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1.
PLoS One ; 15(3): e0229778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187186

RESUMO

BACKGROUND: Memory B cell (mBC) induction and maintenance is one of the keys to long-term protective humoral immunity. MBCs are fundamental to successful medical interventions such as vaccinations and therapy in autoimmunity. However, their lifestyle and anatomic residence remain enigmatic in humans. Extrapolation from animal studies serves as a conceptual basis but might be misleading due to major anatomical distinctions between species. METHODS AND FINDINGS: Multicolor immunofluorescence stainings on fixed and unfixed frozen tissue sections were established using primary antibodies coupled to haptens and secondary signal amplification. The simultaneous detection of five different fluorescence signals enabled the localization and characterization of human CD27+CD20+Ki67- mBCs for the first time within one section using laser scanning microscopy. As a result, human tonsillar mBCs were initially identified within their complex microenvironment and their relative location to naïve B cells, plasma cells and T cells could be directly studied and compared to the human splenic mBC niche. In all investigated tonsils (n = 15), mBCs appeared to be not only located in a so far subepithelial defined area but were also follicle associated with a previous undescribed gradual decline towards the follicular mantle comparable to human spleen. However, mBC areas around secondary follicles with large germinal centers (GCs) in tonsils showed interruptions and a general widening towards the epithelium while in spleen the mBC-containing marginal zones (MZ) around smaller GCs were relatively broad and symmetrical. Considerably fewer IgM+IgD+/- pre-switch compared to IgA+ or IgG+ post-switch mBCs were detected in tonsils in contrast to spleen. CONCLUSIONS: This study extends existing insights into the anatomic residence of human mBCs showing structural similarities of the superficial follicular area in human spleen and tonsil. Our data support the debate of renaming the human splenic MZ to 'superficial zone' in order to be aware of the differences in rodents and, moreover, to consider this term equally for the human palatine tonsil.


Assuntos
Linfócitos B/metabolismo , Centro Germinativo/citologia , Tonsila Palatina/citologia , Baço/citologia , Adolescente , Adulto , Idoso , Linfócitos B/citologia , Microambiente Celular , Criança , Humanos , Pessoa de Meia-Idade , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
2.
Mol Immunol ; 119: 83-91, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32001420

RESUMO

The five-year survival rate of melanoma worsens significantly with advancing tumor stage. We hypothesized that regulatory B cells (Breg) might have participated in the pathogenesis of melanoma. In this study, the PD-L1+ Breg cells were investigated. The expression of PD-L1 by circulating B cells was very low in healthy controls. In melanoma patients, on the other hand, the expression of PD-L1 by circulating B cells was significantly elevated in a manner that was positively associated with tumor stage, with the highest level in stage IV bone metastasis patients. Compared to total B cells, PD-L1+ B cells presented higher IgM and higher IgD expression, and were almost exclusively CD20+CD27-, suggesting that the PD-L1+ B cells exhibited a naive B cell-like phenotype. Healthy naive B cells, which presented little PD-L1, and stage I and stage II melanoma patient naive B cells, which presented detectable but low PD-L1, were unable to suppress T cell response. However, stage III and stage IV naive B cells, which presented moderate PD-L1, could significantly suppress T cell response in a PD-L1-dependent manner. We further found that the level of PD-L1+ B cells was significantly higher in bone metastasis than in the primary tumors. Overall, we demonstrated that PD-L1+ B cells were upregulated in advanced melanoma and were enriched in metastasis compared to primary tumors. Furthermore, PD-L1+ naive B cells could act as a T cell suppressor in a PD-L1-dependent manner.


Assuntos
Linfócitos B Reguladores/imunologia , Antígeno B7-H1/imunologia , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Melanoma/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Antígeno B7-H1/biossíntese , Enterotoxinas/imunologia , Feminino , Humanos , Interferon gama/biossíntese , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Fatores Supressores Imunológicos , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral
3.
Mol Immunol ; 119: 92-100, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32006824

RESUMO

Regulatory B10 cells have been shown to exhibit impaired functions in autoimmune diseases. However, the underlying mechanism is still obscure. In the present study, we aimed to understand the regulatory characteristics of regulatory B10 cells and how these cells are involved in the development of rheumatoid arthritis (RA). Here, we chose CD19+CD24hiCD27+ as the phenotype of regulatory B10 cells. We found that the frequencies of CD19+CD24hiCD27+ regulatory B10 cells were decreased and that their IL-10-producing function was impaired in patients with RA compared with healthy controls (HCs). The impairment in CD19+CD24hiCD27+ B10 cells was partially attributed to the decreased expression of CD27 induced by the upregulated CD70 expression on CD19 + B cells and CD4 + T cells. The proportion of CD19+CD24hiCD27+ regulatory B10 cells could be restored by blocking the CD70-CD27 interaction with an anti-CD70 antibody. Furthermore, the CD70-CD27 interaction significantly elevated IL-10 expression and might compensate for the decreased number of CD19+CD24hiCD27+ B cells. Hence, the CD70-CD27 interaction might play a critical role in the numerical and functional impairments of regulatory B10 cells, thus contributing to RA pathogenesis. In conclusion, the change in CD19+CD24hiCD27+ regulatory B10 cells in RA was only a consequence, not the cause, of RA development, but the increased expression of CD70 might be the culprit.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos B Reguladores/imunologia , Ligante CD27/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Adulto , Antígenos CD19 , Linfócitos B Reguladores/metabolismo , Antígeno CD24 , Regulação para Baixo , Feminino , Humanos , Interleucina-10/biossíntese , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo
4.
Cancer Immunol Immunother ; 69(1): 95-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31807879

RESUMO

INTRODUCTION: In contemporary oncology drug development, implementation of novel early-phase designs with the ability to address multiple research objectives is needed to better refine regimens. This paper describes an adaptive design strategy for identifying a range of optimal regimens based on two endpoints within multiple cohorts. The proposed design was developed to address objectives in an early-phase trial of cancer vaccines in combination with agonistic antibodies to CD40 and CD27. MATERIALS AND METHODS: We describe a model-based design strategy that was developed for a trial evaluating the safety and immunogenicity of vaccination with (1) peptides plus CD40 antibody and TLR3 ligand, (2) systemic administration of an agonistic CD27 antibody, and (3) to assess immune response from (1) and (2) compared to optimal controls in participants with stage IIB-IV melanoma. RESULTS AND CONCLUSIONS: The proposed design is a practical adaptive method for use with combined immunotherapy regimens with multiple objectives within multiple cohorts of interest. Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining optimal strategies to take multiple regimens forward into later phases, incorporating additional endpoints in the dose selection process and testing drug combination therapies to improve efficacy and reduce toxicity. Our goal is to facilitate the acceptance and application of more novel designs in contemporary early development trials.


Assuntos
Imunoterapia/métodos , Melanoma/terapia , Projetos de Pesquisa , Neoplasias Cutâneas/terapia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/imunologia , Vacinas Anticâncer/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Terapia Combinada/métodos , Desenvolvimento de Medicamentos , Humanos , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
5.
Oncology ; 97(6): 365-372, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31533124

RESUMO

INTRODUCTION: Soluble CD27 (sCD27) is associated with somatic immune reaction status. Moreover, sCD27 level is associated with the prognosis of patients with prostate cancer who receive immunotherapy. OBJECTIVE: In this study, we assessed sCD27 levels in patients with advanced lung cancer and determined their correlation with survival and clinicopathologic parameters. METHODS: Serum samples were collected from patients with advanced lung cancer, and sCD27 was quantified via enzyme-linked immunosorbent assay. The association between sCD27 levels and clinicopathologic status and patient survival was retrospectively analyzed. RESULTS: Of 96 patients analyzed, 73 had adenocarcinoma, 7 had squamous cell carcinoma, and 15 had small cell carcinoma. Median serum sCD27 level was 36.54 U/mL (range, undetectable-104.47); this is lower than that previously reported for patients with lung cancer, including those with localized stages. Patients with squamous cell carcinoma had higher sCD27 levels (p = 0.010). Age, performance status, and serum albumin levels were significantly correlated with serum sCD27 level. Patients with high serum sCD27 levels (≥32.52 U/mL; n = 58) had poorer prognosis than those with low serum sCD27 levels (<32.52 U/mL, n = 38; median survival, 7.3 vs. 21.8 months, respectively, p< 0.0001). CONCLUSIONS: High sCD27 level is associated with poor prognosis and may reflect the immune-exhausted status of patients with advanced lung cancer.


Assuntos
Neoplasias Pulmonares/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade
6.
J Immunol ; 203(6): 1650-1664, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31391234

RESUMO

IgD-CD27- double negative (DN) B cells with proinflammatory characteristics are abnormally elevated in a proportion of multiple sclerosis (MS) patients. In this study, the origin and selection characteristics of DN B cells were studied in MS patients and healthy controls (HC). Expression of developmental markers on peripheral blood DN, IgD-CD27+ class-switched memory (CSM) and IgD+CD27- naive B cells of HC (n = 48) and MS patients (n = 96) was determined by flow cytometry. High-throughput adaptive immune receptor repertoire sequencing was performed on peripheral blood DN and CSM B cells of HC and MS patients (n = 3 each). DN B cells from HC and MS patients showed similar phenotypic and Ig repertoire characteristics. Phenotypic analysis indicated a mature state of DN B cells by low CD5, CD10, and CD38 expression. However, the frequency of CD95+ and IgA+ cells was lower in DN versus CSM B cells. DN B cells are Ag experienced, as shown by somatic hypermutation of their Ig genes in adaptive immune receptor repertoire sequencing, although they showed a lower mutation load than CSM B cells. Shared clones were found between DN and CSM B cells, although >95% of the clones were unique to each population, and differences in V(D)J usage and CDR3 physicochemical properties were found. Thus, DN B cells arise in HC and MS patients via a common developmental pathway that is probably linked to immune aging. However, DN and CSM B cells develop through unique differentiation pathways, with most DN B cells representing an earlier maturation state.


Assuntos
Linfócitos B/imunologia , Imunoglobulina D/imunologia , Esclerose Múltipla/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Imunidade Adaptativa/imunologia , Adulto , Feminino , Genes de Imunoglobulinas/imunologia , Humanos , Switching de Imunoglobulina/imunologia , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Immunohorizons ; 3(6): 208-218, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31356167

RESUMO

Tuberculosis (TB) remains a leading cause of death from infectious diseases worldwide. Mycobacterium bovis is the causative agent of bovine TB and zoonotic TB infection. γδ T cells are known to participate in the immune control of mycobacterial infections. Data in human and nonhuman primates suggest that mycobacterial infection regulates memory/effector phenotype and adaptive immune functions of γδ T cells. To date, the impact of M. bovis infection on bovine γδ T cells and their effector and memory differentiation remains unknown. In this study, we show that circulating γδ T cells from M. bovis-infected cattle can be differentiated based on the expression of CD27, which is indicative of their capacity to respond to virulent M. bovis infection: CD27+ γδ T cells proliferated in response to M. bovis Ag and, thus, may comprise the adaptive γδ T cell compartment in cattle. We further show that bovine M. bovis-specific γδ T cells express surface markers characteristic of central memory T cells (CD45R-CD27+CD62Lhi) and that M. bovis-specific CD4 and γδ T cells both upregulate the expression of the tissue-homing receptors CXCR3 and CCR5 during infection. Our studies contribute significantly to our understanding of γδ T cell differentiation during TB infection and provide important insights into the link between phenotypic and functional subsets in the bovine. Accurate characterization of γδ T cell effector and memory-like responses induced during mycobacterial infection will contribute to improved strategies for harnessing the γδ T cell response in protection against TB for humans and animals.


Assuntos
Antígenos Comuns de Leucócito/metabolismo , Mycobacterium bovis/imunologia , Subpopulações de Linfócitos T/imunologia , Tuberculose Bovina/imunologia , Tuberculose/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Animais , Bovinos , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Memória Imunológica , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo
8.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 436-439, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357759

RESUMO

Objective: To evaluate the changes in natural killer cell subsets marked with CD27 and CD11b for HBV carrier mice. Methods: The pAAV-HBVl.2 plasmid was injected into the tail vein of C57BL/6 mice by hydrodynamic injection method to construct HBV-carrier model group and empty vector as the control group. Liver function and virological examination at different time points were used to judge the construction of HBV- plasmid carrier animal model. Flow cytometry was used to detect the frequency of NK cells and CD11b combined with CD27 NK cell subsets in spleen and liver. GraphPad Prism software was used for statistical analysis. Results: HBV-carrier mouse model was successfully constructed. There were no statistically significant difference in NK cell frequencies between spleen and liver of HBV carrier mice (P> 0.05), compared to control group. NK cells were divided into four subsets with in combination to CD27 and CD11b: CD11b(+)CD27(-)(CD11b(+)SP), CD11b(+)CD27(+)(DP), CD11b(-)CD27(+)(CD27(+)SP) and CD11b-CD27-(DN). Furthermore, the spleen of HBV-carrier mice had no statistically significant difference (P> 0.05) with the frequency of the four NK-cell subsets. The frequency of DN NK cell subsets was significantly increased in the liver of HBV carrier mice than control group (P< 0.001); however, the frequency of CD11b(+)SP cell subsets was significantly decreased (P < 0.05).There were no statistical significance in the frequency comparison between NK subgroups of DP and CD27(+)SP NK cell subsets (P> 0.05). Conclusion: HBV-carrier mice with abnormal distribution of hepatic NK cell subsets significantly increased and decreased the frequency of DN NK cell subsets and CD11b(+)SP cell subsets.


Assuntos
Antígeno CD11b , Vírus da Hepatite B , Células Matadoras Naturais , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Animais , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Células Matadoras Naturais/citologia , Camundongos , Camundongos Endogâmicos C57BL
9.
Mediators Inflamm ; 2019: 4742634, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31236064

RESUMO

Chlamydia pneumoniae (Cpn) infection causes multiple acute and chronic human diseases. The role of DCs in host defense against Cpn infection has been well documented. The same is true for invariant natural killer T (iNKT) cells and NK cells, but the interaction among cells is largely unknown. In this study, we investigated the influence and mechanism of iNKT cell on the differentiation and function of NK cell in Cpn lung infection and the role played by DCs in this process. We found that expansion of IFN-γ-producing NK cells quickly happened after the infection, but this response was altered in iNKT knockout (KO) mice. The expression of activation markers and the production of IFN-γ by different NK subsets were significantly lower in KO mice than wild-type (WT) mice. Using in vitro DC-NK coculture and in vivo adoptive transfer approaches, we further examined the role of DCs in iNKT-mediated modulation of NK cell function. We found that NK cells expressed lower levels of activation markers and produced less IFN-γ when they were cocultured with DCs from KO mice than WT mice. More importantly, we found that the adoptive transfer of DCs from the KO mice induced less NK cell activation and IFN-γ production. The results provided evidence on the modulating effect of iNKT cell on NK cell function, particularly the critical role of DCs in this modulation process. The finding suggests the complexity of cellular interactions in Cpn lung infection, which should be considered in designing preventive and therapeutic approaches for diseases and infections.


Assuntos
Infecções por Chlamydophila/imunologia , Chlamydophila pneumoniae/patogenicidade , Células Dendríticas/metabolismo , Células Matadoras Naturais/metabolismo , Pneumopatias/imunologia , Pneumopatias/microbiologia , Animais , Feminino , Interferon gama/metabolismo , Pneumopatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
10.
J Immunol ; 203(3): 639-646, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31209102

RESUMO

Signaling through CD27 plays a role in T cell activation and memory. However, it is currently unknown how this costimulatory receptor influences CD4+ effector T (Teff) cells in inflamed tissues. In the current study, we used a murine model of inducible self-antigen expression in the epidermis to elucidate the functional role of CD27 on autoreactive Teff cells. Expression of CD27 on Ag-specific Teff cells resulted in enhanced skin inflammation when compared with CD27-deficient Teff cells. CD27 signaling promoted the accumulation of IFN-γ and IL-2-producing T cells in skin draining lymph nodes in a cell-intrinsic fashion. Surprisingly, this costimulatory pathway had minimal effect on early T cell activation and proliferation. Instead, signaling through CD27 resulted in the progressive survival of Teff cells during the autoimmune response. Using BH3 profiling to assess mitochondrial cell priming, we found that CD27-deficient cells were equally as sensitive as CD27-sufficient cells to mitochondrial outer membrane polarization upon exposure to either BH3 activator or sensitizer peptides. In contrast, CD27-deficient Teff cells expressed higher levels of active caspase 8. Taken together, these results suggest that CD27 does not promote Teff cell survival by increasing expression of antiapoptotic BCL2 family members but instead acts by preferentially suppressing the cell-extrinsic apoptosis pathway, highlighting a previously unidentified role for CD27 in augmenting autoreactive Teff cell responses.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Epiderme/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Transferência Adotiva , Animais , Apoptose/fisiologia , Autoimunidade/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspase 8/metabolismo , Proliferação de Células/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Memória Imunológica/imunologia , Inflamação/imunologia , Interferon gama/metabolismo , Interleucina-2/metabolismo , Linfonodos/imunologia , Ativação Linfocitária/imunologia , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Modelos Animais , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
11.
Clin Rheumatol ; 38(10): 2909-2915, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31187337

RESUMO

Rheumatoid arthritis (RA) has been associated with early senescent features. However, the effects of disease progression on senescence markers are largely unknown. Here, we evaluated key senescence markers in RA, including telomere length and T cell differentiation stages as well as cytomegalovirus (CMV) serology, previously associated with premature aging. In a cross-sectional study, 44 patients with active (Ac-RA), 26 patients with controlled (Co-RA), and 30 healthy controls were recruited. Peripheral blood was collected and differentiation stages of T cells analyzed by multi-color flow cytometry. Enzyme-linked immunosorbent assays were used to evaluate the CMV serology. The telomere length was measured by multiplex quantitative PCR. Patients with Ac-RA presented lower percentage of intermediate-differentiated T cells (CD4+CD27-CD28+ and CD8+CD27-CD28+; p < 0.001). All patients had a reduced proportion of cytotoxic T cells, and higher CD4/CD8 ratio compared with controls (p < 0.001). A lower proportion of CMV IgG+ subjects was found in the Co-RA group, (P < 0.001), although no differences in the CMV IgG titers were observed between groups. The groups had similar leukocyte telomere length. In addition, age was negatively correlated with CD8+CD27+CD28+ T (early-differentiated) cells (P < 0.05). Positive correlations between CMV IgG titers and age (P < 0.05) and CD4+CD27-CD28- T (late-differentiated) cells (P < 0.01) were observed. Furthermore, disease duration was correlated with CD4+CD27+CD28+ T cells (r = - 0.318, p < 0.05) and CD4+CD27-CD28- T cells (r = 0.308, p < 0.05). Our findings indicate that CMV and age may have a similar impact on T cells in both RA patients and controls. KEY POINTS: • Patients and controls were homogenous regarding CMV IgG titers and TL. • A lower proportion of CMV IgG+ subjects was found in the Co-RA group. • Anti-CMV levels were positively correlated with age and percentage of CD4+CD27-CD28- (late-differentiated) T cells.


Assuntos
Artrite Reumatoide/sangue , Senescência Celular , Progressão da Doença , Idoso , Artrite Reumatoide/patologia , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Estudos Transversais , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/complicações , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Reumatologia , Telômero/ultraestrutura , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
12.
Allergol Immunopathol (Madr) ; 47(4): 372-377, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31176517

RESUMO

INTRODUCTION: Chronic granulomatous disease (CGD) is a disorder of phagocyte function, characterized by pyogenic infections and granuloma formation caused by defects in NADPH oxidase complex activity. Although the effect of CGD mainly reflects the phagocytic compartment, B cell responses are also impaired in patients with CGD. MATERIALS AND METHODS: Flow cytometric analysis was performed on peripheral blood samples from 35 CGD patients age-matched with healthy controls (HC). The target cells of our study were the naive (IgD+/CD27-), memory (IgD-/CD27+), and B1a (CD5+) cells. Immunoglobulins (Igs) were also measured. This study was performed in a Latin American cohort. RESULTS: We found significantly higher levels of naive B cells and B1a cells, but lower levels of memory B cells were found in CGD patients compared to HC. There was no significant difference of cell percentages per inheritance type. DISCUSSION: Our findings suggest that the deficiency of NADPH oxidase components can affect the differentiation of naive B cells to memory B cells. Consequently, memory cells will be low, which also influenced the expression of CD27 in memory B cells and as a result, the percentage of naive cells increases. An altered phenotype of B lymphocytes in CGD patients may contribute to the opportunistic infections and autoimmune disorders that are seen in this disease.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Doença Granulomatosa Crônica/imunologia , NADPH Oxidase 2/genética , Adolescente , Adulto , Separação Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Citometria de Fluxo , Doença Granulomatosa Crônica/genética , Humanos , Memória Imunológica , Imunofenotipagem , Lactente , Masculino , México , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto Jovem
13.
Scand J Immunol ; 90(2): e12792, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31141193

RESUMO

Depletion of B cells is beneficial in rheumatoid arthritis (RA) patients with autoantibodies to citrullinated proteins (ACPA) and/or the Fc portion of immunoglobulins (rheumatoid factor [RF]), suggesting a role for B cells in disease pathogenesis. To date, however, the identity of specifically pathogenic B cell subsets has not been discovered. One candidate population is identified by the low expression or absence of complement receptor 2 (CD21-/low B cells). In this study, we sought to determine whether there was any correlation between CD21-/low B cells and clinical outcome in patients with established RA, either ACPA+ /RF+ (n = 27) or ACPA- /RF- (n = 10). Healthy donors (n = 17) were included as controls. The proportion of the CD21-/low CD27- IgD- memory B cell subset in peripheral blood (PB) was significantly increased in ACPA+ /RF+ RA patients compared with healthy donors, and the frequency of this subset correlated with joint destruction (r = 0.57, P < 0.04). The levels of the chemokines CXCL-9 and CXCL-10 were higher in synovial fluid than in plasma, and PB CD21-/low cells expressed the receptor, CXCR3. In synovial fluid, most of the B cells were CD21-/low , approximately 40% of that population was CD27- IgD- , and a third of those expressed the pro-osteoclastogenic factor receptor activator of the nuclear factor κB ligand (RANKL). This subset also secreted RANKL, in addition to other factors such as IL-6, even in the absence of stimulation. We interpret these data as reason to propose the hypothesis that the CD27- IgD- subset of CD21-/low B cells may mediate joint destruction in patients with ACPA+ /RF+ RA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Subpopulações de Linfócitos B/imunologia , Imunoglobulina D/metabolismo , Receptores de Complemento 3d/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto , Quimiocina CXCL10/sangue , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/sangue , Quimiocina CXCL9/metabolismo , Feminino , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Ligante RANK/biossíntese , Receptores CXCR3/biossíntese , Líquido Sinovial/metabolismo
14.
Blood Cells Mol Dis ; 77: 34-42, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30953940

RESUMO

OBJECTIVES: Aplastic anemia (AA) is T cell immune-mediated autoimmune disease. Aberrant T cell activation involves an imbalance in T cell homeostasis in AA. However, whether the T cell activation molecule CD27 and its ligand CD70 participate in the immune pathogenesis of AA remains ill defined. METHODS: The frequencies of CD27/CD70 and perforin/granzyme B in different T cell subsets were detected in AA patients and healthy individuals by flow cytometry. RESULTS: We first time demonstrate a significantly elevated proportion of CD27+ and significantly decreased CD70+ T cells from AA. Changed frequency of CD27+ and CD70+ in different T cell subsets appeared to be associated with AA severity. In very severe aplastic anemia (VSAA) and severe aplastic anemia (SAA), increased CD8+CD27+ T cells present with a cytotoxic effector phenotype by elevating perforin proportion. CONCLUSIONS: Elevated proportion of CD27 in T cells may contribute to distinct immune pathogenesis for different severities of AA. The CD8+CD27+perforin+ T cells combined with CD8+CD70+ T cells may serve as an immune biomarker for AA severity estimation.


Assuntos
Anemia Aplástica/diagnóstico , Anemia Aplástica/metabolismo , Ligante CD27/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Perforina/metabolismo , Subpopulações de Linfócitos T/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto , Anemia Aplástica/imunologia , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Feminino , Citometria de Fluxo , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Adulto Jovem
15.
J Neuroimmunol ; 332: 31-36, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928869

RESUMO

BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases. METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease. RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL. CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.


Assuntos
Proteínas do Líquido Cefalorraquidiano/análise , Inflamação/líquido cefalorraquidiano , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/análise , Adolescente , Adulto , Idoso , Raquianestesia , Biomarcadores/líquido cefalorraquidiano , Diagnóstico Diferencial , Feminino , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/diagnóstico , Sensibilidade e Especificidade , Procedimentos Cirúrgicos Urológicos , Adulto Jovem
16.
Virchows Arch ; 475(4): 425-434, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30980190

RESUMO

The anticancer effects of immune checkpoint inhibitors against CTLA4 and CD274-PDCD1 axes are evident. However, these immunotherapies for colorectal cancers (CRCs) are now limited to a small subset of patients with microsatellite unstable tumors. Thus, therapeutics targeting other types of CRCs is desired. The CD70-CD27 axis plays a co-stimulatory role in promoting the expansion and differentiation of T-lymphocytes through the activation of NFκB pathway. Aberrant activation of the CD70-CD27 axis accelerates tumor cell proliferation, survival, and immune evasion of tumor cells. Based on these observations, drugs modulating the CD70-CD27 axis have been developed with expectation of anticancer effects. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD70, CD27, and FOXP3 expression to assess their clinical usage and the application of CD70-CD27 axis modulating drugs. CRC tumor cells rarely (2.2%) expressed CD70. In contrast, tumor-surrounding fibroblasts showed various CD70 expressions (fCD70) in 14.9%. The logistic regression analysis revealed significant association of fCD70 expression with incomplete resection status (OR, 2.60; 95% CI, 1.10-6.13; P = 0.029). Overall survival was significantly decreased in the cohort of the patients with fCD70-positive tumor (P = 0.0078). Furthermore, significantly more CD27+ tumor-associated lymphocytes were detected within the primary CRCs without metastases (P = 0.024). Thus, the CD70-CD27 axis may have several roles in CRCs independent from their mismatch repair (MMR) system status. CD70-CD27 pathway-modulating therapies may be applied to CRC patients regardless of their tumor MMR status.


Assuntos
Ligante CD27/biossíntese , Fibroblastos Associados a Câncer/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/imunologia , Ligante CD27/análise , Ligante CD27/imunologia , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
17.
Clin Exp Immunol ; 197(1): 111-129, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30883691

RESUMO

Both major subcategories of inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease are characterized by infiltration of the gut wall by inflammatory effector cells and elevated biomarkers of inflammation in blood and feces. We investigated the phenotypes of circulating lymphocytes in the two types of IBD in treatment-naive pediatric patients by analysis of blood samples by flow cytometry. Multivariate analysis was used to compare the phenotypes of the blood lymphocytes of children with ulcerative colitis (n = 17) or Crohn's disease (n = 8) and non-IBD control children with gastrointestinal symptoms, but no signs of gut inflammation (n = 23). The two IBD subcategories could be distinguished based on the results from the flow cytometry panel. Ulcerative colitis was characterized by activated T cells, primarily in the CD8+ population, as judged by increased expression of human leukocyte antigen D-related (HLA-DR) and the ß1-integrins [very late antigen (VLA)] and a reduced proportion of naive (CD62L+ ) T cells, compared with the non-IBD controls. This T cell activation correlated positively with fecal and blood biomarkers of inflammation. In contrast, the patients with Crohn's disease were characterized by a reduced proportion of B cells of the memory CD27+ phenotype compared to the non-IBD controls. Both the patients with ulcerative colitis and those with Crohn's disease showed increased percentages of CD23+ B cells, which we demonstrate here as being naive B cells. The results support the notion that the two major forms of IBD may partially have different pathogenic mechanisms.


Assuntos
Subpopulações de Linfócitos B/imunologia , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Feminino , Humanos , Memória Imunológica , Mediadores da Inflamação/sangue , Integrina beta1/sangue , Ativação Linfocitária , Masculino , Modelos Imunológicos , Fenótipo , Receptores de IgE/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue
18.
Hum Immunol ; 80(4): 263-269, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30769033

RESUMO

Synovial inflammation is observed in patients with osteoathritis (OA) and likely contributed to its exacerbation. Regulatory B (Breg) cells are shown to suppress inflammation in various diseases, including rheumatoid arthritis (RA). To examine whether Breg cells also participated in OA, we examined the synovial fluid from OA patients, and compared with that in RA patients. In OA synovial fluid, IL-10-producing B cells were present directly ex vivo and were increased upon stimulation, indicating that B cells were a source of IL-10 directly at the affected site of OA patients. Interestingly, the frequency of IL-10+ cells in synovial B cells was higher in OA patients than in RA patients, but the total number of IL-10+ B cells in OA was lower than that in RA, suggesting that OA patients presented lower B cell infiltration than RA patients. Phenotypical analysis demonstrated that the IL-10+ B cells were IgM+ and CD27+, but not CD24hi or CD38hi. To allow functional analysis of IgM+CD27+ B cells, the IgM+CD27+ B cells in the blood of OA patients were examined. These blood IgM+CD27+ B cells expressed more IL-10, but less CD80 and CD86 than non-IgM+CD27+ B cells. Blood IgM+CD27+ B cells suppressed the proliferation and IFN-γ expression of autologous T cells, and this effect could be reverted if IL-10 was inhibited. Furthermore, we found that patients with more severe OA presented lower levels of IL-10+ B cells in the synovial fluid. Together, our study described an IgM+CD27+ B cell subset in OA patients, which represented the major IL-10-secreting B cell type in the synovial fluid of OA patients and possessed regulatory function.


Assuntos
Linfócitos B Reguladores/imunologia , Interleucina-10/metabolismo , Osteoartrite/imunologia , Membrana Sinovial/imunologia , Linfócitos T/imunologia , Adulto , Artrite Reumatoide/imunologia , Células Cultivadas , Feminino , Humanos , Imunoglobulina M/metabolismo , Imunomodulação , Imunofenotipagem , Interferon gama/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
19.
Clin Res Hepatol Gastroenterol ; 43(3): 273-281, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30713032

RESUMO

BACKGROUND: Immune response failure against hepatitis C virus (HCV) has been associated with an increased regulatory T cell (Treg) activity. After liver transplantation (LT), 80% of patients experience an accelerated progression of hepatitis C recurrence. The aim of this work was to assess the involvement of Tregs, T helper (Th) 1, 2 and 17 cells in recurrent hepatitis C. METHODS: Peripheral blood cells obtained before and one month after LT from 22 recipients were analysed. Forty-four key molecules related to Treg, Th1, 2 and 17 responses, were evaluated using qRT-PCR. Liver recipients were classified in two groups according to graft fibrosis evaluated by the METAVIR score on the biopsy performed one year after LT (mild: F ≤ 1, n = 13; severe: F > 1, n = 9). Patients developing a severe recurrence were compared with patients with a mild recurrence. RESULTS: mRNA levels of Treg markers obtained one month after LT were significantly increased in patients with a severe disease course when compared to patients with a mild recurrence. Markers of the Th1 response were elevated in the same group. No differences in the markers determined before LT were observed. CONCLUSION: These findings suggest that Treg, induced by a multifactorial process, which could include a strong Th1 response itself, may play a role in suppressing the early antiviral response, leading to a severe recurrence of hepatitis C.


Assuntos
Hepatite C Crônica/diagnóstico , Transplante de Fígado , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo , Idoso , Biomarcadores/metabolismo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Ligante de CD40/genética , Ligante de CD40/metabolismo , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Progressão da Doença , Feminino , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Subunidade alfa de Receptor de Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
20.
Proc Natl Acad Sci U S A ; 116(8): 3136-3145, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30728302

RESUMO

Successful efforts to activate T cells capable of recognizing weak cancer-associated self-antigens have employed altered peptide antigens to activate T cell responses capable of cross-reacting on native tumor-associated self. A limitation of this approach is the requirement for detailed knowledge about the altered self-peptide ligands used in these vaccines. In the current study we considered allorecognition as an approach for activating CTL capable of recognizing weak or self-antigens in the context of self-MHC. Nonself antigen-presenting molecules typically contain polymorphisms that influence interactions with the bound peptide and TCR interface. Recognition of these nonself structures results in peptide-dependent alloimmunity. Alloreactive T cells target their inducing alloantigens as well as third-party alloantigens but generally fail to target self-antigens. Certain residues located on the alpha-1/2 domains of class I antigen-presenting molecules primarily interface with TCR. These residues are more conserved within and across species than are residues that determine peptide antigen binding properties. Class I variants designed with amino acid substitutions at key positions within the conserved helical structures are shown to provide strong activating signals to alloreactive CD8 T cells while avoiding changes in naturally bound peptide ligands. Importantly, CTL activated in this manner can break self-tolerance by reacting to self-peptides presented by native MHC. The ability to activate self-tolerant T cells capable of cross-reacting on self-peptide-MHC in vivo represents an approach for inducing autoimmunity, with possible application in cancer vaccines.


Assuntos
Apresentação do Antígeno/imunologia , Citotoxicidade Imunológica , Antígenos de Histocompatibilidade Classe I/imunologia , Linfócitos T Citotóxicos/imunologia , Sequência de Aminoácidos/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Humanos , Tolerância Imunológica , Ligantes , Ativação Linfocitária/imunologia , Camundongos , Peptídeos/genética , Peptídeos/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
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