RESUMO
Due to their increasing rates of morbidity and mortality, childhood malignancies are considered a global health priority, with acute lymphoblastic leukemias (ALLs) showing the highest incidence worldwide. Control of malignant clone emergence and the subsequent normal-leukemic hematopoietic cell out-competition require antitumor monitoring mechanisms. Investigation of cancer surveillance innate cells may be critical to understand the mechanisms contributing in either disease progression or relapse, and to promote displacement of leukemic hematopoiesis by the normal counterpart. We report here that NK cell production is less and low hematopoietic progenitor numbers contribute to this defect. By investigating the expression of the activation molecule class I restricted T-cell associated molecule (CRTAM) along the hematopoietic lineage differentiation pathway, we have identified lymphoid precursor populations coexpressing CD34, CD56/CD3/CD19, and CRTAM as the earliest developmental stage where activation may take place in specialized niches that display the ligand nectin-like-2. Of note, bone marrow (BM) from patients with ALL revealed high contents of preactivated CD56high NK cells expressing CRTAM and endowed with an exhaustion-like phenotype and the functional capability of producing IL-10 and TGF-ß in vitro. Our findings suggest, for the first time, that the tumor microenvironment in ALL directly contribute to exhaustion of NK cell functions by the CRTAM/Necl-2 interaction, and that the potential regulatory role of exhausted-like NK cells may favor malignant progression at the expense of anti-tumor responses. Phenotypic and functional identity of this unique suppressor-like NK cell population within the leukemic BM would be of special interest for the pathobiology of ALL and development of targeting strategies.
Assuntos
Medula Óssea/imunologia , Molécula 1 de Adesão Celular/genética , Proteínas da Matriz Extracelular/genética , Células Matadoras Naturais/imunologia , Chaperonas Moleculares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Microambiente Tumoral/imunologia , Antígenos CD/genética , Antígenos CD/imunologia , Medula Óssea/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Molécula 1 de Adesão Celular/imunologia , Diferenciação Celular , Criança , Técnicas de Cocultura , Citotoxicidade Imunológica , Proteínas da Matriz Extracelular/imunologia , Regulação da Expressão Gênica , Humanos , Vigilância Imunológica , Imunofenotipagem , Interleucina-10/genética , Interleucina-10/imunologia , Células K562 , Células Matadoras Naturais/patologia , Ativação Linfocitária , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , Chaperonas Moleculares/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Cultura Primária de Células , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia , Microambiente Tumoral/genéticaRESUMO
Molecular chaperones (or heat shock proteins) are evolutionarily conserved and essential proteins that play a key role in cell survival through cytoprotective mechanisms. Despite their possible clinical applications, the understanding of these structures is still quite limited. The aim of the present study is to review the literature to understand the physiological importance, implication in various diseases (especially in cancer and neurodegenerative diseases), possible applicability, and future prospects of heat shock proteins. The cytoprotective mechanisms of molecular chaperones can be co-opted by oncogenic processes favoring tumor growth, invasion, evasion of apoptosis, and metastasis, thus making inhibitors to these molecules possible therapeutic options for cancer patients. However, there is also evidence showing that upregulation of heat shock proteins can have an antineoplastic effect through immunomodulatory activity. This is why chaperones have already been investigated for conventional chemotherapy under specific conditions, yielding interesting results. The induction of heat shock protein activity is also of potential benefit in many other diseases where structural and functional preservation of proteins may enhance cell survival, including neurodegeneration, trauma, stroke, and cardiovascular disease. In addition, the immune properties of chaperones can potentially be exploited for such diseases as diabetes, atherosclerosis, and other chronic inflammatory conditions. Thus, continuing efforts to clarify the role of chaperones may guide the development of new therapeutic modalities capable of minimizing the impact of diseases such as cancer, heart disease, and diabetes as well as obtaining better results in neurological conditions currently lacking alternative treatments.
Assuntos
Chaperonas Moleculares/fisiologia , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/imunologia , Proteínas de Choque Térmico/fisiologia , Humanos , Chaperonas Moleculares/antagonistas & inibidores , Chaperonas Moleculares/biossíntese , Chaperonas Moleculares/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/metabolismo , Dobramento de ProteínaRESUMO
Chaperone production is an essential step for proper folding of certain proteins. Accumulation of misfolded/unfolded proteins within the endoplasmic reticulum (ER) lumen triggers a signalling pathway named unfolded protein response (UPR). Upon activation, the UPR pathway augments transcription of ER chaperones increasing protein folding, decreases protein translation to ameliorate the ER overload, increases protein degradation, and activates the apoptotic programme if all previous measures fail. In this review, we will cover the chaperones involved in folding of proteins related to the immune response, followed by an overview of the UPR pathway. Lastly, we will discuss data from this last decade that demonstrate how the improper activation of the UPR pathway has been uncovered as a mechanism responsible for failure to mount a proper immune response, both innate and adaptive.
Assuntos
Linfócitos B/imunologia , Retículo Endoplasmático/imunologia , Imunidade Inata/imunologia , Chaperonas Moleculares/imunologia , Resposta a Proteínas não Dobradas/imunologia , Animais , Humanos , Modelos Imunológicos , Dobramento de ProteínaRESUMO
Rheumatic fever (RF) is a post-infectious autoimmune disease due to sequel of group A streptococcus (GAS) pharyngitis. Rheumatic heart disease (RHD), the major manifestation of RF, is characterized by inflammation of heart valves and myocardium. Molecular mimicry between GAS antigens and host proteins has been shown at B and T cell level. However the identification of the autoantigens recognized by B and T cells within the inflammatory microenvironment of heart tissue in patients with RHD is still incompletely elucidated. In the present study, we used two-dimensional gel electrophoresis (2-DE) and mass spectrometry to identify valvular tissue proteins target of T cells from chronic RHD patients. We could identify three proteins recognized by heart infiltrating and peripheral T cells as protein disulfide isomerase ER-60 precursor (PDIA3), 78kD glucose-regulated protein precursor (HSPA5) and vimentin, with coverage of 45%, 43 and 34%, respectively. These proteins were recognized in a proliferation assay by peripheral and heart infiltrating T cells from RHD patients suggesting that they may be involved in the autoimmune reactions that leads to valve damage. We also observed that several other proteins isolated by 2-DE but not identified by mass spectrometry were also recognized by T cells. The identified cardiac proteins are likely relevant antigens involved in T cell-mediated autoimmune responses in RF/RHD that may contribute to the development of RHD.
Assuntos
Proteínas de Choque Térmico/imunologia , Valva Mitral/imunologia , Chaperonas Moleculares/imunologia , Isomerases de Dissulfetos de Proteínas/imunologia , Cardiopatia Reumática/imunologia , Linfócitos T/imunologia , Vimentina/imunologia , Western Blotting , Doença Crônica , Eletroforese em Gel Bidimensional , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/sangue , Proteínas de Choque Térmico/genética , Humanos , Ativação Linfocitária , Espectrometria de Massas , Valva Mitral/química , Chaperonas Moleculares/sangue , Chaperonas Moleculares/genética , Isomerases de Dissulfetos de Proteínas/sangue , Isomerases de Dissulfetos de Proteínas/genética , Proteômica , Vimentina/sangue , Vimentina/genéticaRESUMO
BACKGROUND INFORMATION: Toxoplasma gondii is among the most successful parasites, with nearly half of the human population chronically infected. T. gondii has five sHsps [small Hsps (heat-shock proteins)] located in different subcellular compartments. Among them, Hsp20 showed to be localized at the periphery of the parasite body. sHsps are widespread, constituting the most poorly conserved family of molecular chaperones. The presence of sHsps in membrane structures is unusual. RESULTS: The localization of Hsp20 was further analysed using high-resolution fluorescent light microscopy as well as electron microscopy, which revealed that Hsp20 is associated with the outer surface of the IMC (inner membrane complex), in a set of discontinuous stripes following the same spiralling trajectories as the subpellicular microtubules. The detergent extraction profile of Hsp20 was similar to that of GAP45 [45 kDa GAP (gliding-associated protein)], a glideosome protein associated with the IMC, but was different from that of IMC1 protein. Although we were unable to detect interacting protein partners of Hsp20 either in normal or stressed tachyzoites, an interaction of Hsp20 with phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate phospholipids could be observed. CONCLUSIONS: Hsp20 was shown to be associated with a specialized membranous structure of the parasite, the IMC. This discontinuous striped-arrangement is unique in T. gondii, indicating that the topology of the outer leaflet of the IMC is not homogeneous.