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1.
Zhonghua Bing Li Xue Za Zhi ; 48(10): 762-766, 2019 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-31594039

RESUMO

Objective: To investigate the clinicopathological features of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Methods: Five cases of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract from the Affiliated Hospital of Qingdao University from 2016 to 2019 were retrospectively reviewed. The clinical and pathological parameters were analyzed by combining clinical data and reviewing the available literature of 35 cases (34 cases abroad and 1 case in China). Results: There were 4 males and 1 female with a median age of 47 years (18-66 years). All patients had abdominal pain and constitutional symptoms including diarrhea, emaciation, intermittent mucous stool or oral and epiglottic ulcers. Endoscopic manifestations included multiple punctate congestion, erosion and ulcer at the terminal ileum and colorectum. Two cases had congestion and erosion of antrum and angle of stomach, and the lesions did not fuse and form tumors. Histologically, the lamina propria was expanded by a dense, medium to small lymphocyte infiltration, which was monomorphic, with slightly irregular nuclei without prominent nucleolus or lymphoepithelial lesions. There were admixed small amount of plasma cells and eosinophils. In 4 cases, immunohistochemistry showed the lesional cells were positive for CD3, CD8, TIA1, and negative for CD4, CD56, granzyme B and Ki-67 index was ≤10%. In situ hybridization showed that EBER was negative and clonal TCR gene rearrangement was detected. One consultation case was CD3(+), CD5(-) and Ki-67 index of 10%, although other indicators were not done. All five patients were treated with symptomatic support. In follow-up observation for 2 to 25 months, all patients were alive with the disease. Conclusions: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract is a newly classified monoclonal T-cell proliferative disease, with low incidence, clinical inertia and long-term survival. It has unique clinicopathological features but pathologically it is easily misdiagnosed as inflammatory bowel disease or T-cell lymphoma. Correct diagnosis is of great important clinical significance.


Assuntos
Trato Gastrointestinal/patologia , Transtornos Linfoproliferativos/fisiopatologia , Adolescente , Adulto , Idoso , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Estudos Retrospectivos , Linfócitos T/patologia , Adulto Jovem
2.
Nat Med ; 25(9): 1408-1414, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477906

RESUMO

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.


Assuntos
Antígenos CD19/administração & dosagem , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/imunologia , Adolescente , Antígenos CD19/genética , Antígenos CD19/imunologia , Criança , Pré-Escolar , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva , Linfócitos T/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
3.
Hematol Oncol ; 37(4): 483-486, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408541

RESUMO

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.


Assuntos
Eritema Infeccioso/complicações , Doença de Hodgkin/etiologia , Linfoma de Células B/etiologia , Neoplasias Primárias Múltiplas/etiologia , Viremia/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/patologia , Medula Óssea/patologia , Medula Óssea/virologia , Criança , Eritema Infeccioso/sangue , Eritema Infeccioso/patologia , Eritema Infeccioso/virologia , Doença de Hodgkin/patologia , Humanos , Linfoma de Células B/patologia , Masculino , Neoplasias Primárias Múltiplas/patologia , Pancitopenia/etiologia , Pseudolinfoma/etiologia , Indução de Remissão , Rituximab/administração & dosagem , Linfócitos T/patologia , Sequenciamento Completo do Exoma
4.
J Cancer Res Clin Oncol ; 145(8): 2149-2156, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273513

RESUMO

BACKGROUND: First-line rituximab therapy together with chemotherapy is the standard care for patients with advanced follicular B-cell lymphoma, as rituximab together with chemotherapy prolongs progression-free and overall survival (Herold et al. 2007; Marcus et al. 2005). However, as not all patient subgroups benefit from combined immuno-chemotherapy, we asked whether the microenvironment may predict benefit from rituximab-based therapy. DESIGN: To address this question, we performed a retrospective immunohistochemical analysis on pathological specimens of 18 patients recruited into a randomized clinical trial, where patients with advanced follicular lymphoma were randomized into either chemotherapy or immuno-chemotherapy with rituximab (Herold et al. 2007). RESULTS: We show here that rituximab exerts beneficial effects, especially in the subgroup of follicular lymphoma patients with low intrafollicular CD3, CD5, CD8, and ZAP70 and high CD56 and CD68 expression. CONCLUSION: Rituximab may overcome immune-dormancy in follicular lymphoma in cases with lower intrafollicular T-cell numbers and higher CD56 and CD68 cell counts. As this was a retrospective analysis on a small subgroup of patients, these data need to be corroborated in larger clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos do Interstício Tumoral/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/imunologia , Rituximab/administração & dosagem , Linfócitos T/patologia , Clorambucila/administração & dosagem , Feminino , Humanos , Imunoterapia , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
5.
Virchows Arch ; 475(5): 637-648, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31218405

RESUMO

A "phenotypic switch" (PS) is a well-known phenomenon that occurs in hematopoietic neoplasms, often after treatment. However, in cutaneous T cell lymphoma (CTCL), this event has rarely been reported, and thus, very little is known about its relevance to disease prognosis. We report two cases of patients that were diagnosed with a CD4+ mycosis fungoides with positive T cell receptor gene rearrangement studies. Both patients originally responded to treatment, but subsequently, their CTCL came back with a different phenotype of a CD4- CTCL. Gene rearrangement studies were performed on the second occurrence in order to prove that this was the same lymphoma. Both patients died from their CTCL. Additionally, we collected seven cases of primary CTCL from the literature with tissue samples from before and after treatment with molecular studies confirming these neoplasms contained the same T cell clone, providing evidence of a true PS. This too revealed a poor prognosis in the majority of these cases. CTCL should be worked up to determine whether a PS has occurred after therapy since it could confuse management of patients and appears to portend a poor prognosis.


Assuntos
Linfoma Cutâneo de Células T/diagnóstico , Micose Fungoide/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Linfoma Cutâneo de Células T/patologia , Linfoma Cutâneo de Células T/cirurgia , Pessoa de Meia-Idade , Micose Fungoide/patologia , Micose Fungoide/cirurgia , Fenótipo , Prognóstico , Neoplasias Cutâneas/patologia , Linfócitos T/patologia
6.
Immunology ; 157(4): 322-330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31206171

RESUMO

Primary and chronic human immunodeficiency virus (HIV) infection alters γδ T-cell features. However, there is no evidence about early combined antiretroviral therapy (cART) and γδ T-cell dynamics. In the present study, HIV-positive individuals were divided into those with early primary infection (EPI) and those with late primary infection (LPI). The analysis of γδ T cells was performed by flow cytometry before and after therapy. Polyfunctional profile was assessed after in vitro peripheral blood mononuclear cell (PBMC) exposure to specific antigens. The results show that primary infection induced an expansion of Vδ1 T cells in LPI. Before treatment, a massive activation of γδ T-cell subsets was observed in both groups of patients, that correlated with disease progression and was significantly reduced after cART introduction. Despite this, CD107A-expressing Vδ1 T cells in both groups were significantly fewer than in healthy donors, but were restored by therapy introduction. Polyfunctional analysis of Vδ1 T cells from HIV-positive individuals revealed a lower frequency of CD107A+  CCL-4+ Vδ1 T-cell subsets than healthy donors that persists after therapy. Functional profile of Vδ2 was similar to that in healthy donors before therapy but, at 6 months, a lower frequency of CD107A, interferon-γ- or tumor necrosis factor-α-producing Vδ2 T cells was observed in the EPI group. Finally, individuals with LPI showed a lower frequency of quadruple-functional Vδ2 T-cell subset. In conclusion, during primary HIV infection, the baseline Vδ1 T-cell activation is correlated with immune reconstitution potential. Moreover, an altered γδ polyfunctional profile occurred, persisting after cART. Further studies are needed to understand whether a longer treatment of primary infection may increase γδ T-cell functionality.


Assuntos
Antirretrovirais/administração & dosagem , Infecções por HIV/imunologia , HIV-1/imunologia , Ativação Linfocitária/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Adulto , Quimiocina CCL4/imunologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Interferon gama/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/imunologia
7.
Clin Nucl Med ; 44(10): 829-830, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31162258

RESUMO

FDG PET/CT was performed in a 20-year-old woman to find the underlying cause of hemophagocytic lymphohistiocytosis. The images revealed hypermetabolic activity in multiple lymph nodes and in the spleen. Lymphoma was suspected. However, the pathology of bone marrow, lymph nodes, and the spleen demonstrated chronic active Epstein-Barr virus-associated T-cell lymphoproliferative disorders.


Assuntos
Fluordesoxiglucose F18 , Herpesvirus Humano 4/fisiologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfoma/complicações , Linfoma/virologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Linfócitos T/patologia , Proliferação de Células , Feminino , Humanos , Linfoma/diagnóstico por imagem , Adulto Jovem
8.
PLoS Genet ; 15(5): e1008020, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31125342

RESUMO

Breast cancer is the second leading cause of cancer-related deaths in the United States, with the majority of these deaths due to metastatic lesions rather than the primary tumor. Thus, a better understanding of the etiology of metastatic disease is crucial for improving survival. Using a haplotype mapping strategy in mouse and shRNA-mediated gene knockdown, we identified Rnaseh2c, a scaffolding protein of the heterotrimeric RNase H2 endoribonuclease complex, as a novel metastasis susceptibility factor. We found that the role of Rnaseh2c in metastatic disease is independent of RNase H2 enzymatic activity, and immunophenotyping and RNA-sequencing analysis revealed engagement of the T cell-mediated adaptive immune response. Furthermore, the cGAS-Sting pathway was not activated in the metastatic cancer cells used in this study, suggesting that the mechanism of immune response in breast cancer is different from the mechanism proposed for Aicardi-Goutières Syndrome, a rare interferonopathy caused by RNase H2 mutation. These results suggest an important novel, non-enzymatic role for RNASEH2C during breast cancer progression and add Rnaseh2c to a panel of genes we have identified that together could determine patients with high risk for metastasis. These results also highlight a potential new target for combination with immunotherapies and may contribute to a better understanding of the etiology of Aicardi-Goutières Syndrome autoimmunity.


Assuntos
Imunidade Adaptativa , Doenças Autoimunes do Sistema Nervoso/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Malformações do Sistema Nervoso/genética , Ribonuclease H/genética , Animais , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/mortalidade , Doenças Autoimunes do Sistema Nervoso/patologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metástase Linfática , Camundongos , Camundongos Nus , Mutação , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Malformações do Sistema Nervoso/imunologia , Malformações do Sistema Nervoso/mortalidade , Malformações do Sistema Nervoso/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Ribonuclease H/antagonistas & inibidores , Ribonuclease H/imunologia , Análise de Sequência de RNA , Transdução de Sinais , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/patologia
9.
Medicine (Baltimore) ; 98(18): e15237, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045763

RESUMO

RATIONALE: Idiopathic multicentric Castleman disease (iMCD) is a systemic disease with multiple regions of lymphadenopathy and systemic symptoms and associated with rheumatoid arthritis (RA) and collagen diseases. However, few reported have described the coexistence of iMCD and RA and the mechanisms by which iMCD induces arthritis remain elusive. We experienced a rare case of iMCD, wherein the patient exhibited symptoms of polyarthritis with high-grade fever. PATIENT CONCERNS: A 34-year-old woman was admitted to our hospital for further evaluation of a high fever with polyarthritis. The levels of both rheumatoid factor and anticitrullinated protein antibody were negative. F-fluorodeoxyglucose/positron emission tomography-computed tomography showed lymphadenopathy with increased fluoro-2-deoxy-D-glucose uptake. Magnetic resonance imaging and musculoskeletal ultrasonography revealed active synovitis in the hands which was consistent with RA. DIAGNOSES: We diagnosed iMCD based on human herpesvirus 8 negativity, HIV negativity, systemic lymphadenopathy, and pathologic findings of the lymph nodes. The patient did not satisfy the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for RA. Cytokine assay showed elevated serum levels of interleukin-17 and CXCL10, comparable to those in patients with RA. INTERVENTIONS: We administered 15 mg/d of predonisolone. OUTCOMES: After this treatment, the patient's symptoms showed improvement. As of this writing, we tapered the prednisolone to 7.5 mg/d, and the patient's remission has been maintained for >4 months. LESSONS: The present case suggests that RA-like active synovitis may coexist in iMCD, resulting from aberrant T-cell activation and histologic examination using lymph node biopsy may help enable early diagnosis of iMCD.


Assuntos
Artrite Reumatoide/complicações , Hiperplasia do Linfonodo Gigante/complicações , Linfadenopatia/diagnóstico por imagem , Sinovite/diagnóstico por imagem , Adulto , Artrite/diagnóstico , Artrite/etiologia , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/patologia , Hiperplasia do Linfonodo Gigante/sangue , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Hiperplasia do Linfonodo Gigante/patologia , Quimiocina CXCL10/sangue , Diagnóstico Diferencial , Feminino , Febre/diagnóstico , Febre/etiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Herpesvirus Humano 8 , Humanos , Interleucina-17/sangue , Linfadenopatia/patologia , Imagem por Ressonância Magnética/métodos , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Sinovite/patologia , Linfócitos T/patologia , Resultado do Tratamento
10.
Zhonghua Yan Ke Za Zhi ; 55(5): 374-380, 2019 May 11.
Artigo em Chinês | MEDLINE | ID: mdl-31137150

RESUMO

Objective: To evaluate the clinicopathological features of ocular natural killer(NK)/T cell lymphoma. Methods: Data of 21 patients (22 eyes) with ocular NK/T cell lymphoma treated at Eye & ENT Hospital of Fudan University from January 2006 to March 2018 were retrospectively analyzed for clinical data, morphology, immunophenotype and outcomes. Results: There were 10 males and 11 females with ages from 3 to 77 years (mean, 43 years). There were 20 unilateral cases (10 left eyes and 10 right eyes) and 1 bilateral case. Except for 1 case of corneal perforation resulting from the involvement of the conjunctiva and cornea, the other cases all involved the orbit (including eyelids and conjunctiva) as demonstrated by radiologic studies, with the lacrimal sac involved in 3 cases, and the nasal cavity or maxillary sinus involved in 2 cases. Three patients had been previously diagnosed sinonasal NK/T cell lymphoma with radiotherapy and chemotherapy. Two patients had a history of ovarian NK/T cell lymphoma with chemotherapy. One patient had multiple ulcers of skin and mucosa at presentation. There were 13 primary ocular NK/T cell lymphomas without evidence of nasal or systemic involvement. All patients presented with eyelid swelling and decreased visual acuity. There were proptosis in 18 cases, motility restriction in 13 cases, eyelid ulceration in 3 cases, and fever in 4 cases. They had all been previously diagnosed as orbital pseudotumor or cellulitis and there was no response to steroids and antibiotics. Pathological examination showed atypical lymphoid infiltration with an angioinvasive growth pattern causing coagulative necrosis. Cytologically, the medium-sized neoplastic cells showed irregular folded nuclei. The neoplastic cells were positive for cytoplasmic CD3ε, CD56, and cytotoxic molecules and Epstein-Barr virus-encoded RNA (EBER) in situ hybridization. Seven patients were lost to follow-up. Ten patients died 2.0 to 17.0 months after diagnosis (mean, 6.3 months) despite treatment with chemotherapy and radiotherapy. Conclusions: Ocular NK/T cell lymphoma is a rare form of ocular lymphoma. There are primary NK/T cell lymphoma and secondary ocular NK/T cell lymphoma with nasal or systemic involvement. The rarity of this tumor and inflammatory signs make it challenging to identify these tumors early. The neoplastic cells are positive for cytoplasmic CD3ε, CD56, cytotoxic molecules and EBER in situ hybridization. Despite aggressive therapy, it demonstrates high lethality with poor prognosis. (Chin J Ophthalmol, 2019, 55: 374-380).


Assuntos
Infecções por Vírus Epstein-Barr/patologia , Neoplasias Oculares/patologia , Células Matadoras Naturais/patologia , Linfoma de Células B , Linfoma de Células T/patologia , Neoplasias Orbitárias/patologia , Neoplasias Cutâneas/patologia , Linfócitos T/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/imunologia , Neoplasias Oculares/imunologia , Neoplasias Oculares/terapia , Neoplasias Oculares/virologia , Feminino , Humanos , Linfoma de Células T/imunologia , Linfoma de Células T/terapia , Linfoma de Células T/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/virologia , Resultado do Tratamento , Adulto Jovem
11.
Genes Cells ; 24(7): 485-495, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31125466

RESUMO

Mammalian STE20-like protein kinase 1/2 (MST1/2) and nuclear Dbf2-related kinase 1/2 (NDR1/2) are core components of Hippo signaling that are also known to be important regulators of lymphocyte trafficking. However, little is understood about the roles of other Hippo pathway molecules in these cells. Here, we present the first analysis of the function of Mps one binder kinase activator-1 (MOB1) in T lymphocytes in vivo. T-cell-specific double knockout (DKO) of MOB1A/B in mice [tMob1 DKO mice] reduces the number of naïve T cells in both the circulation and secondary lymphoid organs, but leads to an accumulation of CD4+ CD8- and CD4- CD8+ single-positive (SP) cells in the thymus. In vitro, naïve MOB1A/B-deficient T cells show increased apoptosis and display impaired trafficking capacity in response to the chemokine CCL19. These defects are linked to suppression of the activation of MST and NDR kinases, but are independent of the downstream transcriptional co-activator Yes-associated protein 1 (YAP1). Thus, MOB1 proteins play an important role in thymic egress and T-cell survival that is mediated by a pathway other than conventional Hippo-YAP1 signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação da Expressão Gênica , Fosfoproteínas/metabolismo , Fosfoproteínas/fisiologia , Proteínas Quinases/fisiologia , Linfócitos T/imunologia , Timócitos/imunologia , Animais , Apoptose , Células Cultivadas , Quimiotaxia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/metabolismo , Linfócitos T/patologia , Timócitos/metabolismo , Timócitos/patologia
12.
Curr Top Microbiol Immunol ; 421: 229-265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31123892

RESUMO

Helicobacter pylori is a prevalent human pathogen that successfully establishes chronic infection, which leads to clinically significant gastric diseases including chronic gastritis, peptic ulcer disease (PUD), and gastric cancer (GC). H. pylori is able to produce a persistent infection due in large part to its ability to hijack the host immune response. The host adaptive immune response is activated to strategically and specifically attack pathogens and normally clears them from the infected host. Since B and T lymphocytes are central mediators of adaptive immunity, in this chapter we review their development and the fundamental mechanisms regulating their activation in order to understand how some of the normal processes are subverted by H. pylori. In this review, we place particular emphasis on the CD4+ T cell responses, their subtypes, and regulatory mechanisms because of the expanding literature in this area related to H. pylori. T lymphocyte differentiation and function are finely orchestrated through a series of cell-cell interactions, which include immune checkpoint receptors. Among the immune checkpoint receptor family, there are some with inhibitory properties that are exploited by tumor cells to facilitate their immune evasion. Gastric epithelial cells (GECs), which act as antigen-presenting cells (APCs) in the gastric mucosa, are induced by H. pylori to express immune checkpoint receptors known to sway T lymphocyte function and thus circumvent effective T effector lymphocyte responses. This chapter reviews these and other mechanisms used by H. pylori to interfere with host immunity in order to persist.


Assuntos
Linfócitos B/patologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Evasão da Resposta Imune , Linfócitos T/patologia , Linfócitos B/imunologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/microbiologia , Humanos , Linfócitos T/imunologia
13.
Int J Mol Sci ; 20(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978945

RESUMO

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.


Assuntos
Ativação Linfocitária , Linfócitos T/imunologia , Resposta a Proteínas não Dobradas , Animais , Asma/imunologia , Asma/patologia , Estresse do Retículo Endoplasmático , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Doenças Reumáticas/imunologia , Doenças Reumáticas/patologia , Linfócitos T/citologia , Linfócitos T/patologia
15.
Int J Mol Sci ; 20(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884772

RESUMO

In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin's lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/imunologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/análise , Antígeno B7-H1/antagonistas & inibidores , Humanos , Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Terapia de Alvo Molecular/métodos , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia
16.
Cell Mol Life Sci ; 76(11): 2111-2132, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30826860

RESUMO

Although the pathogenesis of endometriosis is not fully understood, it is often considered to be an inflammatory disease. An increasing number of studies suggest that differential expression of anti-inflammatory cytokines (e.g., interleukin-4 and -10, and transforming growth factor-ß1) occurs in women with endometriosis, including in serum, peritoneal fluid and ectopic lesions. These anti-inflammatory cytokines also have indispensable roles in the progression of endometriosis, including by promoting survival, growth, invasion, differentiation, angiogenesis, and immune escape of the endometriotic lesions. In this review, we provide an overview of the expression, origin, function and regulation of anti-inflammatory cytokines in endometriosis, with brief discussion and perspectives on their future clinical implications in the diagnosis and therapy of the disease.


Assuntos
Endometriose/imunologia , Endométrio/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Células Estromais/imunologia , Fator de Crescimento Transformador beta1/imunologia , Progressão da Doença , Endometriose/genética , Endometriose/patologia , Endométrio/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação , Interleucina-10/genética , Interleucina-4/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Macrófagos/imunologia , Macrófagos/patologia , Transdução de Sinais , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Fator de Crescimento Transformador beta1/genética
17.
Int J Hematol ; 109(5): 603-611, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30850927

RESUMO

X-Linked severe combined immunodeficiency (X-SCID) is a severe form of primary immunodeficiency characterized by absence of T cells and NK cells. X-SCID is caused by a loss-of-function mutation in the IL2RG gene that encodes common gamma chain (γc), which plays an essential role in lymphocyte development. We report the first case of hypomorphic X-SCID caused by a synonymous mutation in the IL2RG gene leading to a splice anomaly, in a family including two patients with diffuse cutaneous warts, recurrent molluscum contagiosum, and mild respiratory infections. The mutation caused aberrant splicing of IL2RG mRNA, subsequently resulted in reduced γc expression. The leaky production of normally spliced IL2RG mRNA produced undamaged protein; thus, T cells and NK cells were generated in the patients. Functional assays of the patients' T cells and NK cells revealed diminished cytokine response in the T cells and absent cytokine response in the NK cells. In addition, the TCR repertoire in these patients was limited. These data suggest that a fine balance between aberrant splicing and leaky production of normally spliced IL2RG mRNA resulted in late-onset combined immunodeficiency in these patients.


Assuntos
Subunidade gama Comum de Receptores de Interleucina , Mutação , Sítios de Splice de RNA , Processamento de RNA , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Adolescente , Feminino , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Processamento de RNA/genética , Processamento de RNA/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/patologia
18.
J Nippon Med Sch ; 86(1): 43-47, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918156

RESUMO

Acute exacerbation of pre-existing interstitial lung disease (ILD) associated with systemic anticancer therapy is recognized as a life-threatening adverse event of lung cancer treatment. Programmed cell death 1 (PD-1) checkpoint inhibitors, such as nivolumab, often induce pneumonitis in patients with cancer; however, the tolerance and safety of nivolumab for advanced lung cancer with ILD are unclear. We report a 72-year-old patient with lung cancer with pathologically proven idiopathic pulmonary fibrosis who was treated with nivolumab. She demonstrated pneumonitis with an organized pneumonia (OP) pattern, but no acute exacerbation of ILD featuring a diffuse alveolar damage (DAD) pattern. She was successfully treated with corticosteroid therapy, and maintained good disease control after the discontinuation of nivolumab. She also showed pseudoprogression of the primary tumor, implying infiltration of T-cells into the lung. These findings suggest that T-cell activation by nivolumab treatment might not be directly associated with acute ILD exacerbation, and that treatable OP might be a major pulmonary complication of nivolumab in patients with pre-existing ILD, similar to patients without underlying ILD.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Pneumonia em Organização Criptogênica/induzido quimicamente , Nivolumabe/efeitos adversos , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Pneumonia em Organização Criptogênica/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Pulmão/patologia , Doenças Pulmonares Intersticiais/induzido quimicamente , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Metilprednisolona/administração & dosagem , Nivolumabe/uso terapêutico , Prednisolona/administração & dosagem , Linfócitos T/patologia , Resultado do Tratamento
19.
Pediatr Hematol Oncol ; 36(1): 17-27, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30870043

RESUMO

Long-term survival rates for pediatric patients with cancer have significantly improved, but novel approaches are desired for those with refractory/relapsed solid tumors. Recently, programed cell death-1/programed cell death-ligand-1 blockade has emerged as an effective option for many intractable cancers. However, not all patients show objective response to such therapy. On the other hand, several other checkpoint pathways, including Herpes virus entry mediator (HVEM)/B- and T-lymphocyte attenuator (BTLA), galectin-9 (GAL9)/T-cell immunoglobulin and mucin domain-3 (TIM3), and major histocompatibility complex class II (MHC-II)/lymphocyte activation gene-3 (LAG3), also regulate immune responses in the tumor microenvironment and may be alternative targets for novel immune therapies. In this study, we examined 65 common pediatric solid tumors and characterized the expression of Herpes virus entry mediator, GAL9, and MHC-II on tumor cells and their corresponding receptors B- and T-lymphocyte attenuator, TIM3, and LAG3, respectively, on tumor-infiltrating lymphocytes (TILs) with immunohistochemistry. Whereas the expression of GAL9 and MHC-II was limited, 73% of rhabdomyosarcomas and 100% of osteosarcomas expressed moderate to high levels of Herpes virus entry mediator on the tumor. TILs were detected in all tumor samples except one osteosarcoma. Interestingly, 45% of rhabdomyosarcomas, and 45% of osteosarcomas expressed moderate to high levels of both Herpes virus entry mediator on the tumor cells and B- and T-lymphocyte attenuator on the TILs. Results showed that a subset of pediatric solid tumors expressed tumor-associated checkpoint molecules, and TILs expressed corresponding receptors for these checkpoint molecules. Thus, immunogenic environments may be created, and checkpoint blockade may induce favorable immune responses.


Assuntos
Linfócitos B/imunologia , Neoplasias Ósseas/imunologia , Proteínas de Neoplasias/imunologia , Osteossarcoma/imunologia , Rabdomiossarcoma/imunologia , Linfócitos T/imunologia , Adolescente , Linfócitos B/patologia , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Osteossarcoma/patologia , Rabdomiossarcoma/patologia , Linfócitos T/patologia
20.
Nat Commun ; 10(1): 1065, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911002

RESUMO

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (TSCM) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1+Eomes+T-bet-) BM-TSCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.


Assuntos
Anergia Clonal , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Memória Imunológica/genética , Leucemia Mieloide Aguda/imunologia , Linfócitos T/imunologia , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Feminino , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores KIR/genética , Receptores KIR/imunologia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Transdução de Sinais , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Linfócitos T/patologia , Transplante Homólogo
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