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2.
Sci Rep ; 10(1): 4397, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32157175

RESUMO

Monocytes contribute to immune responses as a source for subsets of dendritic cells and macrophages. Human blood monocytes are classified as classical, non-classical and intermediate cells. However, the particular functions of these subsets have been hard to define, with conflicting results and significant overlaps. One likely reason for these ambiguities is in the heterogeneity of these monocyte subsets regrouping cells with divergent functions. To better define monocyte populations, we have analysed expression of 17 markers by multicolour flow cytometry in samples obtained from 28 control donors. Data acquisition was tailored to detect populations present at low frequencies. Our results reveal the existence of novel monocyte subsets detected as larger CD14+ cells that were CD16+ or CD16neg. These large monocytes differed from regular, smaller monocytes with respect to expression of various cell surface molecules, such as FcR, chemokine receptors, and adhesion molecules. Unsupervised multidimensional analysis confirmed the existence of large monocytes and revealed interindividual variations that were grouped according to unique patterns of expression of adhesion molecules CD62L, CD49d, and CD43. Distinct inflammatory responses to TLR agonists were found in small and large monocytes. Overall, refining the definition of monocyte subsets should lead to the identification of populations with specific functions.


Assuntos
Integrina alfa4/metabolismo , Selectina L/metabolismo , Leucossialina/metabolismo , Monócitos/metabolismo , Biomarcadores/metabolismo , Citometria de Fluxo , Proteínas Ligadas por GPI/metabolismo , Voluntários Saudáveis , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Fenótipo , Receptores de IgG/metabolismo , Aprendizado de Máquina não Supervisionado
3.
Acta Psychiatr Scand ; 138(5): 464-471, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29869414

RESUMO

OBJECTIVE: Bipolar Disorder (BD) is characterized by deregulated adaptive immune processes. Recent genome-wide association studies (GWAS) implicate the major histocompatibility complex (MHC) region in BD. The present study investigates the potential influence of variations in human leukocyte antigen (HLA) on BD risk and/or clinical presentations. This may have relevance to the dysregulated inflammatory processes commonly found in BD. METHOD: DNAs from 475 BD patients and 195 healthy controls (HC) were genotyped for classical HLA class I and II loci. RESULTS: We found that: (i) the HLA-A*02~B*44~DRB1*07 sub-haplotype is less prevalent in BD, vs. HC (pc = 2.4 × 10-2 ); (ii) the 57.1 and the 8.1-derived ancestral haplotypes i.e. HLA-A*02~B*57~Cw*06~DRB1*07~DQB1*09 and HLA-A*02~B*08~Cw*07 are associated with rapid cycling (pc = 1.9 × 10-3 and 1.05 × 10-2 , respectively); (iii) the 8.1AH-derived HLA class II-DRB*03~HLA-DQB1*02 sub-haplotype is more frequent in BD patients with a history of suicidal behaviors (pc = 2.1 × 10-2 ); and (iv) disease onset by an hypomanic episode or by psychotic symptoms are, respectively, more frequent in BD patients bearing the 7.1 AH-derived A*03~B*07~DRB1*15 sub-haplotype (pc = 8.5 × 10-3 ) and the HLA-A*02~B*07~DRB1*15 sub-haplotype (pc = 4.0 × 10-2 ). CONCLUSION: Corroborating the established link between these HLA haplotypes/sub haplotypes and common immune disorders, our findings suggest possible HLA-mediated proinflammatory processes operating in BD.


Assuntos
Transtorno Bipolar/genética , Antígenos HLA-A/genética , Antígenos de Histocompatibilidade Classe II/genética , Inflamação/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Int J Immunogenet ; 44(3): 114-121, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28374504

RESUMO

Nitric oxide synthase (NOS) catalyses the production of nitric oxide (NO) from L-Arginine, which participates in diverse biological processes including inflammation and apoptosis. Macrophages, chondrocytes, osteoblasts and osteoclasts express inducible NOS (iNOS) at the site of synovial inflammation. NO produced at the inflamed joint may contribute to peri-articular bone loss, mediate apoptosis and regulate Th1/Th2 balance in rheumatoid arthritis (RA). Variations in the promoter region of NOS gene regulate the nitric oxide synthase expression and iNOS (NOS2) polymorphisms have been associated with susceptibility to autoimmune disorders. Hence, this study was conducted to identify the possible contributions of NOS2 -1659G/A, -1026C/A, -277A/G promoter polymorphisms towards development of RA in South Indian Tamils. A total of 242 (219 females, 23 males) patients with RA (mean age 41.2 ± 10.9 years, disease duration 8.5 ± 4.3 years) and 279 age- and sex-matched healthy individuals of South Indian Tamil ethnicity were genotyped for NOS2 -1659C/T, -1026G/T and -277A/G promoter polymorphisms by TaqMan chemistry. Nature of disease (erosive or nonerosive), the presence of extra-articular manifestations, seropositivity for rheumatoid factor and anticyclic citrullinated peptide, serum C-reactive protein (CRP) level and response to therapy were assessed for all patients. The three single nucleotide polymorphisms (SNPs) were in Hardy-Weinberg equilibrium. The frequency of GG genotype and G allele of NOS2-277 was higher in patients (pc = 5.7 × 10-9 , OR = 6.09, 95% CI = 3.09-12.8 and pc = 4 × 10-13 , OR = 2.37, 95% CI = 2.06-3.62, respectively) compared to controls. Similarly, the frequency of NOS2-1026 (rs2779249) GT genotype and the T allele was higher in patients with RA (pc = .01, OR = 1.61, 95% CI = 1.09-2.36, and pc = .04, OR = 1.40, 95% CI = 1.02-1.91, respectively). However, no significant difference in frequency of NOS2-1659C/T polymorphism was observed between patients and controls. None of the studied SNPs were associated with erosive disease, seropositivity or extra-articular manifestations. The -277A/G and -1026 G/T promoter polymorphisms in iNOS may confer susceptibility to RA in South Indian Tamils.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença , Óxido Nítrico Sintase Tipo II/genética , Regiões Promotoras Genéticas , Adolescente , Adulto , Idoso , Alelos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Proteína C-Reativa , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Polimorfismo de Nucleotídeo Único
5.
Clin Exp Immunol ; 187(3): 369-375, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27783394

RESUMO

NKG2D (KLRK1) is a C-type lectin receptor present on natural killer (NK) cells, γδ, CD8+ and CD4+ T cells. Upon ligand binding, NKG2D mediates activatory and co-stimulatory signals to NK cells and activated CD4+ T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0·03, odds ratio (OR) = 2·44, 95% confidence interval (CI) = 1·09-5·98 and 10 versus 4%, Pc = 0·04, OR = 2·45, 95% CI = 1·05-6·39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0·03, OR = 0·41, 95% CI = 0·17-0·91 and Pc = 0·04, OR = 0·41, 95% CI = 0·16-0·96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G-C-A-G-A-T-C-C was higher in patients than in controls (12 versus 8%, P = 0·04, OR = 1·61, 95% CI = 1·01-2·55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Haplótipos/genética , Humanos , Lectinas Tipo C , Masculino , Pessoa de Meia-Idade , Razão de Chances , Adulto Jovem
6.
HLA ; 88(5): 253-258, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27753285

RESUMO

Rheumatoid arthritis (RA) is a complex multifactorial autoimmune disease characterized by inflammatory arthritis. The precise etiology and pathogenesis of RA remains elusive but evidence points towards stochastic interactions between genetic and environmental factors. This study investigated the distribution of human leucocyte antigen (HLA)-DRB1/DQB1 alleles in South Indian patients with rheumatoid arthritis (RA) and their influence on RA susceptibility and clinical phenotype. Low resolution HLA-DRB1 and -DQB1 typing was performed in 271 RA patients and 233 healthy controls by polymerase chain reaction (PCR) using sequence-specific primers (SSP). HLA-DRB1*10 was found to be more frequent in patients (Pc = 0.004, OR = 2.23, 95% CI = 1.5-3.34) than controls. This difference persisted in RF positive (Pc = 9 × 10-6 , OR = 2.45, 95% CI = 1.62-3.74), ACPA positive (Pc = 0.007, OR = 2.10, 95% CI = 1.35-3.29), ACPA negative (Pc = 0.001, OR = 2.45, 95% CI = 1.50-3.97) and both RF and ACPA positive subgroup of patients (Pc = 0.003, OR = 2.22, 95% CI = 1.41-3.51). On the contrary, the HLA-DRB1*13 (Pc = 0.01, OR = 0.43, 95% CI = 0.25-0.73) and HLA-DRB1*14 (Pc = 0.003, OR = 0.43, 95% CI = 0.26-0.69) alleles were over-represented in controls than patients. Further, distribution of the prominent Caucasian RA risk allele DRB1*04 did not differ between patients and controls in our study population. We did not find any association between DQB1 alleles and RA susceptibility or autoantibody status. The haplotypes DQB1*05-DRB1*10 (P = 6.8 × 10-6 , OR = 2.46, 95% CI = 1.63-3.79) and DQB1*06-DRB1*15 (P = 0.03, OR = 1.41, 95% CI = 1.02-1.96) were more frequent in patients while DQB1*05-DRB1*14 (P = 8.4 × 10-4 , OR = 0.44, 95% CI = 0.26-0.74) and DQB1*06-DRB1*13 (P = 9.5 × 10-4 , OR = 0.40, 95% CI = 0.21-0.72) were higher in controls. To conclude, HLA-DRB1*10 is associated with RA while HLA-DRB1*13 and HLA-DRB1*14 alleles confer protection in south Indian Tamils.


Assuntos
Alelos , Artrite Reumatoide/genética , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Polimorfismo de Nucleotídeo Único , Adulto , Artrite Reumatoide/etnologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Autoanticorpos/sangue , Autoanticorpos/genética , Estudos de Casos e Controles , Etnicidade , Feminino , Expressão Gênica , Frequência do Gene , Cadeias beta de HLA-DQ/imunologia , Cadeias HLA-DRB1/imunologia , Haplótipos , Teste de Histocompatibilidade , Humanos , Índia , Masculino , Pessoa de Meia-Idade
7.
Bone Marrow Transplant ; 51(5): 687-91, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26855158

RESUMO

Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade , Neoplasias/terapia , Doadores não Relacionados , Adulto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Pessoa de Meia-Idade , Neoplasias/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Imunologia de Transplantes , Resultado do Tratamento
8.
Am J Transplant ; 16(5): 1408-20, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26614587

RESUMO

Kidney transplantation is the most successful treatment option for patients with end-stage renal disease, and chronic antibody-mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA-DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab')2 fragment of HLA-DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL-6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt-dependent manner. We previously showed that HLA-DR-expressing ECs induce polarization of Th17 and FoxP3(bright) regulatory T cell (Treg) subsets. Preactivation of ECs with anti-HLA-DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL-6-dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA-DR alloantibodies selectively bound and increased EC secretion of IL-6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody-mediated endothelial damage independent of complement activation and FcR-expressing effector cells.


Assuntos
Endotélio Vascular/imunologia , Antígenos HLA-DR/imunologia , Isoanticorpos/imunologia , Leucócitos Mononucleares/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/citologia , Células Th17/imunologia , Células Cultivadas , Técnicas de Cocultura , Humanos , Interferon gama/metabolismo , Interleucina-6/metabolismo , Transplante de Rim , Linfócitos T Reguladores/imunologia , Transplante Homólogo
9.
Tissue Antigens ; 86(3): 155-62, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26206374

RESUMO

Stem cell (SC)-based therapies are a developing mean to repair, restore, maintain, or enhance organ functioning through life span. They are in particular a fast track to restore function in failing heart. Various types of SCs have been used in experimental and clinical studies showing the potential of these cells to revolutionize the treatment of heart diseases. Autologous cells have been privileged to overpass immunological barriers. The field has progressed tremendously and the hurdles, which have been largely overlooked in the excitement over the expected benefit the immunogenicity, have been revealed. Also, manufacturing of patient-specific clinical grade SC product, whether adult stem or reprogrammed induced pluripotent SCs, and the availability of these cells in sufficient amounts and status when needed is questionable. In contrast, adult SCs derived from healthy donors, thus allogeneic, have the advantage to be immediately available as an 'off-the-shelf' therapeutic product. The challenge is to overcome the immunological barriers to their transplantation. Recent research provided new insights into the mode of action and immune behavior of SCs in autologous as well as allogeneic settings. Lessons are learned and immune paradigms are changing: allogenicity, if balanced could be part of the dynamic and durable mechanisms that are critical to sustain cardiac regeneration and repair. We discuss the hurdles, lessons, and advances accomplished in the field through the progressive journey of cardiac-derived stem/progenitor cells toward allogeneic cardiac regenerative/reparative therapy.


Assuntos
Coração/fisiologia , Regeneração , Transplante de Células-Tronco , Insuficiência Cardíaca/terapia , Humanos , Imunomodulação , Pesquisa Translacional Biomédica , Transplante Homólogo
10.
Acta Psychiatr Scand ; 132(3): 218-25, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25939888

RESUMO

OBJECTIVE: Given the importance of nitric oxide system in oxidative stress, inflammation, neurotransmission and cerebrovascular tone regulation, we postulated its potential dysfunction in bipolar disorder (BD) and suicide. By simultaneously analysing variants of three isoforms of nitric oxide synthase (NOS) genes, we explored interindividual genetic liability to suicidal behaviour in BD. METHOD: A total of 536 patients with BD (DSM-IV) and 160 healthy controls were genotyped for functionally relevant NOS1, NOS2 and NOS3 polymorphisms. History of suicidal behaviour and violent suicide attempt was documented for 511 patients with BD. Chi-squared test was used to perform genetic association analyses and logistic regression to test for gene-gene interactions. RESULTS: NOS3 rs1799983 T homozygous state was associated with violent suicide attempts (26.4% vs. 10.8%, in patients and controls, P = 0.002, corrected P (Pc) = 0.004, OR: 2.96, 95% CI = 1.33-6.34), and this association was restricted to the early-onset BD subgroup (37.9% vs. 10.8%, in early-onset BD and controls, P = 0.0003, Pc = 0.0006 OR: 5.05, 95% CI: 1.95-12.45), while we found no association with BD per se and no gene-gene interactions. CONCLUSION: Our results bring further evidence for the potential involvement of endothelial NOS gene variants in susceptibility to suicidal behaviour. Future exploration of this pathway on larger cohort of suicidal behaviour is warranted.


Assuntos
Transtorno Bipolar/genética , Óxido Nítrico Sintase Tipo III/genética , Ideação Suicida , Adulto , Transtorno Bipolar/enzimologia , Transtorno Bipolar/psicologia , Feminino , Estudos de Associação Genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo II/genética , Polimorfismo de Nucleotídeo Único , Tentativa de Suicídio
11.
Tissue Antigens ; 85(3): 182-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25656292

RESUMO

The study was conducted to investigate the frequency of three gene polymorphisms in the 3'-untranslated region (3'-UTR) of human leucocyte antigen-G (HLA-G) gene in south Indian patients with rheumatoid arthritis (RA) and analyze their influence on disease susceptibility, phenotype and treatment response. HLA-G 14 bp insertion (Ins)/deletion (del) (rs66554220), HLA-G +3142G>C (rs1063320) and +3187A>G (rs9380142) polymorphism was analyzed in 221 RA patients and 200 healthy controls. Frequency of HLA-G genotypes or alleles did not differ between patients and controls. Analysis based on rheumatoid factor (RF) status revealed that the frequency of allele 'A' (rs9380142) was significantly higher in RF-positive than in RF-negative patients [84% vs 74%, Yates-corrected P value (Pc) = 0.04, odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.0-3.2]. A similar difference was maintained in RF-positive female patients than their RF-negative counterparts (83% vs 71%, Pc = 0.02, OR = 1.9, 95% CI = 1.0 to 3.4) and between RF-positive and RF-negative young onset RA (YORA) patients (84% vs 73%, Pc = 0.03, OR = 1.9, 95% CI = 1.0-3.2), suggesting that rs9380142 polymorphism influenced RF status. The 14 bp Ins allele of rs66554220 was significantly more prevalent in RF-positive YORA than in RF-positive late onset RA (LORA) patients (51% vs 25%, P = 0.03, OR = 3.1, 95% CI = 1.1-9.8). Frequency of the four major haplotypes [InsGA (48%), DelGA (22%), DelCG (18%), DelCA (9.7%)] observed did not differ between cases and controls. HLA-G does not appear to be a risk factor for development of RA in south Indian Tamils but may act as a genetic modifier of clinical phenotype in terms of autoantibody production, gender preference and age at disease onset.


Assuntos
Regiões 3' não Traduzidas , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Autoanticorpos/sangue , Antígenos HLA-G/genética , Polimorfismo Genético , Adulto , Idade de Início , Alelos , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Antígenos HLA-G/imunologia , Haplótipos , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/genética , Fator Reumatoide/imunologia , Fatores de Risco , Fatores Sexuais
12.
Tissue Antigens ; 84(5): 465-70, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25284481

RESUMO

Polymorphism of interferon regulatory factor 5 (IRF5), a latent transcription factor gene has been associated with various auto-immune diseases. Our aim was to study the IRF5rs2004640 gene polymorphism and its association with disease susceptibility, disease phenotype and treatment response in South Indian Tamil patients with rheumatoid arthritis (RA).The study was conducted on 217 RA patients fulfilling the American College of Rheumatology (ACR) 2010 criteria and 482 healthy controls (HCs) without family history of autoimmune disease. The IRF5rs2004640 genotyping was performed using a TaqMan 5' allelic discrimination assay. We found that the IRF5rs2004640T allele [P < 0.0001, odds ratio (OR) 3.25, 95% confidence interval (CI) 2.55-4.12] and TT genotype (P < 0.0001, OR 4.60, 95% CI 3.23-6.57) were significantly more frequent in RA patients as compared with HCs. No association was found between IRF5rs2004640 polymorphism, clinical manifestations, autoantibody profile and treatment response. IRF5rs2004640 T (mutant) allele may be a susceptibility factor conferring risk for RA in South Indian Tamils, whereas G allele (wild type) may be protective.


Assuntos
Alelos , Artrite Reumatoide/genética , Predisposição Genética para Doença , Fatores Reguladores de Interferon/genética , Polimorfismo de Nucleotídeo Único , Adulto , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/etnologia , Feminino , Seguimentos , Humanos , Índia/epidemiologia , Índia/etnologia , Masculino , Pessoa de Meia-Idade
13.
Clin Res Hepatol Gastroenterol ; 38(4): 499-504, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24679666

RESUMO

NOD2/CARD15 and IL23R gene variants play an important role in the susceptibility to Crohn's disease (CD). Studies of genotype-phenotype relationship suggest that these variants are associated with the development of the disease and specific phenotype. Preliminary reports analyzing the association between these variants have never been made on Algerian CD's. In a case-control design, 204 Algerian with CD diagnosed for at least 5years and 201 controls were included were genotyped for single nucleotide polymorphisms (SNP) in the NOD2/CARD15 gene R702W (SNP8, rs2066844), G908R (SNP12, rs2066845) and IL23R R381Q (rs11209026) gene variants were determined using the TaqMan SNP genotyping assays. NOD2/CARD15 908R was carried by 3% of the patients and none in control subjects (χ(2)=8.6, Pc=0.003, OR=13.20). NOD2/CARD15 702W was associated to CD outcome (χ(2)=17.2, Pc=0.00003, OR=12.5) and early onset of disease (group A1, χ(2)=19.3, Pc=1.10(-5), OR=14.05, PM-H=2.10(-6)). IL23R 381Q variants was more frequent in CD's patients than controls (χ(2)=8, Pc=0.005, OR=3.48), it was associated to earlier onset (group A1, χ(2)=7.1, Pc=0.007, OR=1.04, PM-H=0.002), extra-intestinal manifestations (EIM) outcome (χ(2)=10.6, Pc=0.001, OR=1.05, PM-H=0.002) and ileocolonic location (χ(2)=6.8, Pc=0.009, OR=1.05, PM-H=0.001). In this Algerian cohort, NOD2/CARD15 and IL23R variants were associated with CD's outcomes and linked to a particular clinical phenotype.


Assuntos
Doença de Crohn/genética , Variação Genética , Mutação , Proteína Adaptadora de Sinalização NOD2/genética , Receptores de Interleucina/genética , Adulto , Argélia , Estudos de Casos e Controles , Humanos
14.
Pharmacogenomics J ; 14(3): 281-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24322785

RESUMO

HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0-340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2-125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6-192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4-20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4-11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.


Assuntos
Carbamazepina/uso terapêutico , Antígenos HLA-A/genética , Pele/efeitos dos fármacos , Carbamazepina/efeitos adversos , Estudos de Coortes , Humanos
15.
Bone Marrow Transplant ; 49(1): 24-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23955634

RESUMO

HLA matching is a critical determinant of outcomes for patients who have undergone umbilical cord blood transplantation (UCBT). Data have been published on the importance of donor/recipient HLA mismatch direction on UCBT outcomes. HLA mismatch in the graft-versus-host (GVH) direction is defined as a donor homozygous at an HLA locus, while the recipient shares one HLA Ag with the donor. HLA mismatch in the host-versus-graft (HVG) direction is defined as a recipient homozygous with the donor sharing one HLA Ag. In our study we focused on confirming, using an independent population, whether transplantation outcomes would be different when HLA mismatch direction was considered. We analyzed 1565 patients who received a single-unit UCBT for malignant disease. Median age was 15 years and 72% of patients were transplanted for leukemia. In multivariate analysis, using the 5/6 HLA-matched population as reference, one or two HLA mismatches in the GVH or HVG direction were not associated with non-relapse related mortality and survival. On the basis of our results, there is no evidence to support a change in the current practice for cord blood unit selection.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Antígenos HLA/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Histocompatibilidade/imunologia , Adolescente , Adulto , Idoso , Plaquetas/citologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro , Antígenos HLA/química , Teste de Histocompatibilidade , Homozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neutrófilos/citologia , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
16.
Transl Psychiatry ; 2: e201, 2012 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-23212585

RESUMO

Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.


Assuntos
Transtorno Bipolar/virologia , Variações do Número de Cópias de DNA/genética , Retrovirus Endógenos/genética , Genes env/genética , Esquizofrenia/virologia , Toxoplasmose/sangue , Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Estudos de Casos e Controles , Retrovirus Endógenos/metabolismo , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esquizofrenia/sangue , Esquizofrenia/genética
17.
Clin Exp Immunol ; 169(1): 10-6, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22670773

RESUMO

Studies of multiple sclerosis (MS) have concentrated mainly on antigen presentation of peptides derived from the myelin sheath, while the implication of lipid antigen has been less explored in this pathology. As the extracellular environment regulates expression of the lipid antigen-presenting molecule CD1, we have examined whether sera from patients alters CD1 surface expression in monocyte-derived dendritic cells. We have shown that: (i) CD1 group 1 proteins were highly expressed in the presence of MS sera; (ii) sera from MS patients differentially regulated CD1 group 1 versus CD1 group 2 molecular expression; and (iii) CD1 was expressed strongly in monocytes from MS patients under immunosuppressive treatment. Overall, these results reveal that CD1 expression is modified in MS and provide novel information on the regulation of lipid antigen presentation in myeloid cells.


Assuntos
Apresentação de Antígeno , Antígenos CD1/biossíntese , Lipídeos/imunologia , Esclerose Múltipla/imunologia , Células Mieloides/imunologia , Adulto , Idoso , Células Dendríticas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia
18.
Risk Anal ; 32(7): 1122-38, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22443194

RESUMO

Through the use of case-control analyses and quantitative microbial risk assessment (QMRA), relative risks of transmission of cryptosporidiosis have been evaluated (recreational water exposure vs. drinking water consumption) for a Canadian community with higher than national rates of cryptosporidiosis. A QMRA was developed to assess the risk of Cryptosporidium infection through the consumption of municipally treated drinking water. Simulations were based on site-specific surface water contamination levels and drinking water treatment log10 reduction capacity for Cryptosporidium. Results suggested that the risk of Cryptosporidium infection via drinking water in the study community, assuming routine operation of the water treatment plant, was negligible (6 infections per 10¹³ persons per day--5th percentile: 2 infections per 10¹5 persons per day; 95th percentile: 3 infections per 10¹² persons per day). The risk is essentially nonexistent during optimized, routine treatment operations. The study community achieves between 7 and 9 log10 Cryptosporidium oocyst reduction through routine water treatment processes. Although these results do not preclude the need for constant vigilance by both water treatment and public health professionals in this community, they suggest that the cause of higher rates of cryptosporidiosis are more likely due to recreational water contact, or perhaps direct animal contact. QMRA can be successfully applied at the community level to identify data gaps, rank relative public health risks, and forecast future risk scenarios. It is most useful when performed in a collaborative way with local stakeholders, from beginning to end of the risk analysis paradigm.


Assuntos
Criptosporidiose/transmissão , Cryptosporidium/isolamento & purificação , Água Potável/parasitologia , Modelos Estatísticos , Medição de Risco/métodos , Animais , Estudos de Casos e Controles , Simulação por Computador , Criptosporidiose/epidemiologia , Criptosporidiose/parasitologia , Humanos , Ontário/epidemiologia , Oocistos/parasitologia , Contagem de Ovos de Parasitas , Recreação , Estações do Ano
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