RESUMO
We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≥4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype.
Assuntos
Progressão da Doença , Genes MHC Classe I/genética , Infecções por HIV/genética , HIV-1 , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a DNA/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , RNA Longo não Codificante , RNA não Traduzido , Fatores de Tempo , Fatores de Transcrição/genéticaRESUMO
The interest into chemokine polymorphisms came with the discovery of allelic variants of HIV co-receptors (CCR5 and CXCR4 mainly) that confers protection against virus entry into usual permissive cells. Since then, chemokines genetic background has been deeply studied in order to find associations between allelic variants and inflammation-related diseases as well as infectious diseases. In addition to HIV infection, chemokines genetic variations have been involved in other infectious diseases as HCV, Malaria and West Nile Virus, and also in a variety of non-infectious diseases such as cancer, auto-immune and cardiovascular diseases. This review aims to present genetic variations in chemokines encoding genes and discuss their role, sometimes controversial, in a variety of diseases.
Assuntos
Quimiocinas/genética , Predisposição Genética para Doença , Receptores de Quimiocinas/genética , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Movimento Celular , Quimiocinas/imunologia , Humanos , Infecções/genética , Infecções/imunologia , Mediadores da Inflamação/imunologia , Leucócitos/imunologia , Neoplasias/genética , Neoplasias/imunologia , Polimorfismo Genético , Receptores de Quimiocinas/imunologiaRESUMO
Lymphocytes infected with the protozoan parasite Theileria parva are transformed to permanently proliferating cells, an event underlying the pathology of the disease. However, the molecular signalling mediating this process is complex and poorly understood. Here, we show that down-regulation of JNK signalling by transient over expression of a dominant-negative mutant of JNK (JNK-APF) significantly increases Annexin-V-phycoerythrin (V-PE) labelling on infected B cell populations observed using flow cytometry. To establish whether this increase was specifically due to apoptosis, we used a novel single-cell imaging method: micro-rotation (MR)-imaging, designed to allow high-resolution 3-dimensional imaging of single cells in suspension. With this method we visualized subcellular patterns of V-PE uptake and chromatin organization in lymphocytes co-transfected with JNK-APF and GFP-tagged histone-H2B. This single-cell approach allowed us to clearly reveal characteristic apoptotic phenotypes, whose patterns reflected progressive states of programmed cell death due to JNK down-regulation. Our results strongly suggest a role for JNK in the survival of Theileria-infected B cells, and demonstrate the powerful utility of a new and unique 3-dimensional imaging method for living cells in suspension.