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1.
J Clin Endocrinol Metab ; 100(9): E1206-15, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26196948

RESUMO

CONTEXT: Current methods of preoperative diagnostics frequently fail to discriminate between benign and malignant thyroid neoplasms. In encapsulated follicular-patterned tumors (EnFPT), this discrimination is challenging even using histopathological analysis. Autoantibody response against tumor-associated antigens is a well-documented phenomenon with prominent diagnostic potential; however, autoantigenicity of thyroid tumors remains poorly explored. OBJECTIVES: Objectives were exploration of tumor-associated antigen repertoire of thyroid tumors and identification of candidate autoantibody biomarkers capable of discrimination between benign and malignant thyroid neoplasms. DESIGN, SETTING, AND PATIENTS: Proteins isolated from FTC-133 cells were subjected to two-dimensional Western blotting using pooled serum samples of patients originally diagnosed with either papillary thyroid carcinoma (PTC) or EnFPT represented by apparently benign follicular thyroid adenomas, as well as healthy individuals. Immunoreactive proteins were identified using liquid chromatography-tandem mass-spectrometry. Pathological reassessment of EnFPT was performed applying nonconservative criteria for capsular invasion and significance of focal PTC nuclear changes (PTC-NCs). Recombinant T-complex protein 1 subunitζ (TCP-1ζ) was used to examine an expanded serum sample set of patients with various thyroid neoplasms (n = 89) for TCP-1ζ autoantibodies. All patients were included in tertiary referral centers. RESULTS: A protein demonstrating a distinct pattern of EnFPT-specific seroreactivity was identified as TCP-1ζ protein. A subsequent search for clinicopathological correlates of TCP-1ζ seroreactivity revealed nonclassical capsular invasion or focal PTC-NC in all TCP-1ζ antibody-positive cases. Further studies in an expanded sample set confirmed the specificity of TCP-1ζ autoantibodies to malignant EnFPT. CONCLUSIONS: We identified TCP-1ζ autoantibodies as a potential biomarker for presurgical discrimination between benign and malignant encapsulated follicular-patterned thyroid tumors. Our results suggest the use of nonconservative morphological criteria for diagnosis of malignant EnFPT in biomarker identification studies and provide a peculiar example of uncovering the diagnostic potential of a candidate biomarker using incorporation of pathological reassessment in the pipeline of immunoproteomic research.


Assuntos
Adenocarcinoma Folicular/diagnóstico , Autoanticorpos/sangue , Carcinoma Papilar/diagnóstico , Chaperonina com TCP-1/imunologia , Neoplasias da Glândula Tireoide/diagnóstico , Adenocarcinoma Folicular/sangue , Adenocarcinoma Folicular/imunologia , Adenocarcinoma Folicular/patologia , Adulto , Biomarcadores/sangue , Carcinoma Papilar/sangue , Carcinoma Papilar/imunologia , Carcinoma Papilar/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/patologia , Adulto Jovem
2.
Cancer Immunol Res ; 1(3): 190-200, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24777681

RESUMO

A mutation in the hydin gene has been recently described as one possible mechanism leading to lethal congenital hydrocephalus in mice, and a similar defect is proposed to be involved in an autosomal recessive form of hydrocephalus in human. Here, we report for the first time on the cancer association and immunogenicity of two HYDIN variants in humans. One is a previously described sequence derived from the chromosome 1 gene copy, that is, KIAA1864. The second is encoded by a novel alternative transcript originating from the chromosome 16, which we identified by immunoscreening of a testis-derived cDNA expression library with sera of patients with colorectal cancer, and called MO-TES391. Both variants are targeted by immunoglobulin G antibodies in a significant subset of cancer patients but only rarely in healthy donors. Moreover, we identify HLA-A*0201-restricted sequences derived from MO-TES391 and KIAA1864, which are specifically recognized by human cytotoxic CD8(+) T cells. Taken together, these results suggest frequent and coordinated adaptive immune responses against HYDIN variants in patients with cancer and propose HYDIN as a novel cancer-associated antigen.


Assuntos
Imunidade Adaptativa/genética , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas dos Microfilamentos/imunologia , Processamento Alternativo , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 16 , Antígeno HLA-A2/metabolismo , Humanos , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Mutação , Neoplasias/imunologia , RNA Mensageiro/imunologia , RNA Mensageiro/metabolismo
3.
Blood ; 116(18): 3456-64, 2010 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-20634375

RESUMO

Secondary lymphoid organs provide a unique microenvironment for generation of immune responses. Using a cell type-specific conditional knockout approach, we have dissected contributions of tumor necrosis factor (TNF) produced by B cells (B-TNF) or T cells (T-TNF) to the genesis and homeostatic organization of secondary lymphoid organs. In spleen, lymph nodes and Peyer patches, the cellular source of TNF, and its molecular form (soluble versus membrane-bound) appeared distinct. In spleen, in addition to major B-TNF signal, a complementary T-TNF signal contributed to the microstructure. In contrast, B-TNF predominantly controlled the development of follicular dendritic cells and B-cell follicles in Peyer patches. In lymph nodes, cooperation between TNF expressed by B and T cells was necessary for the maintenance of microarchitecture and for generation of an efficient humoral immune response. Unexpectedly, soluble but not membrane TNF expressed by B cells was essential for the organization of the secondary lymphoid organs. Thus, the maintenance of each type of secondary lymphoid organ is orchestrated by distinct contributions of membrane-bound and soluble TNF produced by B and T lymphocytes.


Assuntos
Linfócitos B/imunologia , Linfonodos/imunologia , Nódulos Linfáticos Agregados/imunologia , Baço/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Regulação da Expressão Gênica , Imunidade Humoral , Linfonodos/citologia , Linfonodos/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nódulos Linfáticos Agregados/citologia , Baço/citologia , Baço/ultraestrutura , Fator de Necrose Tumoral alfa/genética
4.
Eur J Immunol ; 39(10): 2906-15, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19735075

RESUMO

TNF, lymphotoxin (LT)-alpha, LT-beta and LIGHT are members of a larger superfamily of TNF-related cytokines that can cross-utilize several receptors. Although LIGHT has been implicated in thymic development and function, the role of TNF and LT remains incompletely defined. To address this, we created a model of modest homeostatic overexpression of TNF/LT cytokines using the genomic human TNF/LT locus as a low copy number Tg. Strikingly, expression of Tg TNF/LT gene products led to profound early thymic atrophy characterized by decreased numbers of thymocytes and cortical thymic epithelial cells, partial block of thymocyte proliferation at double negative (DN) 1 stage, increased apoptosis of DN2 thymocytes and severe decline of T-cell numbers in the periphery. Results of backcrossing to TNFR1-, LTbetaR- or TNF/LT-deficient backgrounds and of reciprocal bone marrow transfers implicated both LT-alpha/LT-beta to LTbetaR and TNF/LT-alpha to TNFR1 signaling in accelerated thymus degeneration. We hypothesize that chronic infections can promote thymic atrophy by upregulating LT and TNF production.


Assuntos
Atrofia/genética , Expressão Gênica/genética , Linfotoxina-alfa/genética , Linfotoxina-beta/genética , Timo/patologia , Fator de Necrose Tumoral alfa/genética , Animais , Apoptose/genética , Apoptose/imunologia , Atrofia/patologia , Transplante de Medula Óssea , Contagem de Células , Proliferação de Células , Células Epiteliais/patologia , Dosagem de Genes/genética , Humanos , Queratina-8/metabolismo , Receptor beta de Linfotoxina/genética , Linfotoxina-alfa/metabolismo , Linfotoxina-beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Células-Tronco/patologia , Subpopulações de Linfócitos T/patologia , Linfócitos T/patologia , Timo/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Cancer Immunol Immunother ; 57(6): 871-81, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18026951

RESUMO

PURPOSE: Tankyrases 1 and 2 are telomere-associated poly(ADP-ribose) polymerases (PARP) that can positively regulate telomere elongation and interact with multiple cellular proteins. Recent reports implicated tankyrases as tumor antigens and potential targets of anticancer treatment. We examined expression of tankyrases in colon tumors and immune response to these enzymes in patients with different types of cancer. METHODS: mRNA and protein expression was evaluated by quantitative real-time RT-PCR and Western blotting, respectively. Humoral immune response to recombinant tankyrases was investigated by modified enzyme-linked immunoassays. Cellular immune response was analysed by ELISPOT and (51)Cr release assays. RESULTS: We found that both mRNA and protein levels of tankyrase 2 (TNKL) are upregulated in colon tumors. In contrast, protein level of tankyrase 1 (TNKS) is downregulated, while mRNA level shows variable changes. More than a quarter of colon cancer patients develop humoral immune response to at least one of the two tankyrases. In this study we mapped common and unique B-cell epitopes located in different domains of the two proteins. Additionally, we present evidence for T-cell responses both to epitopes that are unique for TNKL and to those shared between TNKL and TNKS. CONCLUSION: Our study favors a biomarker usage of antibody response to tankyrases. Spontaneous CD8(+) T-cell responses to these enzymes are rare and further investigation is needed to evaluate tankyrases as potential targets for cancer immunotherapy.


Assuntos
Formação de Anticorpos , Neoplasias do Colo/enzimologia , Imunidade Celular , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Tanquirases/biossíntese , Sequência de Aminoácidos , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Neoplasias do Colo/patologia , Mapeamento de Epitopos/métodos , Epitopos/química , Humanos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Tanquirases/metabolismo
6.
J Immunol ; 179(10): 6919-32, 2007 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17982083

RESUMO

Using a mouse model for genetic analysis of host resistance to virulent Mycobacterium tuberculosis, we have identified a genetic locus sst1 on mouse chromosome 1, which controls progression of pulmonary tuberculosis. In vitro, this locus had an effect on macrophage-mediated control of two intracellular bacterial pathogens, M. tuberculosis and Listeria monocytogenes. In this report, we investigated a specific function of the sst1 locus in antituberculosis immunity in vivo, especially its role in control of pulmonary tuberculosis. We found that the sst1 locus affected neither activation of Th1 cytokine-producing T lymphocytes, nor their migration to the lungs, but rather controlled an inducible NO synthase-independent mechanism of innate immunity. Although the sst1(S) macrophages responded to stimulation with IFN-gamma in vitro, their responsiveness to activation by T cells was impaired. Boosting T cell-mediated immunity by live attenuated vaccine Mycobacterium bovis bacillus Calmette-Guérin or the adoptive transfer of mycobacteria-activated CD4(+) T lymphocytes had positive systemic effect, but failed to improve control of tuberculosis infection specifically in the lungs of the sst1(S) animals. Thus, in the mouse model of tuberculosis, a common genetic mechanism of innate immunity mediated control of tuberculosis progression in the lungs and the efficiency of antituberculosis vaccine. Our data suggest that in immunocompetent humans the development of pulmonary tuberculosis and the failure of the existing vaccine to protect against it, in some cases, may be explained by a similar defect in a conserved inducible NO synthase-independent mechanism of innate immunity, either inherited or acquired.


Assuntos
Vacina BCG/farmacologia , Movimento Celular/genética , Imunidade Inata/genética , Locos de Características Quantitativas/genética , Tuberculose Pulmonar/genética , Animais , Vacina BCG/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Cromossomos/genética , Cromossomos/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Imunidade Inata/efeitos dos fármacos , Listeria monocytogenes/imunologia , Listeriose/genética , Listeriose/imunologia , Listeriose/patologia , Camundongos , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Locos de Características Quantitativas/imunologia , Células Th1/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Vacinação
7.
Cancer Lett ; 255(2): 255-62, 2007 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-17562356

RESUMO

We have identified RAP80/UIMC1, the protein highly expressed in testis, as a new cancer-associated antigen. Sera from 5% to 10% of patients with different types of cancer contain specific antibodies to RAP80/UIMC1. In order to investigate the possible reasons for RAP80/UIMC1 immunogenicity, we characterized its numerous splice isoforms and mapped immunogenic regions of the protein. The majority of RAP80/UIMC1 transcripts was detected both in normal tissues and in colon tumors. There are several RAP80/UIMC1 isoforms that are predominantly expressed in testis, however we did not observe elevated expression of these transcripts in tumors from seropositive patients. We mapped the major immunogenic region of RAP80/UIMC1 to the central part of the protein encoded by exon 9 which is present in a number of ubiquitous splice forms. Thus, based on our data, autoreactivity to RAP80/UIMC1 is related to reasons other than overexpression or tumor-specific splicing.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias/imunologia , Proteínas Nucleares/metabolismo , Testículo/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Anticorpos Antineoplásicos/sangue , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteínas de Ligação a DNA , Mapeamento de Epitopos , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/metabolismo , Feminino , Chaperonas de Histonas , Humanos , Masculino , Dados de Sequência Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia
8.
Immunol Lett ; 100(1): 88-93, 2005 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16055198

RESUMO

Thymidylate synthase (TYMS), the critical enzyme for DNA synthesis and a target for chemotherapy, was recently characterized as an oncogene and a potential target for specific immunotherapy. Here we report TYMS-specific antibody response in a fraction of colon cancer patients. Humoral immune response to TYMS is induced by chemotherapy using TYMS inhibitors, such as 5-fluorouracil (5-FU), and may be associated with tumor burden. Therefore, TYMS may serve as a useful serological biomarker for monitoring the course of disease and treatment in cancer patients.


Assuntos
Anticorpos/sangue , Antimetabólitos Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/sangue , Neoplasias do Colo/sangue , Fluoruracila/administração & dosagem , Timidilato Sintase/imunologia , Anticorpos/imunologia , Biomarcadores Tumorais/imunologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Humanos , Monitorização Fisiológica/métodos , Carga Tumoral/efeitos dos fármacos
9.
Int J Cancer ; 117(5): 800-6, 2005 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-15981215

RESUMO

Antibodies to cancer antigens can often be detected in the sera of patients, although the mechanism of the underlying humoral immune response is poorly understood. Using immunoscreening of tumor-derived cDNA expression libraries (SEREX), we identified human histone deacetylase 3 (HDAC3) as serologically defined antigen in colon cancer. Closely related HDAC1 and HDAC2 do not elicit humoral response in colon cancer patients. We show that the C-terminal region of HDAC3 protein lacking the homology to other Class I HDAC contains at least 3 distinct B-cell epitopes that are recognized by the serum antibodies. HDAC3 in combination with other SEREX antigens may become a useful molecular biomarker with diagnostic or prognostic value for a subset of colon cancer patients.


Assuntos
Anticorpos Antineoplásicos/biossíntese , Neoplasias do Colo/enzimologia , Neoplasias do Colo/imunologia , Histona Desacetilases/química , Sequência de Aminoácidos , Linfócitos B/imunologia , Sequência de Bases , Western Blotting , Primers do DNA , Epitopos/imunologia , Histona Desacetilases/imunologia , Humanos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
10.
Nature ; 434(7034): 767-72, 2005 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-15815631

RESUMO

An estimated eight million people are infected each year with the pathogen Mycobacterium tuberculosis, and more than two million die annually. Yet only about 10% of those infected develop tuberculosis. Genetic variation within host populations is known to be significant in humans and animals, but the nature of genetic control of host resistance to tuberculosis remains poorly understood. Previously we mapped a new genetic locus on mouse chromosome 1, designated sst1 (for supersusceptibility to tuberculosis 1). Here we show that this locus mediates innate immunity in sst1 congenic mouse strains and identify a candidate gene, Intracellular pathogen resistance 1 (Ipr1), within the sst1 locus. The Ipr1 gene is upregulated in the sst1 resistant macrophages after activation and infection, but it is not expressed in the sst1 susceptible macrophages. Expression of the Ipr1 transgene in the sst1 susceptible macrophages limits the multiplication not only of M. tuberculosis but also of Listeria monocytogenes and switches a cell death pathway of the infected macrophages from necrosis to apoptosis. Our data indicate that the Ipr1 gene product might have a previously undocumented function in integrating signals generated by intracellular pathogens with mechanisms controlling innate immunity, cell death and pathogenesis.


Assuntos
Imunidade Inata/genética , Imunidade Inata/imunologia , Macrófagos/imunologia , Transativadores/genética , Transativadores/metabolismo , Tuberculose/genética , Tuberculose/imunologia , Animais , Animais Congênicos , Apoptose , Transplante de Medula Óssea , Progressão da Doença , Predisposição Genética para Doença/genética , Humanos , Interferon gama/imunologia , Listeria monocytogenes/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor , Dados de Sequência Molecular , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Necrose , Proteínas Nucleares/química , Proteínas Nucleares/genética , Polimorfismo Genético/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Taxa de Sobrevida , Transativadores/química , Transgenes/genética , Tuberculose/microbiologia , Tuberculose/patologia
11.
Immunol Lett ; 85(1): 71-4, 2003 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-12505200

RESUMO

Screening of expression cDNA libraries derived from human neoplasms with autologous sera (SEREX) is an established method for defining antigens immunogenic in individual cancer patients. Although the majority of SEREX-derived cDNA clones encode autoantigens, some of them represent shared cancer antigens with cancer-related serological profiles. Routine evaluation of multiple SEREX-derived clones in serological assays using panels of allogeneic sera from cancer patients is an important step towards defining disease parameters of diagnostic and prognostic significance. Here we show how the seroreactivity of multiple SEREX-derived antigens can be simultaneously evaluated using a rapid semi-quantitative protocol of allogeneic screening, which we call SMARTA (serological mini-arrays of recombinant tumor antigens).


Assuntos
Formação de Anticorpos/imunologia , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/imunologia , Testes Sorológicos/métodos , Anticorpos Antineoplásicos , Antígenos de Neoplasias/genética , Autoanticorpos , Clonagem Molecular , DNA Complementar , Perfilação da Expressão Gênica , Biblioteca Gênica , Humanos , Proteínas Recombinantes/imunologia
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