patients （both P=0.001）, and percentage of CD19^＋CD27high B-cells in AS patients with peripheral joint involvement was significantly higher than that in cases with axial involvement alone or healthy volunteers （P=0.005 and 0.006, respectively）; （2） The percentage of CD19~ B-cells in AS patients was positively correlated with Bath Ankylosing Spondylitis Disease Activity Index （BASDAI） scores, Patient＇s Global Assessment （PGA） scores, total back pain scores and nocturnal back pain scores （r=0.270, 0.255, 0.251 and 0.266, P=-0.029, 0.039, 0.042 and 0.031, respectively）; （3） At week 6 and week 12, there were no statistical differences of the percentages of B-cells and subsets between etanercept group and placebo group of AS patients （P 〉0.05）; the percentage of CD19^＋ B-cells in etanercept group was higher than that in healthy volunteers at week 12 （t=3.320, P=0.003）. Conclusions Misbalance is present in B-cells and some subsets in peripheral blood of active AS patients with peripheral joint involved. B-cells might play an important role in the pathogenesis of AS patients. The high percentage of CD19^＋ B-cells in active AS patients cannot be down-regulated after 12-week etanercept treatment.

Skewed CD39/CD73/adenosine pathway contributes to B-cell hyperactivation and disease progression in patients with chronic hepatitis B

Background:The mechanisms underlying B-cell hyperactivation in patients with chronic hepatitis B virus(HBV)infection remain largely undefined.The present study assessed the clinical characteristics of the CD39/CD73/adenosine pathway in patients with chronic hepatitis B(CHB).Methods:We examined CD39 and CD73 expression and adenosine production by B-cells from 202 HBV-infected patients.B-cell-activation phenotypes were assessed by flow cytometry after CpG+CD40 ligand stimulation with or without blockade and activation of the adenosine pathway.Results:CD39 and CD73 expression on circulating B-cells was decreased in CHB patients with high HBV DNA,HBeAg positivity,high HBsAg levels,and active liver inflammation,and was hierarchically restored in complete responders according to HBeAg seroconversion or HBsAg reduction.However,CD39 and CD73 expression on activated memory and tissue-like memory B-cell subsets in complete responders was not increased despite effective antiviral treatments.Furthermore,CD39 and CD73 expression on intra-hepatic B-cells was decreased in inflammatory livers.In vitro,B-cells from CHB patients showed a markedly reduced capacity to generate CD39/CD73-dependent extracellular adenosine and expressed increased levels of activation markers after adenosine-production blockade.Contrastingly,metformin significantly reduced activation-marker expression via regulating AMP-activated protein kinase.Conclusions:The skewed CD39 and CD73 expression on B-cells was associated with a high viral burden,liver inflammation,and antiviral efficacy in CHB patients,and the skewed CD39/CD73/adenosine pathway contributed to B-cell hyperactivation.Regulation of the CD39/CD73/adenosine pathway using metformin may represent a therapeutic option to reverse HBVinduced immune pathogenesis.

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation

Aim:To test the hypothesis that lymphocyte infiltration in brain arteriovenous malformation(bAVM)is not associated with iron deposition(indicator of micro-hemorrhage).Methods:Sections of unruptured,previously untreated bAVM specimens(n=19)were stained immunohistochemically for T-lymphocytes(CD3+),B-lymphocytes(CD20+),plasma cells(CD138+)and macrophages(CD68+).Iron deposition was assessed by hematoxylin and eosin and Prussian blue stains.Superficial temporal arteries(STA)were used as control.Results:Both T-lymphocytes and macrophages were present in unruptured,previously untreated bAVM specimens,whereas few B cells and plasma cells were detected.Iron deposition was detected in 8 specimens(42%;95%confidence intervals=20-67%).The samples with iron deposition tended to have more macrophages than those without(666±313 vs.478±174 cells/mm2;P=0.11).T-cells were clustered on the luminal side of the endothelial surface,on the vessel-wall,and in the perivascular regions.There was no correlation between T-lymphocyte load and iron deposition(P=0.88).No macrophages and lymphocytes were detected in STA controls.Conclusion:T-lymphocytes were present in bAVM specimens.Unlike macrophages,the load and location of T-lymphocytes were not associated with iron deposition,suggesting the possibility of an independent cell-mediated immunological mechanism in bAVM pathogenesis.