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1.
Scand J Immunol ; 91(3): e12853, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31793005

RESUMO

What is the evolutionary mechanism for the TCR-MHC-conserved interaction? We extend Dembic's model (Dembic Z. In, Scand J Immunol e12806, 2019) of thymus positive selection for high-avidity anti-self-MHC Tregs among double (CD4 + CD8+)-positive (DP) developing thymocytes. This model is based on competition for self-MHC (+ Pep) complexes presented on cortical epithelium. Such T cells exit as CD4 + CD25+FoxP3 + thymic-derived Tregs (tTregs). The other positively selected DP T cells are then negatively selected on medulla epithelium removing high-avidity anti-self-MHC + Pep as T cells commit to CD4 + or CD8 + lineages. The process is likened to the competitive selection and affinity maturation in Germinal Centre for the somatic hypermutation (SHM) of rearranged immunoglobulin (Ig) variable region (V[D]Js) of centrocytes bearing antigen-specific B cell receptors (BCR). We now argue that the same direct SHM processes for TCRs occur in post-antigenic Germinal Centres, but now occurring in peripheral pTregs. This model provides a potential solution to a long-standing problem previously recognized by Cohn and others (Cohn M, Anderson CC, Dembic Z. In, Scand J Immunol e12790, 2019) of how co-evolution occurs of species-specific MHC alleles with the repertoire of their germline TCR V counterparts. We suggest this is not by 'blind', slow, and random Darwinian natural selection events, but a rapid structured somatic selection vertical transmission process. The pTregs bearing somatic TCR V mutant genes then, on arrival in reproductive tissues, can donate their TCR V sequences via soma-to-germline feedback as discussed in this journal earlier. (Steele EJ, Lindley RA. In, Scand J Immunol e12670, 2018) The high-avidity tTregs also participate in the same process to maintain a biased, high-avidity anti-self-MHC germline V repertoire.


Assuntos
Alelos , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Diferenciação Celular , Seleção Clonal Mediada por Antígeno , Evolução Molecular , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Mamíferos , Mutação , Ligação Proteica , Receptores de Antígenos de Linfócitos T/genética , Timócitos/imunologia , Timócitos/metabolismo
3.
Immunol Rev ; 291(1): 190-213, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402495

RESUMO

Signals emanating from the B-cell receptor (BCR) promote proliferation and survival in diverse forms of B-cell lymphoma. Precision medicine strategies targeting the BCR pathway have been generally effective in treating lymphoma, but often fail to produce durable responses in diffuse large B-cell lymphoma (DLBCL), a common and aggressive cancer. New insights into DLBCL biology garnered from genomic analyses and functional proteogenomic studies have identified novel modes of BCR signaling in this disease. Herein, we describe the distinct roles of antigen-dependent and antigen-independent BCR signaling in different subtypes of DLBCL. We highlight mechanisms by which the BCR cooperates with TLR9 and mutant isoforms of MYD88 to drive sustained NF-κB activity in the activated B-cell-like (ABC) subtype of DLBCL. Finally, we discuss progress in detecting and targeting oncogenic BCR signaling to improve the survival of patients with lymphoma.


Assuntos
Leucemia Linfoide/etiologia , Leucemia Linfoide/metabolismo , Linfoma/etiologia , Linfoma/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Animais , Autoantígenos/imunologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/terapia , Linfoma/diagnóstico , Linfoma/terapia , Receptores de Antígenos de Linfócitos B/genética
4.
Immunol Rev ; 291(1): 123-133, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402498

RESUMO

Ubiquitination is a form of posttranslational protein modification that affects the activity of target proteins by regulating their intracellular degradation, trafficking, localization, and association with other regulators. Recent studies have placed protein ubiquitination as an important regulatory mode to control immune system development, function, and pathogenesis. In this review, we will mainly update the research progress from our laboratory on the roles of the Cbl family of E3 ubiquitin ligases in the development and function of lymphocytes and non-lymphoid cells. In addition, we will highlight our current understanding of the mechanisms used by this family of proteins, especially Cbl and Cbl-b, to co-ordinately regulate the function of various receptors and transcription factors in the context of immune regulation and diseases.


Assuntos
Sistema Imunitário/metabolismo , Organogênese/imunologia , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Ativação Linfocitária/imunologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Ubiquitinação
5.
Immunohorizons ; 3(8): 389-401, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427364

RESUMO

The germinal center (GC) is the anatomical site where humoral immunity evolves. B cells undergo cycles of proliferation and selection to produce high-affinity Abs against Ag. Direct linkage of a TLR9 agonist (CpG) to a T-dependent Ag increases the number of GC B cells. We used a T-dependent Ag complexed with CpG and a genetic model for ablating the TLR9 signaling adaptor molecule MyD88 specifically in B cells (B-MyD88- mice) together with transcriptomics to determine how this innate pathway positively regulates the GC. GC B cells from complex Ag-immunized B-MyD88- mice were defective in inducing gene expression signatures downstream of c-Myc and mTORC1. In agreement with the latter gene signature, ribosomal protein S6 phosphorylation was increased in GC B cells from wild-type mice compared with B-MyD88- mice. However, GC B cell expression of a c-Myc protein reporter was enhanced by CpG attached to Ag in both wild-type and B-MyD88- mice, indicating a B cell-extrinsic effect on c-Myc protein expression combined with a B cell-intrinsic enhancement of gene expression downstream of c-Myc. Both mTORC1 activity and c-Myc are directly induced by T cell help, indicating that TLR9 signaling in GC B cells either enhances their access to T cell help or directly influences these pathways to further enhance the effect of T cell help. Taken together, these findings indicate that TLR9 signaling in the GC could provide a surrogate prosurvival stimulus, "TLR help," thus lowering the threshold for selection and increasing the magnitude of the GC response.


Assuntos
Antígenos/química , Linfócitos B/imunologia , Centro Germinativo/metabolismo , Ligantes , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor Toll-Like 9/agonistas , Animais , Antígenos/metabolismo , Ativação Linfocitária/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Transcriptoma , gama-Globulinas/imunologia
6.
Mol Immunol ; 114: 72-80, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31344551

RESUMO

Scleroderma is an inflammatory autoimmune disease characterized by extensive tissue fibrosis. The imbalance of effector T (Teff) and regulatory T (Treg) cells and the production of autoantibodies contribute to the pathogenesis of this disease. Metformin (MET) has anti-inflammatory and anti-fibrotic effects, but its effect on the in vivo pathogenesis of scleroderma remains unknown. Therefore, we investigated the potential therapeutic effects of MET treatment of mice with bleomycin (BLM)-induced scleroderma. Scleroderma was induced in female C57BL mice by daily subcutaneous injections of BLM for 28 days. After each 2 h BLM injection, mice received MET (200, 100 or 50 mg/kg) or saline (control) by intraperitoneal injection. At the end of the fourth week, spleen mononuclear cells were collected for flow cytometry analysis. Skin samples were harvested for immunohistochemistry and quantification of other biological parameters.Our results showed that BLM increased dermal thickness, collagen deposition, and hydroxyproline level, and MET markedly mitigated these effects. MET also restored the Treg/Teff cell balance. Accordingly, the level of IL-17A and RORγt (related to Th17 cells) decreased, but Foxp3 (related to Treg function) increased in a dose-dependent manner. In addition, MET treatment inhibited spleen germinal center formation. These results indicate that the immunomodulatory and anti-fibrosis effects of MET on BLM-induced scleroderma are mediated by the upregulation of Treg cell differentiation, inhibition of Teff cell differentiation, and suppression of spleen germinal center formation. These results suggest that MET may be a potential therapeutic for scleroderma.


Assuntos
Bleomicina/farmacologia , Centro Germinativo/efeitos dos fármacos , Metformina/farmacologia , Dermatopatias/induzido quimicamente , Dermatopatias/tratamento farmacológico , Baço/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Centro Germinativo/metabolismo , Hidroxiprolina/metabolismo , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Dermatopatias/metabolismo , Baço/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
7.
Diagn Pathol ; 14(1): 56, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189479

RESUMO

OBJECTIVES: Standard treatment with a thiotepa-based regimen in countries with a limited resource is less feasible. Aims of the study were to evaluate the treatment outcome, and identify the prognostic factors in patients with primary central nervous system lymphoma (PCNSL). METHODS: We conducted a retrospective study of 43 patients diagnosed with PCNSL, DLBCL subtype, who were treated with either HDMTX-based regimen, whole brain radiotherapy (WBRT), or both between 2010 and 2017. RESULTS: There were 43 patients with a median age of 65 years (range 34-89 years). Protein expression of CD10, Bcl6, MUM1, Bcl2 and MYC were found in 19, 86, 91, 91 and 23%, respectively. Both germinal center B cell (GCB) and double-expressor (MYC+/Bcl2+) lymphomas were found in 21%. Multiple brain lesions and maximum tumor diameter (MTD) ≥5 cm were seen in 27 and 10 patients, respectively. Chemotherapy combined with WBRT, chemotherapy and WBRT were given to 20, 14 and 9 patients, respectively. Overall complete remission (CR) rate was 55.8%. Those receiving a combined-modality therapy had a higher CR rate than those treated with either chemotherapy (75% versus 36%, p = 0.036) or WBRT (75% versus 44%, p = 0.109). Median follow-up time was 17 months, and a 7-year overall survival (OS) was 40%. Features associated with a prolonged OS were an ECOG score ≤ 2 (p = 0.001), multiple brain lesions (p = 0.010), multiple area of brain involvement (p = 0.023), MTD < 5 cm (p = 0.004), GCB subtype (p = 0.003) and positive CD10 staining (p = 0.007). Expression of Bcl2 protein was associated with a significantly worse OS in the non-GCB DLBCL patients. DISCUSSION: The factors affecting treatment outcomes in PCNSL were cell of origin of DLBCL, lesion characteristics, patients' status and treatment regimen.


Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Terapia Combinada/métodos , Feminino , Centro Germinativo/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Resultado do Tratamento
8.
PLoS One ; 14(5): e0216470, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31063496

RESUMO

BACKGROUND: Human B-cell lymphoma 6 (BCL6) gene, usually coding protein of 706 amino acids, is closely associated with large B cell lymphoma. Researches showed that protein mutation or change of expression levels usually happened in the mounting non-hodgkin lymphoma (NHL). Thus BCL6 is considered to be involved in germinal center (GC)-derived lymphoma. RESULTS: The BCL61-350 gene codons were optimized for prokaryotic system. After expression of BCL61-350 in E. coli, the BCL61-350 protein was purified with Ni column. Then the BCL61-350 protein, mixing with QuickAntibody-Mouse5W adjuvant, was injected into Balb/c mice. After immunization and cell fusion, a stable cell line named 1E6A4, which can secrete anti-BCL6 antibody, was obtained. The isotype of 1E6A4 mAb was determined as IgG2a, and the affinity constant reached 5.12×1010 L/mol. Furthermore, the specificity of the mAb was determined with ELISA, western blot and immunohistochemistry. Results indicated that the 1E6A4 mAb was able to detect BCL6 specifically and sensitively. CONCLUSIONS: BCL61-350 antigen has been successfully generated with an effective and feasible method, and a highly specific antibody named 1E6A4 against BCL6 has been screened and characterized in this study, which was valuable in clinical diagnosis.


Assuntos
Anticorpos Monoclonais Murinos , Imunoglobulina G , Linfoma de Células B/diagnóstico , Linfoma de Células B/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Animais , Anticorpos Monoclonais Murinos/química , Anticorpos Monoclonais Murinos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Imunoglobulina G/química , Imunoglobulina G/imunologia , Imuno-Histoquímica , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-bcl-6/biossíntese
10.
EMBO J ; 38(11)2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31015337

RESUMO

In contrast to other B-cell antigen receptor (BCR) classes, the function of IgD BCR on mature B cells remains largely elusive as mature B cells co-express IgM, which is sufficient for development, survival, and activation of B cells. Here, we show that IgD expression is regulated by the forkhead box transcription factor FoxO1, thereby shifting the responsiveness of mature B cells towards recognition of multivalent antigen. FoxO1 is repressed by phosphoinositide 3-kinase (PI3K) signaling and requires the lipid phosphatase Pten for its activation. Consequently, Pten-deficient B cells expressing knock-ins for BCR heavy and light chain genes are unable to upregulate IgD. Furthermore, in the presence of autoantigen, Pten-deficient B cells cannot eliminate the autoreactive BCR specificity by secondary light chain gene recombination. Instead, Pten-deficient B cells downregulate BCR expression and become unresponsive to further BCR-mediated stimulation. Notably, we observed a delayed germinal center (GC) reaction by IgD-deficient B cells after immunization with trinitrophenyl-ovalbumin (TNP-Ova), a commonly used antigen for T-cell-dependent antibody responses. Together, our data suggest that the activation of IgD expression by Pten/FoxO1 results in mature B cells that are selectively responsive to multivalent antigen and are capable of initiating rapid GC reactions and T-cell-dependent antibody responses.


Assuntos
Linfócitos B/fisiologia , Centro Germinativo/fisiologia , Imunoglobulina D/genética , PTEN Fosfo-Hidrolase/fisiologia , Receptores de Antígenos de Linfócitos B/genética , Animais , Células Cultivadas , Proteína Forkhead Box O1/fisiologia , Regulação da Expressão Gênica/imunologia , Centro Germinativo/metabolismo , Imunoglobulina D/imunologia , Imunoglobulina D/metabolismo , Camundongos , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
11.
Cell ; 177(3): 524-540, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31002794

RESUMO

B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.


Assuntos
Linfócitos B/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Antígenos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Memória Imunológica , Plasmócitos/imunologia , Plasmócitos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinas/imunologia
12.
Int J Cancer ; 145(9): 2459-2467, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30973963

RESUMO

Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (EPO) and darbepoetin, may alleviate anemia in diffuse large B-cell lymphoma (DLBCL) patients. However, many cancer cells express EPO receptors (EPOR), through which exogenously administered ESAs potentially promote cancer cell growth. We conducted preclinical/phase II studies to investigate the safety and efficacy of ESAs for managing chemotherapy-related anemia in DLBCL patients. We examined EPOR expression in germinal center B-cell (GCB)- and activated B-cell (ABC)-DLBCL cell lines, and investigated the effects of ESAs on cell proliferation, and rituximab-mediated complement-dependent cytotoxicity (CDC). The clinical study enrolled 50 histologically confirmed DLBCL patients receiving rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) who had hemoglobin levels <10.0 g/dl after a maximum of three R-CHOP cycles and received ≥4 doses of fixed-dose darbepoetin (360 µg) once every 3 weeks. EPOR mRNA was detected in all GCB-DLBCL cell lines, but little/none was detected in ABC-DLBCL cell lines. GCB-DLBCL and ABC-DLBCL cell proliferation was unaffected by EPO or darbepoetin. Rituximab-mediated CDC of DLBCL cell lines with/without EPOR expression was not affected adversely by EPO. In the clinical study, baseline mean hemoglobin was 9.19 g/dl; the overall mean change in hemoglobin was 1.59 ± 1.3 g/dl (16 weeks). Forty-eight percent of enrolled patients achieved a hematopoietic response. Our study shows that ESAs do not affect the growth of DLBCL cells or rituximab-mediated CDC under the experimental conditions that we used, and the appropriate use of ESAs may be effective and safe for DLBCL patients with anemia after R-CHOP.


Assuntos
Anemia/induzido quimicamente , Anemia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Hematínicos/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Idoso , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Centro Germinativo/efeitos dos fármacos , Centro Germinativo/metabolismo , Hemoglobinas/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Estudos Prospectivos , Rituximab/uso terapêutico , Vincristina/efeitos adversos , Vincristina/uso terapêutico
13.
Nat Commun ; 10(1): 823, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30778076

RESUMO

Follicular helper T cells (Tfh) play critical roles instructing, and initiating T-cell dependent antibody responses. The underlying mechanisms that enhance their function is therefore critical for vaccine development. Here we apply gene array analysis identifying adenosine deaminase (ADA) as a key molecule that delineates a human Tfh helper program in proliferating circulating Tfh (cTfh) cells and Germinal Centers Tfh (GC-Tfh). ADA-1 expression and enzymatic activity are increased in efficient cTfh2-17/GC-Tfh cells. Exogenous ADA-1 enhances less efficient cTfh1 and pro-follicular Tfh PD-1+ CXCR5+ cells to provide B cell help, while pharmacological inhibition of ADA-1 activity impedes cTfh2-17/GC-Tfh function and diminished antibody response. Mechanistically, ADA-1 controls the Tfh program by influencing IL6/IL-2 production, controlling CD26 extracellular expression and could balance signals through adenosine receptors. Interestingly, dysfunctional Tfh from HIV infected-individual fail to regulate the ADA pathway. Thus, ADA-1 regulates human Tfh and represents a potential target for development of vaccine strategy.


Assuntos
Adenosina Desaminase/metabolismo , Infecções por HIV/patologia , Linfócitos T Auxiliares-Indutores/fisiologia , Adenosina Desaminase/genética , Adenilil Ciclases/metabolismo , Linfócitos B/citologia , Técnicas de Cocultura , Dipeptidil Peptidase 4/metabolismo , Centro Germinativo/metabolismo , Infecções por HIV/metabolismo , Humanos , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Linfócitos T Auxiliares-Indutores/virologia
14.
Nat Commun ; 10(1): 250, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651557

RESUMO

T cell dependent secretory IgA (SIgA) generated in the Peyer's patches (PPs) of the small intestine shapes a broadly diverse microbiota that is crucial for host physiology. The mutualistic co-evolution of host and microbes led to the relative tolerance of host's immune system towards commensal microorganisms. The ATP-gated ionotropic P2X7 receptor limits T follicular helper (Tfh) cells expansion and germinal center (GC) reaction in the PPs. Here we show that transient depletion of intestinal ATP can dramatically improve high-affinity IgA response against both live and inactivated oral vaccines. Ectopic expression of Shigella flexneri periplasmic ATP-diphosphohydrolase (apyrase) abolishes ATP release by bacteria and improves the specific IgA response against live oral vaccines. Antibody responses primed in the absence of intestinal extracellular ATP (eATP) also provide superior protection from enteropathogenic infection. Thus, modulation of eATP in the small intestine can affect high-affinity IgA response against gut colonizing bacteria.


Assuntos
Trifosfato de Adenosina/metabolismo , Gastroenterite/imunologia , Microbioma Gastrointestinal/fisiologia , Imunoglobulina A Secretora/metabolismo , Infecções por Salmonella/imunologia , Trifosfato de Adenosina/imunologia , Administração Oral , Animais , Apirase/imunologia , Apirase/metabolismo , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Modelos Animais de Doenças , Escherichia coli/imunologia , Escherichia coli/metabolismo , Feminino , Gastroenterite/microbiologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Íleo/imunologia , Íleo/metabolismo , Íleo/microbiologia , Imunoglobulina A Secretora/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Receptores Purinérgicos P2X7/imunologia , Receptores Purinérgicos P2X7/metabolismo , Infecções por Salmonella/microbiologia , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade , Shigella flexneri/imunologia , Shigella flexneri/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
15.
Leuk Res ; 76: 107-111, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30360939

RESUMO

Gene expression profiling (GEP) separated diffuse large B-cell lymphoma (DLBCL) in two different entities, i.e. activated B cell-like (ABC) and germinal center B cell-like (GCB) lymphomas with ABC lymphomas demonstrating a less favorable outcome. NF-kB pathway activating mutations in MYD88, CD79A/B and CARD11 are predominantly found in ABC type lymphomas. Targeted therapies affecting NF-kB pathways have shown therapeutic potential in this subtype. Immunohistochemistry algorithms have been developed as a tool for distinguishing these entities in routine clinical diagnostics. To test whether this immunohistochemistry classifier would detect the biological differences between the entities 147 DLBCLs were subtyped into ABC and GCB using the Visco-Young algorithm. Mutation analysis demonstrated mutations in MYD88 or CD79 A/B in 21% (10/47) of non-GCB type but only in 3% (1/31) of GCB lymphomas (p = 0.012) in nodal lymphomas. In primary extra nodal lymphomas, however, 17.5% (4/23) of GCB type and 37.5% (15/40) of non-GCB lymphomas carried mutations in MYD88 and CD79 A/B. While the Visco-Young algorithm was sufficient to detect biological differences (i.e. mutation patterns) in nodal DLBCL it did not distinguish GCB and non-GCB type lymphomas of primary extranodal sites. Here, the morphological sites of the lymphomas seem to be more important for their molecular pattern than their immunohistochemical status.


Assuntos
Linfócitos B/metabolismo , Biomarcadores Tumorais , Linfoma Difuso de Grandes Células B/genética , Mutação , Idoso , Idoso de 80 Anos ou mais , Perfilação da Expressão Gênica , Centro Germinativo/metabolismo , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/metabolismo , Pessoa de Meia-Idade
16.
Blood ; 133(1): 94-99, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30279226

RESUMO

Patient outcomes for steroid-dependent or -refractory chronic graft-versus-host diesease (cGVHD) are poor, and only ibrutinib has been US Food and Drug Administration (FDA) approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B cells to produce antibodies that are associated with disease pathogenesis. The transcriptional corepressor B-cell lymphoma 6 (BCL6) is a member of the Broad-complex, Tramtrack, and Bric-abrac/poxvirus and zinc finger (BTB/POZ) transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T cells and B cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target. A small-molecule BCL6 inhibitor reversed active cGVHD in a mouse model of multiorgan system injury with bronchiolitis obliterans associated with a robust GC reaction, but not in cGVHD mice with scleroderma as the prominent manifestation. For cGVHD patients with antibody-driven cGVHD, targeting of BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents.


Assuntos
Linfócitos B/imunologia , Bronquiolite Obliterante/complicações , Centro Germinativo/efeitos dos fármacos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-6/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/imunologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/patologia , Doença Crônica , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
17.
Lab Invest ; 99(4): 539-550, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30446717

RESUMO

Myocyte enhancer-binding factor 2B (MEF2B) has been implicated as a transcriptional regulator for BCL6. However, details about the interaction between MEF2B and BCL6 during expression, as well as the relationship of MEF2B to the expression of other germinal center (GC) markers, have not yet been fully explained. Using germinal center B-cell-like diffuse large B-cell lymphoma (GC-DLBCL) and activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines, we analyzed the expression of MEF2B and its associations with BCL6, CD10, and ERK. Furthermore, small interfering RNA (siRNA) was used to study the possible effects of MEF2B knockdown on these proteins and cell growth. Analysis of the BCL6 transcriptional complex was performed using electrophoretic mobility shift assay. The correlation between MEF2B expression and the genetic type of DLBCL was assessed using immunohistochemistry on 111 patient samples, and via in silico analysis of publicly available microarray (Gene Expression Omnibus (GEO)) datasets. Our results indicate that the expression of MEF2B protein is important for the growth of GC-DLBCL cells, as evidenced by MEF2B knockdown inhibition of cell growth and the subsequent suppression of BCL6, CD10, and ERK phosphorylation. Analysis of BCL6 transcription factors in nuclear extracts of MEF2-expressing DLBCL cells showed involvement of MEF2B with AP-2α and BCL6 proteins in the formation of the BCL6 gene transcriptional complex. Indeed, differential expression of MEF2B in the GC-DLBCL is statistically significant compared to the ABC-DLBCL in the GEO datasets, as well as in tissue microarray, as indicated via immunohistochemistry (Visco-Young algorithm). Our findings indicate that MEF2B is an essential component of the BCL6 gene transcriptional complex for the regulation of DLBCL growth via the promotion of BCL6 expression. Beyond its regulatory role in DLBCL growth, MEF2B expression correlated positively with BCL6 and CD10 expression, and was preferentially expressed in the GBC-DLBCL group.


Assuntos
Centro Germinativo/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linhagem Celular , Humanos , Imuno-Histoquímica , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Transfecção
18.
Brain Behav Immun ; 76: 48-60, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30414952

RESUMO

Germinal centers (GC) are vital to adaptive immunity. BCL6 and miR-155 are implicated in control of GC reaction and lymphomagenesis. FBXO11 causes BCL6 degradation through ubiquitination in B-cell lymphomas. Chronic psychological stress is known to drive immunosuppression. Corticosterone (CORT) is an adrenal hormone expressed in response to stress and can similarly impair immune functions. However, whether GC formation is disrupted by chronic psychological stress and its molecular mechanism remain to be elucidated. To address this issue, we established a GC formation model in vivo, and a GC B cell differentiation model in vitro. Comparing Naive B cells to GC B cells in vivo and in vitro, the differences of BCL6 and FBXO11 mRNA do not match the changes at the protein level and miR-155 levels that were observed. Next we demonstrated that CORT increase, induced by chronic psychological stress, reduced GC response, IgG1 antibody production and miR-155 level in vivo. The effect of chronic psychological stress can be blocked by a glucocorticoid receptor (GR) antagonist. Similarly, impaired GC B cell generation and isotope class switching were observed. Furthermore, we found that miR-155 and BCL6 expression were downregulated, but FBXO11 expression was upregulated in GC B cells treated with CORT in vitro. In addition, we demonstrated that miR-155 directly down-regulated FBXO11 expression by binding to its 3́-untranslated region. The subsequent overexpression of miR-155 significantly blocked the stress-induced impairment of GC response, due to changes in FBXO11 and BCL6 expression, as well as increased apoptosis in B cells both in vivo and in vitro. Our findings suggest perturbation of GC reaction may play a role in chronic psychological stress-induced immunosuppression through a glucocorticoid pathway, and miR-155-mediated post-transcriptional regulation of FBXO11 and BCL6 expression may contribute to the impaired GC response.


Assuntos
Centro Germinativo/metabolismo , MicroRNAs/metabolismo , Estresse Psicológico/metabolismo , Animais , Apoptose/fisiologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Proteínas de Ligação a DNA/genética , Proteínas F-Box/metabolismo , Feminino , Centro Germinativo/fisiologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Estresse Psicológico/fisiopatologia
19.
Clin Cancer Res ; 25(2): 735-746, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348636

RESUMO

PURPOSE: Follicular lymphoma arises from a germinal center B-cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). We explored the relation that exists between the differentiation arrest of follicular lymphoma cells and loss-of-function of CREBBP acetyltransferase.Experimental Design: The study used human primary cells obtained from either follicular lymphoma tumors characterized for somatic mutations, or inflamed tonsils for normal germinal center B cells. Transcriptome and functional analyses were done to decipher the B- and T-cell crosstalk. Responses were assessed by flow cytometry and molecular biology including ChIP-qPCR approaches. RESULTS: Conversely to normal B cells, follicular lymphoma cells are unable to upregulate the transcription repressor, PRDM1, required for plasma cell differentiation. This defect occurs although the follicular lymphoma microenvironment is enriched in the potent inducer of PRDM1 and IL21, highly produced by Tfhs. In follicular lymphoma carrying CREBBP loss-of-function mutations, we found a lack of IL21-mediated PRDM1 response associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1 gene. Moreover, in these follicular lymphoma cells, pan-HDAC inhibitor, vorinostat, restored their PRDM1 response to IL21 by lowering BCL6 bound to PRDM1. This finding was reinforced by our exploration of patients with follicular lymphoma treated with another pan-HDAC inhibitor. Patients showed an increase of plasma cell identity genes, mainly PRDM1 and XBP1, which underline the progression of follicular lymphoma B cells in the differentiation process. CONCLUSIONS: Our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat patients with follicular lymphoma through the induction of the expression of plasma cell genes.


Assuntos
Proteína de Ligação a CREB/genética , Inibidores de Histona Desacetilases/farmacologia , Interleucinas/metabolismo , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Mutação , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína de Ligação a CREB/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Interleucinas/farmacologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Modelos Biológicos , Gradação de Tumores , Plasmócitos/metabolismo , Plasmócitos/patologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transcriptoma
20.
Front Immunol ; 9: 2704, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524440

RESUMO

Follicular regulatory T cells (Tfr) are a unique subset of CD4 T cells that control and impact adaptive immune responses in the lymphoid follicles and germinal centers (GC). Since their relatively recent discovery, several studies have revealed that Tfr interact with other cells within this niche and shape ensuing responses. Recent advances defining the functional and developmental characteristics of Tfr have revealed key characteristics of Tfr differentiation, GC recruitment and retention, and regulatory properties. Further, Tfr shape the GC response and balance tolerance through interactions with Tfh, by modifying Tfh number, diversity and function, as well as with B cells. Mechanisms by which Tfr regulate the GC include cell-to-cell interactions with Tfh and B cells, as well as altering their environment through cytokine production and sequestration. Tfr have been shown to have a diverse T cell receptor (TCR) repertoire and can be specific for immunizing agents, demonstrating a potential role in vaccine development. Due to these important characteristics and functions, Tfr play a major role in immune tolerance, response to infection, and vaccine efficacy.


Assuntos
Linfócitos B/imunologia , Citocinas/imunologia , Centro Germinativo/metabolismo , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Animais , Linfócitos B/patologia , Centro Germinativo/patologia , Humanos , Linfócitos T Reguladores/patologia
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