Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune ...Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic.In this study,we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia(FOP)patients who underwent lung surgery and served as controls.We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients.In contrast to the FOP patients,Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients.This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients.In summary,our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity.Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.展开更多
Germinal centers （GC） of secondary lymphoid tissues are critical to mounting a high-affinity humoral immune response. B cells within the GC undergo rapid clonal expansion and selection while diversifying their antib...Germinal centers （GC） of secondary lymphoid tissues are critical to mounting a high-affinity humoral immune response. B cells within the GC undergo rapid clonal expansion and selection while diversifying their antibody genes. Although it is generally believed that GC B cells employ a unique proliferative program to accommodate these processes, little is known about how the GC-associated cell cycle is orchestrated. The D-type cyclins constitute an important component of the cell cycle engine that enables the cells to respond to physiological changes. Cell type- and developmental stage-specific roles of D-type cyclins have been described but the cyclin D requirement during GC reaction has not been addressed. In this study, we report that cyclin D3 is largely dispensable for proliferation and Ig class switching of in vitro activated B cells. In contrast, GC development in Ccnd3^-/- mice is markedly impaired, as is the T cell-dependent antibody response. Within the GC, although both switched and unswitched B cells are affected by cyclin D3 inactivation, the IgM^- pool is more severely reduced. Interestingly, despite a compensatory increase in cyclln D2 expression, a significant number of Ccnd3^-/- GC B cells accumulate in quiescent GO state. Lastly, although cyclin D3 inactivation did not disrupt BCL6 expression in GC B cells, it completely blocked the GC promoting effect of BCL6 overexpression, suggesting that cyclin D3 acts downstream of BCL6 to regulate GC formation. This is the first demonstration that cyclin D3 plays an important and unique role at the GC stage of B cell development.展开更多
Pediatric diffuse large B-cell lymphoma(DLBCL)is a highly aggressive disease with unique clinical characteristics.This study analyzed the germinal-center type B-cell(GCB)classification and clinical characteristics of ...Pediatric diffuse large B-cell lymphoma(DLBCL)is a highly aggressive disease with unique clinical characteristics.This study analyzed the germinal-center type B-cell(GCB)classification and clinical characteristics of Chinese pediatric DLBCL.A total of 76 patients with DLBCL newly diagnosed in Sun Yatsen University Cancer Center between February 2000 and May 2011,with an age younger than 18 years,were included in the analysis.The male/female ratio was 3.47:1.The median age was 12 years(range,2 to 18 years),and 47(61.8%)patients were at least 10 years old.Of the 76 patients,48(63.2%)had stage III/IV disease,9(11.8%)had bone marrow involvement,1(1.3%)had central nervous system(CNS)involvement,and 5(6.6%)had bone involvement.The GCB classification was assessed in 45 patients:26(57.8%)were classified as GCB subtype,and 19(42.2%)were classified as non-GCB subtype.The modified B-NHL-BFM-90/95 regimen was administered to 50 patients,and the 4-year event-free survival(EFS)rate was 85.8%.Among these 50 patients,31 were assessed for the GCB classification:17(54.8%)were classified as GCB subtype,with a 4-year EFS rate of 88.2%;14(45.2%)were classified as non-GCB subtype,with a 4-year EFS rate of 92.9%.Our data indicate that bone marrow involvement and stage III/IV disease are common in Chinese pediatric DLBCL patients,whereas the percentage of patients with the GCB subtype is similar to that of patients with the non-GCB subtype.The modified B-NHL-BFM-90/95protocol is an active and effective treatment protocol for Chinese pediatric patients with DLBCL.展开更多
Monoclonal antibodies were used to label cutaneous germinal center cell-derived lymphomas <CGCCL) obtained from 10 patients. According to the Kiel classification, they were classified into 2 types. Eight patients h...Monoclonal antibodies were used to label cutaneous germinal center cell-derived lymphomas <CGCCL) obtained from 10 patients. According to the Kiel classification, they were classified into 2 types. Eight patients had centroblastic/centrocytic <CB/CC) lymphomas while 2 patients and centrocytic (CC) lymphomas. After monoclonal antibody labelling, the results were consistent with those of the clinical and morphologic analyses. Of the 10 cases, 9 were B1 positive, 6 were K positive, and 4 were λ positive. In 8 cases labeled with immunoglobulin, 6 were IgGFab positive, 2 were IgM positive and 8 were IgA negative. Five cases (CB/CC 3, CC 2) were both Bl, K and IgG positive (γ K). Four cases CB/CC were both Bl and A positive. Only one case (CB/CC) was both K and IgM positive (μ K). Two cases (CB CC) were both A and IgG positive (γ λ). The results indicate that Bl, K and A are the most important markers to phenotype cutaneous B-cell lymphomas. Our findings also show a higher percentage of y K types in CGCCL as compared with Western countries.展开更多
Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into funct...Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell proteome.However,the critical proteins driving these key mechanisms are still unknown.Here,we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses.TIA1-and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection,expansion and differentiation into B-cell clones producing high-affinity antibodies.Mechanistically,TIA1 and TIAL1 control the transcriptional identity of dark-and light-zone GC B cells and enable timely expression of the prosurvival molecule MCL1.Thus,we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.展开更多
B cells play essential roles in immunity,mainly through the production of high affinity plasma cells(PCs)and memory B(Bmem)cells.The affinity maturation and differentiation of B cells rely on the integration of B-cell...B cells play essential roles in immunity,mainly through the production of high affinity plasma cells(PCs)and memory B(Bmem)cells.The affinity maturation and differentiation of B cells rely on the integration of B-cell receptor(BCR)intrinsic and extrinsic signals provided by antigen binding and the microenvironment,respectively.In recent years,tumor infiltrating B(TIL-B)cells and PCs(TIL-PCs)have been revealed as important players in antitumor responses in human cancers,but their interplay and dynamics remain largely unknown.In lymphoid organs,B-cell responses involve both germinal center(GC)-dependent and GC-independent pathways for Bmem cell and PC production.Affinity maturation of BCR repertoires occurs in GC reactions with specific spatiotemporal dynamics of signal integration by B cells.In general,the reactivation of high-affinity Bmem cells by antigens triggers GC-independent production of large numbers of PC without BCR rediversification.Understanding B-cell dynamics in immune responses requires the integration of multiple tools and readouts such as single-cell phenotyping and RNA-seq,in situ analyses,BCR repertoire analysis,BCR specificity and affinity assays,and functional tests.Here,we review how those tools have recently been applied to study TIL-B cells and TIL-PC in different types of solid tumors.We assessed the published evidence for different models of TIL-B-cell dynamics involving GC-dependent or GC-independent local responses and the resulting production of antigen-specific PCs.Altogether,we highlight the need for more integrative B-cell immunology studies to rationally investigate TIL-B cells as a leverage for antitumor therapies.展开更多
This study identifies endogenous inhibitors of germination associated with seed dormancy in Sapium sebiferum,Chinese tallow.Seed extracts were separated into five distinct fractions(petroleum ether,ether,ethyl acetate...This study identifies endogenous inhibitors of germination associated with seed dormancy in Sapium sebiferum,Chinese tallow.Seed extracts were separated into five distinct fractions(petroleum ether,ether,ethyl acetate,methanol,and aqueous)and tested for their effect on germination of cabbage seeds.There were no significant differences in germination percentages and germination index(GI)between the solvents and the control.The five fractions differentially reduced germination percentage and GI values of cabbage seeds.According to the GI results,the greatest inhibition was with the ether fraction followed by methanol,ethyl acetate,petroleum ether,and aqueous fractions.Gas chromatography–mass spectrometry identified the constituents of the four organic fractions.Compared with the mass spectrum of the National Institute of Standards and Technology library,a compound was confirmed,provided it was more than 85%similar.Analysis of ether extracts identified four compounds:butylated hydroxytoluene(BHT;19.7%),1,2-benzenediol(4.1%),phydroxycinnamic acid,ethyl ester(2.8%),and n-hexadecanoic acid(1.4%).Fourteen,20,and 9 compounds were identified in methanol,ethyl acetate,and petroleum ether extracts,respectively.The IC50 of BHT(the concentration at which BHT inhibits radicle growth by 50%)was 54.8 mg/L,indicating that the presence of BHT might be the primary cause of dormancy in S.sebiferum seeds.展开更多
The transcriptional repressor B cell lymphoma 6(BCL6) controls a large transcriptional network that is required for the formation and maintenance of germinal centers(GC). GC B cells represent the normal counterpart of...The transcriptional repressor B cell lymphoma 6(BCL6) controls a large transcriptional network that is required for the formation and maintenance of germinal centers(GC). GC B cells represent the normal counterpart of most human B-cell lymphomas, which are often characterized by deregulated BCL6 expression or BCL6-mediated pathways. BCL6 suppresses gene transcription largely through recruitment of its co-repressors through its distinct repression domain. Understanding the precise biological roles of each repression domain in normal and malignant B cells is helpful for development of targeted inhibition of BCL6 functions that is emerging as the basis for design of anti-lymphoma therapies. This review focuses on recent progress in the molecular mechanisms of action of BCL6 in B cells and discusses remaining unresolved questions related to how these mechanisms are linked to normal and malignant B cell development.展开更多
Germinal center kinases （GCKs） participate in a variety of signaling pathways needed to regulate cellular functions including apoptosis, cell proliferation, polarity and migration. Recent studies have shown that GCK...Germinal center kinases （GCKs） participate in a variety of signaling pathways needed to regulate cellular functions including apoptosis, cell proliferation, polarity and migration. Recent studies have shown that GCKs are participants in both adaptive and innate immune regulation. However, the differential activation and regulatory mechanisms of GCKs, as well as upstream and downstream signaling molecules, remain to be fully defined. It remains unresolved whether and how GCKs may cross-talk with existing signaling pathways. This review stresses the progresses in research of GCKs relevant to the immune system.展开更多
Subject Code:C08With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Qi Hai(祁海)from the School of Medicine,Tsinghua University revealed a novel mechanism tha...Subject Code:C08With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Qi Hai(祁海)from the School of Medicine,Tsinghua University revealed a novel mechanism that regulates the germinal center reaction,aphysiological process that underlies high-quality展开更多
基金The study was funded by grants from the Special R&D Program of Ministry of Science and Technology(No.2019YFC1316203)Ministry of Science and Technology(No.2020YFC0844700)Clinical Foundation of Tongji Hospital(No.XXGZBDYJ010).
文摘Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic.In this study,we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia(FOP)patients who underwent lung surgery and served as controls.We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients.In contrast to the FOP patients,Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients.This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients.In summary,our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity.Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.
文摘Germinal centers （GC） of secondary lymphoid tissues are critical to mounting a high-affinity humoral immune response. B cells within the GC undergo rapid clonal expansion and selection while diversifying their antibody genes. Although it is generally believed that GC B cells employ a unique proliferative program to accommodate these processes, little is known about how the GC-associated cell cycle is orchestrated. The D-type cyclins constitute an important component of the cell cycle engine that enables the cells to respond to physiological changes. Cell type- and developmental stage-specific roles of D-type cyclins have been described but the cyclin D requirement during GC reaction has not been addressed. In this study, we report that cyclin D3 is largely dispensable for proliferation and Ig class switching of in vitro activated B cells. In contrast, GC development in Ccnd3^-/- mice is markedly impaired, as is the T cell-dependent antibody response. Within the GC, although both switched and unswitched B cells are affected by cyclin D3 inactivation, the IgM^- pool is more severely reduced. Interestingly, despite a compensatory increase in cyclln D2 expression, a significant number of Ccnd3^-/- GC B cells accumulate in quiescent GO state. Lastly, although cyclin D3 inactivation did not disrupt BCL6 expression in GC B cells, it completely blocked the GC promoting effect of BCL6 overexpression, suggesting that cyclin D3 acts downstream of BCL6 to regulate GC formation. This is the first demonstration that cyclin D3 plays an important and unique role at the GC stage of B cell development.
文摘Pediatric diffuse large B-cell lymphoma(DLBCL)is a highly aggressive disease with unique clinical characteristics.This study analyzed the germinal-center type B-cell(GCB)classification and clinical characteristics of Chinese pediatric DLBCL.A total of 76 patients with DLBCL newly diagnosed in Sun Yatsen University Cancer Center between February 2000 and May 2011,with an age younger than 18 years,were included in the analysis.The male/female ratio was 3.47:1.The median age was 12 years(range,2 to 18 years),and 47(61.8%)patients were at least 10 years old.Of the 76 patients,48(63.2%)had stage III/IV disease,9(11.8%)had bone marrow involvement,1(1.3%)had central nervous system(CNS)involvement,and 5(6.6%)had bone involvement.The GCB classification was assessed in 45 patients:26(57.8%)were classified as GCB subtype,and 19(42.2%)were classified as non-GCB subtype.The modified B-NHL-BFM-90/95 regimen was administered to 50 patients,and the 4-year event-free survival(EFS)rate was 85.8%.Among these 50 patients,31 were assessed for the GCB classification:17(54.8%)were classified as GCB subtype,with a 4-year EFS rate of 88.2%;14(45.2%)were classified as non-GCB subtype,with a 4-year EFS rate of 92.9%.Our data indicate that bone marrow involvement and stage III/IV disease are common in Chinese pediatric DLBCL patients,whereas the percentage of patients with the GCB subtype is similar to that of patients with the non-GCB subtype.The modified B-NHL-BFM-90/95protocol is an active and effective treatment protocol for Chinese pediatric patients with DLBCL.
文摘Monoclonal antibodies were used to label cutaneous germinal center cell-derived lymphomas <CGCCL) obtained from 10 patients. According to the Kiel classification, they were classified into 2 types. Eight patients had centroblastic/centrocytic <CB/CC) lymphomas while 2 patients and centrocytic (CC) lymphomas. After monoclonal antibody labelling, the results were consistent with those of the clinical and morphologic analyses. Of the 10 cases, 9 were B1 positive, 6 were K positive, and 4 were λ positive. In 8 cases labeled with immunoglobulin, 6 were IgGFab positive, 2 were IgM positive and 8 were IgA negative. Five cases (CB/CC 3, CC 2) were both Bl, K and IgG positive (γ K). Four cases CB/CC were both Bl and A positive. Only one case (CB/CC) was both K and IgM positive (μ K). Two cases (CB CC) were both A and IgG positive (γ λ). The results indicate that Bl, K and A are the most important markers to phenotype cutaneous B-cell lymphomas. Our findings also show a higher percentage of y K types in CGCCL as compared with Western countries.
基金We thank all personnel from the Toulouse animal facility CREFRE and from the flow cytometry,imaging,transcriptomics and bioinformatics technical platforms of INFINITy.M.D.D-M.is supported by ATIP-Avenir-Plan Cancer(C18003BS),ANR(ANR-20-CE15-0007)foundation ARSEP R19201BB,foundation ARC,La Ligue Contre Le Cancer and INSPIRE(Region Occitanie,Inserm and CHU Toulouse)M.T.is supported with a BBSRC core funding grant and a Wellcome Investigator award(200823/Z/16/Z).D.C.-S.is supported by Boehringer Ingelheim Fonds.
文摘Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell proteome.However,the critical proteins driving these key mechanisms are still unknown.Here,we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses.TIA1-and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection,expansion and differentiation into B-cell clones producing high-affinity antibodies.Mechanistically,TIA1 and TIAL1 control the transcriptional identity of dark-and light-zone GC B cells and enable timely expression of the prosurvival molecule MCL1.Thus,we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.
基金We acknowledge all members of the Milpied and Vivier laboratories at CIML for fruitful discussionsEP is supported by a fellowship funded by Innate Pharma and the RHU PIONeeR project(ANR-17-RHUS-00XX-08)This work was supported by grants from ITMO Cancer and the RHU PIONeeR project.
文摘B cells play essential roles in immunity,mainly through the production of high affinity plasma cells(PCs)and memory B(Bmem)cells.The affinity maturation and differentiation of B cells rely on the integration of B-cell receptor(BCR)intrinsic and extrinsic signals provided by antigen binding and the microenvironment,respectively.In recent years,tumor infiltrating B(TIL-B)cells and PCs(TIL-PCs)have been revealed as important players in antitumor responses in human cancers,but their interplay and dynamics remain largely unknown.In lymphoid organs,B-cell responses involve both germinal center(GC)-dependent and GC-independent pathways for Bmem cell and PC production.Affinity maturation of BCR repertoires occurs in GC reactions with specific spatiotemporal dynamics of signal integration by B cells.In general,the reactivation of high-affinity Bmem cells by antigens triggers GC-independent production of large numbers of PC without BCR rediversification.Understanding B-cell dynamics in immune responses requires the integration of multiple tools and readouts such as single-cell phenotyping and RNA-seq,in situ analyses,BCR repertoire analysis,BCR specificity and affinity assays,and functional tests.Here,we review how those tools have recently been applied to study TIL-B cells and TIL-PC in different types of solid tumors.We assessed the published evidence for different models of TIL-B-cell dynamics involving GC-dependent or GC-independent local responses and the resulting production of antigen-specific PCs.Altogether,we highlight the need for more integrative B-cell immunology studies to rationally investigate TIL-B cells as a leverage for antitumor therapies.
基金provided by the Natural Science Foundation of China(31570662),the Natural Science Foundation of China under Grant 31270711the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutionssupported by the Key Forestry Public Welfare Project under Grant 201304102
文摘This study identifies endogenous inhibitors of germination associated with seed dormancy in Sapium sebiferum,Chinese tallow.Seed extracts were separated into five distinct fractions(petroleum ether,ether,ethyl acetate,methanol,and aqueous)and tested for their effect on germination of cabbage seeds.There were no significant differences in germination percentages and germination index(GI)between the solvents and the control.The five fractions differentially reduced germination percentage and GI values of cabbage seeds.According to the GI results,the greatest inhibition was with the ether fraction followed by methanol,ethyl acetate,petroleum ether,and aqueous fractions.Gas chromatography–mass spectrometry identified the constituents of the four organic fractions.Compared with the mass spectrum of the National Institute of Standards and Technology library,a compound was confirmed,provided it was more than 85%similar.Analysis of ether extracts identified four compounds:butylated hydroxytoluene(BHT;19.7%),1,2-benzenediol(4.1%),phydroxycinnamic acid,ethyl ester(2.8%),and n-hexadecanoic acid(1.4%).Fourteen,20,and 9 compounds were identified in methanol,ethyl acetate,and petroleum ether extracts,respectively.The IC50 of BHT(the concentration at which BHT inhibits radicle growth by 50%)was 54.8 mg/L,indicating that the presence of BHT might be the primary cause of dormancy in S.sebiferum seeds.
文摘The transcriptional repressor B cell lymphoma 6(BCL6) controls a large transcriptional network that is required for the formation and maintenance of germinal centers(GC). GC B cells represent the normal counterpart of most human B-cell lymphomas, which are often characterized by deregulated BCL6 expression or BCL6-mediated pathways. BCL6 suppresses gene transcription largely through recruitment of its co-repressors through its distinct repression domain. Understanding the precise biological roles of each repression domain in normal and malignant B cells is helpful for development of targeted inhibition of BCL6 functions that is emerging as the basis for design of anti-lymphoma therapies. This review focuses on recent progress in the molecular mechanisms of action of BCL6 in B cells and discusses remaining unresolved questions related to how these mechanisms are linked to normal and malignant B cell development.
基金This work was supported by the 973 Program of the Ministry of Science and Technology of China （2010CB529700 and 2012CB910204）, the National Natural Science Foundation of China （NSFC10979005 and NSFC30970566） and the Science and Technology Commission of Shanghai Municipality （11JC14140000）. Dr ZZ is a scholar of the Hundred Talents Program of the Chinese Academy of Sciences. Dr Greene is supported by grants from the NIH, NCI, the Abramson Family Research Institute and the BCRF.
文摘Germinal center kinases （GCKs） participate in a variety of signaling pathways needed to regulate cellular functions including apoptosis, cell proliferation, polarity and migration. Recent studies have shown that GCKs are participants in both adaptive and innate immune regulation. However, the differential activation and regulatory mechanisms of GCKs, as well as upstream and downstream signaling molecules, remain to be fully defined. It remains unresolved whether and how GCKs may cross-talk with existing signaling pathways. This review stresses the progresses in research of GCKs relevant to the immune system.
文摘Subject Code:C08With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Qi Hai(祁海)from the School of Medicine,Tsinghua University revealed a novel mechanism that regulates the germinal center reaction,aphysiological process that underlies high-quality
