Curcumin alleviates experimental colitis via a potential mechanism involving memory B cells and Bcl-6-Syk-BLNK signaling

BACKGROUND Immune dysfunction is the crucial cause in the pathogenesis of inflammatory bowel disease(IBD),which is mainly related to lymphocytes(T or B cells,including memory B cells),mast cells,activated neutrophils,and macrophages.As the precursor of B cells,the activation of memory B cells can trigger and differentiate B cells to produce a giant variety of inducible B cells and tolerant B cells,whose dysfunction can easily lead to autoimmune diseases,including IBD.AIM To investigate whether or not curcumin(Cur)can alleviate experimental colitis by regulating memory B cells and Bcl-6-Syk-BLNK signaling.METHODS Colitis was induced in mice with a dextran sulphate sodium(DSS)solution in drinking water.Colitis mice were given Cur(100 mg/kg/d)orally for 14 consecutive days.The colonic weight,colonic length,intestinal weight index,occult blood scores,and histological scores of mice were examined to evaluate the curative effect.The levels of memory B cells in peripheral blood of mice were measured by flow cytometry,and IL-1β,IL-6,IL-10,IL-7A,and TNF-αexpression in colonic tissue homogenates were analyzed by enzyme-linked immunosorbent assay.Western blot was used to measure the expression of Bcl-6,BLNK,Syk,and other signaling pathway related proteins.RESULTS After Cur treatment for 14 d,the body weight,colonic weight,colonic length,colonic weight index,and colonic pathological injury of mice with colitis were ameliorated.The secretion of IL-1β,IL-6,TNF-α,and IL-7A was statistically decreased,while the IL-35 and IL-10 levels were considerably increased.Activation of memory B cell subsets in colitis mice was confirmed by a remarkable reduction in the expression of IgM,IgG,IgA,FCRL5,CD103,FasL,PD-1,CD38,and CXCR3 on the surface of CD19^(+)CD27^(+)B cells,while the number of CD19^(+)CD27^(+)IL-10^(+)and CD19^(+)CD27^(+)Tim-3^(+)B cells increased significantly.In addition,Cur significantly inhibited the protein levels of Syk,p-Syk,Bcl-6,and CIN85,and increased BLNK and p-BLNK expression in colitis mice.CONCLUSION Cur could effectively alleviate DSS-induced colitis in mice by regulating memory B cells and the Bcl-6-Syk-BLNK signaling pathway.

Safety and Immunogenicity After Primary and Booster Inactivated SARS-Cov-2 Vaccination in Patients with Autoimmune Liver Diseases

Background and Aims:SARS-CoV-2 vaccines-associated autoimmune liver diseases have been reported in several case reports.However,the safety and immunogenicity after primary and booster inactivated SARS-CoV-2 vaccination in patients with autoimmune liver diseases(AILD)is still unknown.Methods:Eighty-four patients with AILD were prospectively followed up after the second dose(primary)of inactivated SARS-CoV-2 vaccine.Some of them received the third dose(booster)of inactivated vaccine.Adverse events(AEs),autoimmune activation,and liver inflammation exacerbation after primary and booster vaccination were recorded.Meanwhile,dynamics of antireceptor-binding-domain IgG(anti-RBD-IgG),neutralizing antibodies(NAbs)and RBD-specific B cells responses were evaluated.Results:The overall AEs in AILD patients after primary and booster vaccination were 26.2%and 13.3%,respectively.The decrease of C3 level and increase of immunoglobulin light chain K andλlevels were observed in AILD patients after primary vaccination,however,liver inflammation was not exacerbated,even after booster vaccination.Both the seroprevalence and titers of anti-RBD-IgG and NAbs were decreased over time in AILD patients after primary vaccination.Notably,the antibody titers were significantly elevated after booster vaccination(10-fold in anti-RBD-IgG and 7.4-fold in NAbs,respectively),which was as high as in healthy controls.Unfortunately,the inferior antibody response was not enhanced after booster vaccination in patients with immunosuppressants.Changes of atypical memory B cells were inversely related to antibody levels,which indicate that the impaired immune memory was partially restored partly by the booster vaccination.Conclusions:The well tolerability and enhanced humoral immune response of inactivated vaccine supports an additional booster vaccination in AILD patients without immunosuppressants.

Generation of human neutralizing monoclonal antibodies against the 2009 pandemic H 1N 1 virus from peripheral blood memory B lymphocytes

The 2009 H 1N 1 influenza pandemic demonstrated the significance of a global health threat to human beings. Although pandemic H 1N 1 vaccines have been rapidly developed, passive serotherapy may offer superior immediate protection against infections in children, the elderly and immune-compromised patients during an influenza pandemic. Here, we applied a novel strategy based on Epstein-Barr virus （EBV）-immortalized peripheral blood memory B cells to screen high viral neutralizing monoclonal antibodies （MAbs） from individuals vaccinated with the 2009 pandemic H1N1 vaccine PANFLU.1. Through a massive screen of 13 090 immortalized memory B-cell clones from three selected vaccinees, seven MAbs were identified with both high viral neutralizing capacities and hemagglutination inhibition （HAl） activities against the 2009 pandemic H 1N 1 viruses. These MAbs may have important clinical implications for passive serotherapy treatments of infected patients with severe respiratory syndrome, especially children, the elderly and immunodeficient individuals. Our successful strategy for generating high-affinity MAbs from EBV-immortalized peripheral blood memory B ceils may also be applicable to other infectious or autoimmune diseases.

Liver-spleen axis dysfunction in COVID-19

Coronavirus disease 2019(COVID-19),caused by the novel severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is an acute infectious disease that spreads mainly through the respiratory route.Besides interstitial pneumonia,a number of other clinical manifestations were noticed in COVID-19 patients.In particular,liver and spleen dysfunctions have been described both as complications of COVID-19 and as potential predisposing factors for severe COVID-19.Liver damage is rather common in COVID-19 patients,and it is most likely multifactorial,caused by the direct insult of SARS-CoV-2 to the liver by the cytokine storm triggered by the virus,by the use of hepatotoxic drugs,and as a consequence of hypoxia.Although generally mild,liver impairment has been found to be associated with a higher rate of intensive care unit admission.A higher mortality rate was reported among chronic liver disease patients.Instead,spleen impairment in patients with COVID-19 has been poorly described.The main anatomical changes are the architectural derangement of the B cell compartment,white pulp atrophy,and reduction or absence of lymphoid follicles,while,from a functional point of view,the IgM memory B cell pool is markedly depleted.The outcome of COVID-19 in asplenic or hyposplenic patients is yet to be defined.In this review,we will summarise the current knowledge regarding the impact of SARS-CoV-2 on the liver and spleen function,as well as the outcome of patients with a pre-existent liver disease or defective spleen function.

B cell dysfunction in chronic hepatitis B virus infection

Chronic hepatitis B(CHB)remains a global health problem.The persistence of hepatitis B surface antigen(HBsAg)in the blood for longer than 6 months after the initial infection is a sign of CHB.The therapeutic goal for the functional cure of CHB is the generation of antibodies against HBsAg.However,the adaptive immune response of patients with CHB cannot generate an efficient antiviral response.Many previous studies have evaluated T cell function and T cell therapy specifically designed to counter hepatitis B virus(HBV)infection.As one of the major components of adaptive immunity,B cells also display dysfunctions in anti-HBsAg antibody(HBsAb)production and antigen presentation.Patients with CHB have amplification of CD19^(+)CD10^(-)CD27^(-)CD21^(-)atypical memory B cell subsets and CD19^(+)CD24^(hi)CD38^(hi) regulatory B cells.Currently,no reviews have summarized specific B cell responses during CHB infection.Thus,in this study,we summarized B cell dysfunction during CHB progression and the potential mechanisms behind these dysfunctions to further our understanding of the mechanisms of adaptive immune response of B cells in the process of CHB development and help provide new methods and ideas for the treatment of CHB.

B lymphocyte-mediated humoral immunity in the pathogenesis of chronic hepatitis B infection

During hepatitis B virus(HBV)infection,the host immune response,including the presence of functional HBV-specific T cells and HBV-specific antibody-producing B cells,ultimately determines the HBV infection outcome:either the virus is cleared,or infection persists.Functional exhaustion of HBV-specific CD8^(+) cytotoxic T cells is the most important immune feature in chronic HBV infection.However,chronic HBV infection also re-writes humoral immunity,whereby B cells are the leading participants.In this review,we highlight HBV-specific B cell responses and propose future directions for research aimed at the generation of more efficient immunotherapeutic strategies.