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1.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33591245

RESUMO

Introduction. Shigella sonnei, the cause of bacillary dysentery, belongs to Gram-negative enteropathogenic bacteria. S. sonnei contains a 210 kb virulence plasmid that encodes an O-antigen gene cluster of LPSs. However, this virulence plasmid is frequently lost during replication. It is well-documented that after losing the O-antigen and becoming rough strains, the Gram-negative bacteria may express an LPS core on its surface. Previous studies have suggested that by using the LPS core, Gram-negative bacteria can interact with several C-type lectin receptors that are expressed on antigen-presenting cells (APCs).Hypothesis/Gap Statement. S. sonnei by losing the virulence plasmid may hijack APCs via the interactions of LPS-CD209/CD207.Aim. This study aimed to investigate if the S. sonnei rough strain, by losing the virulence plasmid, interacted with APCs that express C-type lectins of human CD207, human CD209a and mouse CD209b.Methodology. SDS-PAGE silver staining was used to examine the O-antigen expression of S. sonnei WT and its rough strain. Invasion assays and inhibition assays were used to examine the ability of S. sonnei WT and its rough strain to invade APCs and investigate whether CD209 and CD207 are receptors for phagocytosis of rough S. sonnei. Animal assays were used to observe the dissemination of S. sonnei.Results. S. sonnei did not express O-antigens after losing the virulence plasmid. The S. sonnei rough strain invades with APCs, including human dendritic cells (DCs) and mouse macrophages. CD209 and CD207 are receptors for phagocytosis of rough S. sonnei. Expression of the O-antigen reduces the ability of the S. sonnei rough strain to be disseminated to mesenteric lymph nodes and spleens.Conclusion. This work demonstrated that S. sonnei rough strains - by losing the virulence plasmid - invaded APCs through interactions with CD209 and CD207 receptors.


Assuntos
Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Disenteria Bacilar/microbiologia , Lectinas Tipo C/imunologia , Lectinas de Ligação a Manose/imunologia , Antígenos O , Plasmídeos , Receptores de Superfície Celular/imunologia , Shigella sonnei/patogenicidade , Virulência/genética , Animais , Células CHO , Cricetulus , Células Dendríticas/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/microbiologia , Camundongos , Antígenos O/genética , Antígenos O/metabolismo , Shigella sonnei/genética
2.
Cancer Sci ; 112(4): 1390-1401, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33453147

RESUMO

Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein-1 (VAP-1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP-1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP-1-specific inhibitor U-V296 inhibited murine tumor growth by enhancing IFN-γ-producing tumor antigen-specific CD8+ T cells. U-V296 exhibited significant synergistic anti-tumor effects with ICIs. In the TME of mice treated with U-V296, the expression of genes associated with M2-like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H2 O2 , an enzymatic product of VAP-1, which promoted the production of IL-4 by mouse Th2 and inhibited IFN-γ by mouse Th1 and human tumor-infiltrating lymphocytes, was decreased in tumors and CD31+ tumor vascular endothelial cells in the TMEs of mice treated with VAP-1 inhibitor. TCGA database analysis showed that VAP-1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL-4, IL4R, and IL-13 expression and a negative correlation with IFN-γ expression. These results indicated that VAP-1 is involved in the immunosuppressive TMEs through H2 O2 -associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.


Assuntos
Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Moléculas de Adesão Celular/antagonistas & inibidores , Neoplasias/imunologia , Neoplasias/terapia , Amina Oxidase (contendo Cobre)/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/imunologia , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Feminino , Imunoterapia/mortalidade , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
4.
Rinsho Shinkeigaku ; 60(8): 533-537, 2020 Aug 07.
Artigo em Japonês | MEDLINE | ID: mdl-32641627

RESUMO

A 41-year-old man noticed numbness of the fingers and toes, and gradually developed limb weakness and sensory impairment. The patient was diagnosed with typical chronic inflammatory demyelinating polyradiculoneuropathy. Over the course of clinical diagnosis, the limb and trunk ataxia, and finger tremor became prominent, and the presence anti-neurofascin-155 antibody was examined and confirmed positive. The effects of corticosteroids, intravenous immunoglobulin, and plasma apheresis were limited, and the disease progressed slowly and noticeably. Therefore, cyclosporine was introduced as treatment, and the patient's weakness and ataxia significantly improved. Rituximab treatment is expected to be effective in patients with the same antibody and immunosuppressant treatment may be useful in intractable cases.


Assuntos
Autoanticorpos/sangue , Moléculas de Adesão Celular/imunologia , Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Fatores de Crescimento Neural/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Adulto , Biomarcadores/sangue , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia
5.
Proc Natl Acad Sci U S A ; 117(22): 12295-12305, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424104

RESUMO

The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+ marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find that while SIGN-R1+ macrophages were not essential for initial activation of B cells, they were required for maturation of the response and development of GC B cells. These defects could be corrected when follicular helper T (Tfh) cells were induced before macrophage ablation or when Tfh responses were enhanced. Moreover, we show that in the absence of SIGN-R1+ macrophages, DCIR2+ dendritic cells (DCs), which play a key role in priming Tfh responses, were unable to cluster to the interfollicular regions of the spleen and were instead displaced to the MZ. Restoring SIGN-R1+ macrophages to the spleen corrected positioning of DCIR2+ DCs and rescued the GC B cell response. Our study reveals a previously unappreciated role for SIGN-R1+ macrophages in regulation of the GC reaction and highlights the functional specification of macrophage subsets in the MZ compartment.


Assuntos
Linfócitos B/imunologia , Moléculas de Adesão Celular/imunologia , Centro Germinativo/imunologia , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Receptores de Superfície Celular/imunologia , Baço/imunologia , Animais , Moléculas de Adesão Celular/genética , Lectinas Tipo C/genética , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Superfície Celular/genética , Linfócitos T Auxiliares-Indutores
6.
Infect Immun ; 88(5)2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32094254

RESUMO

Localized skin lesions are characteristic of cutaneous leishmaniasis (CL); however, Leishmania (Viannia) species, which are responsible for most CL cases in the Americas, can spread systemically, sometimes resulting in mucosal disease. Detection of Leishmania has been documented in healthy mucosal tissues (conjunctiva, tonsils, and nasal mucosa) and healthy skin of CL patients and in individuals with asymptomatic infection in areas of endemicity of L (V) panamensis and L (V) braziliensis transmission. However, the conditions and mechanisms that favor parasite persistence in healthy mucosal tissues are unknown. In this descriptive study, we compared the cell populations of the nasal mucosa (NM) of healthy donors and patients with active CL and explored the immune gene expression signatures related to molecular detection of Leishmania in this tissue in the absence of clinical signs or symptoms of mucosal disease. The cellular composition and gene expression profiles of NM samples from active CL patients were similar to those of healthy volunteers, with a predominance of epithelial over immune cells, and within the CD45+ cell population, a higher frequency of CD66b+ followed by CD14+ and CD3+ cells. In CL patients with molecular evidence of Leishmania persistence in the NM, genes characteristic of an anti-inflammatory and tissue repair responses (IL4R, IL5RA, POSTN, and SATB1) were overexpressed relative to NM samples from CL patients in which Leishmania was not detected. Here, we report the first immunological description of subclinically infected NM tissues of CL patients and provide evidence of a local anti-inflammatory environment favoring parasite persistence in the NM.


Assuntos
Leishmaniose Cutânea/imunologia , Mucosa Nasal/imunologia , Adulto , Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-4/imunologia , Subunidade alfa de Receptor de Interleucina-5/imunologia , Leishmania/imunologia , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/imunologia , Pele/imunologia , Transcriptoma/imunologia
7.
Acta Derm Venereol ; 100(5): adv00055, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32039458

RESUMO

Pemphigoid diseases are organ-specific autoimmune diseases of the skin and/or mucous membranes. They are caused by autoantibodies targeting adhesion molecules located at the dermal-epidermal junction. While the diagnostics of pemphigoid diseases and insights into their pathogenesis have improved significantly, the development of novel treatments that are effective and safe remains an unmet medical need. However, numerous pre-clinical studies and early clinical trials have recently been launched. This review summarizes some pathways leading to drug development in pemphigoid diseases, namely: (i) hypothesis-driven drug development; (ii) omics-based drug development; (iii) drug repurposing; (iv) screening-based drug development; and (v) drug development based on careful clinical observations. Ultimately, it is hoped that this will lead to personalized and curative treatments.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Desenvolvimento de Medicamentos , Penfigoide Bolhoso/tratamento farmacológico , Penfigoide Bolhoso/imunologia , Proteínas Tirosina Quinases/administração & dosagem , Autoanticorpos/efeitos dos fármacos , Doenças Autoimunes/patologia , Moléculas de Adesão Celular/imunologia , Fumarato de Dimetilo/uso terapêutico , Doxiciclina/uso terapêutico , Epidermólise Bolhosa Adquirida/tratamento farmacológico , Epidermólise Bolhosa Adquirida/imunologia , Epidermólise Bolhosa Adquirida/patologia , Feminino , Previsões , Humanos , Masculino , Terapia de Alvo Molecular/métodos , Penfigoide Bolhoso/patologia , Dermatopatias Vesiculobolhosas/tratamento farmacológico , Dermatopatias Vesiculobolhosas/imunologia , Dermatopatias Vesiculobolhosas/patologia , Pesquisa Médica Translacional
8.
Neurology ; 95(4): e427-e433, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32102977

RESUMO

OBJECTIVE: To study the presence of nodal and paranodal immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in patients with genetic neuropathies. METHODS: A total of 108 patients with genetic neuropathies from 3 different centers were included. The presence of IgG and IgM antibodies against neurofascin-155 (NF155), nodal neurofascin (NF186 and NF140), and contactin-1 (CNTN1) were investigated with a cell-based assay (CBA) using immunocytochemistry in transfected HEK293 cells. Sera with positive or uncertain results were further tested by ELISA and immunohistochemistry in pig teased-nerve fibers. RESULTS: Six patients with Charcot-Marie-Tooth disease (CMT) had an uncertain staining pattern for IgM against nodal neurofascin that was not confirmed by ELISA. Two patients with CMT had an uncertain staining pattern for IgG against nodal neurofascin that was not confirmed by ELISA or immunohistochemistry. One patient with CMT with a confirmed GJB1 mutation tested positive for IgG against NF155 by CBA and ELISA (1/900), but was not confirmed by immunohistochemistry and was ultimately classified as negative. CONCLUSIONS: Antibodies against nodal or paranodal antigens were not detected in our cohort of patients with CMT, as previously reported. Some patients may falsely test positive for any of the techniques; confirmatory techniques should be incorporated into the routine testing.


Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Moléculas de Adesão Celular/imunologia , Contactina 1/imunologia , Fatores de Crescimento Neural/imunologia , Polineuropatias/imunologia , Adulto , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Polineuropatias/sangue , Nós Neurofibrosos/imunologia
9.
PLoS Pathog ; 16(1): e1007927, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31999794

RESUMO

During the course of fungal infection, pathogen recognition by the innate immune system is critical to initiate efficient protective immune responses. The primary event that triggers immune responses is the binding of Pattern Recognition Receptors (PRRs), which are expressed at the surface of host immune cells, to Pathogen-Associated Molecular Patterns (PAMPs) located predominantly in the fungal cell wall. Most fungi have mannosylated PAMPs in their cell walls and these are recognized by a range of C-type lectin receptors (CTLs). However, the precise spatial distribution of the ligands that induce immune responses within the cell walls of fungi are not well defined. We used recombinant IgG Fc-CTLs fusions of three murine mannan detecting CTLs, including dectin-2, the mannose receptor (MR) carbohydrate recognition domains (CRDs) 4-7 (CRD4-7), and human DC-SIGN (hDC-SIGN) and of the ß-1,3 glucan-binding lectin dectin-1 to map PRR ligands in the fungal cell wall of fungi grown in vitro in rich and minimal media. We show that epitopes of mannan-specific CTL receptors can be clustered or diffuse, superficial or buried in the inner cell wall. We demonstrate that PRR ligands do not correlate well with phylogenetic relationships between fungi, and that Fc-lectin binding discriminated between mannosides expressed on different cell morphologies of the same fungus. We also demonstrate CTL epitope differentiation during different phases of the growth cycle of Candida albicans and that MR and DC-SIGN labelled outer chain N-mannans whilst dectin-2 labelled core N-mannans displayed deeper in the cell wall. These immune receptor maps of fungal walls of in vitro grown cells therefore reveal remarkable spatial, temporal and chemical diversity, indicating that the triggering of immune recognition events originates from multiple physical origins at the fungal cell surface.


Assuntos
Parede Celular/imunologia , Fungos/imunologia , Lectinas Tipo C/imunologia , Mananas/imunologia , Micoses/imunologia , Filogenia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Parede Celular/química , Parede Celular/genética , Fungos/química , Fungos/classificação , Fungos/genética , Humanos , Lectinas Tipo C/genética , Mananas/análise , Micoses/genética , Micoses/microbiologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia
10.
J Immunol ; 204(5): 1214-1224, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31980574

RESUMO

Leukocytes are rapidly recruited to sites of inflammation via interactions with the vascular endothelium. The steroid hormone dehydroepiandrosterone (DHEA) exerts anti-inflammatory properties; however, the underlying mechanisms are poorly understood. In this study, we show that an anti-inflammatory mechanism of DHEA involves the regulation of developmental endothelial locus 1 (DEL-1) expression. DEL-1 is a secreted homeostatic factor that inhibits ß2-integrin-dependent leukocyte adhesion, and the subsequent leukocyte recruitment and its expression is downregulated upon inflammation. Similarly, DHEA inhibited leukocyte adhesion to the endothelium in venules of the inflamed mouse cremaster muscle. Importantly, in a model of lung inflammation, DHEA limited neutrophil recruitment in a DEL-1-dependent manner. Mechanistically, DHEA counteracted the inhibitory effect of inflammation on DEL-1 expression. Indeed, whereas TNF reduced DEL-1 expression and secretion in endothelial cells by diminishing C/EBPß binding to the DEL-1 gene promoter, DHEA counteracted the inhibitory effect of TNF via activation of tropomyosin receptor kinase A (TRKA) and downstream PI3K/AKT signaling that restored C/EBPß binding to the DEL-1 promoter. In conclusion, DHEA restrains neutrophil recruitment by reversing inflammation-induced downregulation of DEL-1 expression. Therefore, the anti-inflammatory DHEA/DEL-1 axis could be harnessed therapeutically in the context of inflammatory diseases.


Assuntos
Proteínas de Ligação ao Cálcio/imunologia , Moléculas de Adesão Celular/imunologia , Desidroepiandrosterona/farmacologia , Leucócitos/imunologia , Transdução de Sinais/imunologia , Animais , Proteína beta Intensificadora de Ligação a CCAAT/imunologia , Antígenos CD18/imunologia , Adesão Celular/imunologia , Endotélio Vascular/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Leucócitos/citologia , Camundongos , Fosfatidilinositol 3-Quinases/imunologia , Regiões Promotoras Genéticas/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptor trkA/imunologia
11.
J Cancer Res Clin Oncol ; 146(1): 127-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31853662

RESUMO

PURPOSE: Ovarian carcinoma (OC) is the most lethal female genital cancer. After a primary curative surgical approach followed by chemotherapy, a fraction of the patients recur with chemoresistant disease. Data indicate a favorable therapeutic effect of tumor-infiltrating neutrophils (TIN) in OC. Our aim was to investigate the prognostic role of CD66b expression, corresponding to neutrophilic infiltration for recurrence-free survival (RFS) and overall survival (OS) in patients with OC. METHODS: A collective of 47 primary serous ovarian carcinoma and their matching recurrences were processed and stained with CD66b using immunohistochemistry. Tumors from patients with RFS of more than 6 months were defined as chemosensitive. Statistical analysis of CD66b expression was performed to assess the clinical endpoints. RESULTS: High density of CD66b expressing neutrophils in primary carcinoma was associated with chemosensitivity (p = 0.014) and longer RFS (p = 0.001). Univariate analysis identified high density of CD66b expressing neutrophils as a predictor for favorable RFS (HR 0.41, 95% CI 0.22-0.76, p < 0.005). Residual disease > 2 cm (HR 3.67, 95% CI 1.62-8.31, p < 0.002) and higher number of chemotherapy cycles (HR 1.28, 95% CI 1.05-1.55, p < 0.013) were associated with worse RFS. Multivariate analysis showed that high density of CD66b expressing neutrophils (HR 0.22, 95% CI 0.10-0.48, p < 0.001) and residual disease > 2 cm (HR 3.69, 95% CI 1.43-9.53, p < 0.007) were independent predictors of RFS but had no impact on OS. CONCLUSION: High CD66b neutrophil density in primary high-grade OC predicts good response to initial chemotherapy and longer recurrence-free survival independent of known risk factors.


Assuntos
Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Neutrófilos/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/imunologia , Adulto , Idoso , Antígenos CD/biossíntese , Moléculas de Adesão Celular/biossíntese , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Valor Preditivo dos Testes
12.
Gynecol Oncol ; 156(2): 430-438, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31839338

RESUMO

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast cell-surface antigen 2 (Trop-2), a transmembrane-calcium-signal-transducer, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to evaluate the expression of Trop-2 in USC and the preclinical activity of SG against primary USC cell-lines and xenografts. METHODS: We used immunohistochemistry (IHC) and flow-cytometry-based assays to evaluate Trop-2 expression and cell-viability in USC tissue and primary tumor-cell-lines after exposure to SG, non-targeting control ADC, and naked antibody hRS7-IgG. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell-lines was evaluated in vitro using 4-hr-Chromium-release-assays. In vivo activity of SG was tested against Trop-2+ USC xenografts by intravenous administration of SG, control ADC, and hRS7. RESULTS: Trop-2 expression by IHC was detected in 95.1% of USC samples (99/104). Primary tumor cell-lines overexpressing Trop-2 were significantly more sensitive to SG when compared to control ADC (p <0.05). Both SG and hRS7 mediated ADCC in Trop2+ USC cell-lines while no cytotoxicity was detected against Trop-2- cells. SG induced significant bystander killing of Trop-2- tumors when admixed with Trop-2+ tumors. SG caused growth-inhibition and increased survival in SG treated mice harboring Trop-2+ xenografts when compared to controls (p <0.05). CONCLUSIONS: SG is remarkably active against USC overexpressing Trop-2 in vitro and in vivo. Our results combined with SG clinical responses recently reported against multiple chemotherapy resistant human tumors further support clinical development of SG in USC patients with advanced/recurrent disease.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/imunologia , Camptotecina/análogos & derivados , Moléculas de Adesão Celular/imunologia , Imunoconjugados/farmacologia , Neoplasias Uterinas/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Antígenos de Neoplasias/biossíntese , Camptotecina/imunologia , Camptotecina/farmacologia , Moléculas de Adesão Celular/biossíntese , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso , Feminino , Citometria de Fluxo , Humanos , Imunoconjugados/imunologia , Imuno-Histoquímica , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , Distribuição Aleatória , Análise Serial de Tecidos , Neoplasias Uterinas/imunologia , Neoplasias Uterinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Surg Res ; 246: 52-61, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31561178

RESUMO

BACKGROUND: Low-density neutrophils (LDN) have been shown to be increased in peripheral blood in patients with various diseases and closely related to immune-mediated pathology. However, the frequency and function of LDN in circulating blood of the patients following abdominal surgery have not been well understood. METHODS: LDN were determined by CD66b(+) cells, which were copurified with mononuclear cells by density gradient preparations of peripheral blood of surgical patients. The effects of the purified LDN on T cell proliferation and tumor cell lysis were examined in vitro. Neutrophil extracellular traps (NETs) production was examined by extracellular nuclear staining. RESULTS: The number of LDN with an immature phenotype is markedly increased in peripheral blood samples in patients after abdominal surgery. The frequency of LDN correlated positively with operative time and intraoperative blood loss. The purified LDN significantly suppressed the proliferation of autologous T cells stimulated with anti-CD3 mAb coated on plate and partially inhibited the cytotoxicity of lymphocytes activated with recombinant interleukin-2 against a human gastric cancer cell, OCUM-1. The LDN also produced NETs after short-term culture in vitro, which efficiently trap many OCUM-1. These results suggest that surgical stress recruits immunosuppressive LDN in the circulation in the early postoperative period. CONCLUSIONS: The LDN may support the lodging of circulating tumor cells via NETs formation and inhibit T cell-mediated antitumor response in target organs, which may promote postoperative cancer metastases. Functional blockade of LDN might be an effective strategy to reduce tumor recurrence after abdominal surgery.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Neoplasias Gastrointestinais/cirurgia , Recidiva Local de Neoplasia/imunologia , Neutrófilos/imunologia , Estresse Fisiológico/imunologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Humanos , Contagem de Leucócitos , Recidiva Local de Neoplasia/epidemiologia , Células Neoplásicas Circulantes/imunologia , Neutrófilos/metabolismo , Duração da Cirurgia , Linfócitos T/imunologia
14.
J Invest Dermatol ; 140(2): 370-379.e8, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31425706

RESUMO

Atopic dermatitis (AD) is often concomitant with increased levels of IgE against not only foreign allergens but also autoallergens. AD patients with autoallergy are likely to be more severe and difficult to treat, and self-reactive IgE might be a contributing factor in the pathogenesis of AD. However, how autoallergens are recognized by the immune system and what immune responses are induced subsequently remain largely unknown. We found that the serum level of IgE against transglutaminase 3 (TGase3) was significantly higher in AD patients than in healthy individuals and was positively correlated with disease severity. The expression of TGase3 in the lesional skin of AD patients was markedly increased compared with that of the controls, and Th2 cytokines and/or allergen promoted the expression of TGase3 in keratinocytes. TGase3 bond monocytes-derived dendritic cells (MoDCs) via dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), which resulted in the production of IL-6 and activation of the NF-κB signaling pathway in MoDCs; and TGase3-treated MoDCs facilitated Th1 polarization. Moreover, skin inflammation in the mouse model of MC903-induced AD was attenuated when TGase3 was inhibited. In conclusion, TGase3 was revealed as an autoallergen in AD and actively involved in skin inflammation; TGase3-targeting might be a therapeutic strategy for the treatment of AD.


Assuntos
Autoantígenos/imunologia , Moléculas de Adesão Celular/metabolismo , Dermatite Atópica/imunologia , Lectinas Tipo C/metabolismo , Receptores de Superfície Celular/metabolismo , Pele/imunologia , Transglutaminases/imunologia , Adolescente , Adulto , Idoso , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/sangue , Autoantígenos/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular/imunologia , Células Cultivadas , Criança , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dermatite Atópica/sangue , Dermatite Atópica/diagnóstico , Dermatite Atópica/patologia , Modelos Animais de Doenças , Feminino , Voluntários Saudáveis , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-6/imunologia , Interleucina-6/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Lectinas Tipo C/imunologia , Ativação Linfocitária , Masculino , Camundongos , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Cultura Primária de Células , Receptores de Superfície Celular/imunologia , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Pele/citologia , Pele/patologia , Células Th1/imunologia , Transglutaminases/sangue , Transglutaminases/metabolismo , Adulto Jovem
15.
Infect Immun ; 88(2)2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31712270

RESUMO

Cytoadherence-linked asexual gene 9 (Clag9), a conserved Plasmodium protein expressed during the asexual blood stages, is involved in the cytoadherence of infected red blood cells (RBCs) to the endothelial lining of blood vessels. Here, we show that Plasmodium falciparum Clag9 (PfClag9) is a component of the PfClag9-RhopH complex that is involved in merozoite binding to human erythrocytes. To characterize PfClag9, we expressed four fragments of PfClag9, encompassing the entire protein. Immunostaining analysis using anti-PfClag9 antibodies showed expression and localization of PfClag9 at the apical end of the merozoites. Mass spectrometric analysis of merozoite extracts after immunoprecipitation using anti-PfClag9 antibody identified P. falciparum rhoptry-associated protein 1 (PfRAP1), PfRAP2, PfRAP3, PfRhopH2, and PfRhopH3 as associated proteins. The identified rhoptry proteins were expressed, and their association with PfClag9 domains was assessed by using protein-protein interaction tools. We further showed that PfClag9 binds human RBCs by interacting with the glycophorin A-band 3 receptor-coreceptor complex. In agreement with its cellular localization, PfClag9 was strongly recognized by antibodies generated during natural infection. Mice immunized with the C-terminal domain of PfClag9 were partially protected against a subsequent challenge infection with Plasmodium berghei, further supporting a biological role of PfClag9 during natural infection. Taken together, these results provide direct evidence for the existence of a PfRhopH-Clag9 complex on the Plasmodium merozoite surface that binds to human RBCs.


Assuntos
Moléculas de Adesão Celular/imunologia , Eritrócitos/imunologia , Merozoítos/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Humanos , Malária Falciparum/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei/imunologia , Mapas de Interação de Proteínas/imunologia
16.
Ann Clin Transl Neurol ; 6(11): 2304-2316, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31657126

RESUMO

OBJECTIVE: To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti-neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti-NF155 antibodies (NF155- CIDP). METHODS: Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155- CIDP, and 28 with non-inflammatory neurological disease (NIND). RESULTS: CSF CXCL8/IL-8, IL-13, TNF-α, CCL11/eotaxin, CCL2/MCP-1, and IFN-γ were significantly higher, while IL-1ß, IL-1ra, and G-CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155- CIDP, CXCL8/IL-8 and IL-13 were significantly higher, and IL-1ß, IL-1ra, and IL-6 were lower, in NF155+ CIDP. CXCL8/IL-8, IL-13, CCL11/eotaxin, CXCL10/IP-10, CCL3/MIP-1α, CCL4/MIP-1ß, and TNF-α levels were positively correlated with markedly elevated CSF protein, while IL-13, CCL11/eotaxin, and IL-17 levels were positively correlated with increased CSF cell counts. IL-13, CXCL8/IL-8, CCL4/MIP-1ß, CCL3/MIP-1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155- CIDP had significantly increased IFN-γ compared with NIND, and exhibited positive correlations of IFN-γ, CXCL10/IP-10, and CXCL8/IL-8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155- CIDP were separable, and that IL-4, IL-10, and IL-13 were the three most significant discriminators. INTERPRETATION: Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti-NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.


Assuntos
Autoanticorpos , Moléculas de Adesão Celular/imunologia , Citocinas/líquido cefalorraquidiano , Fatores de Crescimento Neural/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/líquido cefalorraquidiano , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Int J Mol Sci ; 20(20)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658587

RESUMO

The peptide TFF3 is a member of a family of secretory lectins, and is typically synthesized by mucous epithelia together with mucins. It is mainly released from intestinal goblet cells as a high-molecular mass heterodimer with IgG Fc binding protein (FCGBP). Herein, we investigated human saliva by fast protein liquid chromatography (FPLC) and proteomics and identified high- and low-molecular-mass forms of TFF3. Whereas the high-molecular-mass forms represent a heterodimer with FCGBP, the low-molecular-mass forms represent homodimeric TFF3 forms. Proteomic analysis also revealed a C-terminally truncated form of TFF3. We hypothesize that salivary TFF3-FCGBP might play a role in the innate immune defense of the oral cavity and that TFF3 might also bind to microbial glycans. The known interaction of TFF3 with the agglutinin DMBT-1, a typical constituent of human saliva, further supports this protective role.


Assuntos
Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/metabolismo , Dimerização , Saliva/metabolismo , Fator Trefoil-3/química , Fator Trefoil-3/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular/imunologia , Proteínas de Ligação a DNA/metabolismo , Humanos , Imunidade Inata , Polissacarídeos , Domínios e Motivos de Interação entre Proteínas , Proteômica , Saliva/imunologia , Fator Trefoil-3/imunologia , Proteínas Supressoras de Tumor/metabolismo
18.
Semin Immunol ; 42: 101296, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31604530

RESUMO

The type I membrane protein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) distinctively exhibits significant alternative splicing that allows for tunable functions upon homophilic binding. CEACAM1 is highly expressed in the tumor environment and is strictly regulated on lymphocytes such that its expression is restricted to activated cells where it is now recognized to function in tolerance pathways. CEACAM1 is also an important target for microbes which have co-opted these attributes of CEACAM1 for the purposes of invading the host and evading the immune system. These properties, among others, have focused attention on CEACAM1 as a unique target for immunotherapy in autoimmunity and cancer. This review examines recent structural information derived from the characterization of CEACAM1:CEACAM1 interactions and heterophilic modes of binding especially to microbes and how this relates to CEACAM1 function. Through this, we aim to provide insights into targeting CEACAM1 for therapeutic intervention.


Assuntos
Antígenos CD/imunologia , Moléculas de Adesão Celular/imunologia , Animais , Antígenos CD/química , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/química , Humanos
19.
Bioorg Chem ; 92: 103250, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31580982

RESUMO

Leukocyte transendothelial migration is one of the most important step in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases. Leukocyte migration inhibitors are considered as promising and potentially effective therapeutic agents to treat inflammatory and auto-immune disorders. In this study, based on previous trioxotetrahydropyrimidin based integrin inhibitors that suboptimally blocked leukocyte adhesion, twelve molecules with a modified scaffold were designed, synthesized, and tested in vitro for their capacity to block the transendothelial migration of immune cells. One of the molecules, namely, methyl 4-((2-(tert-butyl)-6-((2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene) methyl) phenoxy) methyl) benzoate, (compound 12), completely blocked leukocyte transendothelial migration, without any toxic effects on immune or endothelial cells (IC50 = 2.4 µM). In vivo, compound 12 exhibited significant therapeutic effects in inflammatory bowel disease (IBD)/Crohn's disease, multiple sclerosis, fatty liver disease, and rheumatoid arthritis models. A detailed acute and chronic toxicity profile of the lead compound in vivo did not reveal any toxic effects. Such a type of molecule might therefore provide a unique starting point for designing a novel class of leukocyte transmigration blocking agents with broad therapeutic applications in inflammatory and auto-immune pathologies.


Assuntos
Linfócitos B/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Pirimidinas/síntese química , Linfócitos T/efeitos dos fármacos , Migração Transcelular de Célula/efeitos dos fármacos , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Linfócitos B/imunologia , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação , Estrutura Molecular , Monócitos/imunologia , Mucoproteínas/imunologia , Pirimidinas/química , Pirimidinas/farmacologia , Linfócitos T/imunologia , Molécula 1 de Adesão de Célula Vascular/imunologia
20.
Cell Rep ; 29(4): 889-903.e10, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31644911

RESUMO

Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.


Assuntos
Fator 3-alfa Nuclear de Hepatócito/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Fatores de Transcrição/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/genética , Feminino , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/genética , Camundongos , Mucoproteínas/imunologia , Mucoproteínas/metabolismo , Proteínas Oncogênicas/imunologia , Proteínas Oncogênicas/metabolismo
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