Associação de polimorfismos nas sequências regulatórias dos genes HLA-G, IL-10 e TNF e a sua respectiva expressão gênica em lesões de mucosa em pacientes portadores de doença inflamatória intestinal / Association of HLA-G, IL-10 and TNF regulatory sequence polymorphisms and respective gene expression in biopsies of Brazilian patients with Inflammatory Bowel Disease

Fatores genéticos e imunológicos foram associados à patogenese da doença inflamatória intestinal (DII), ela inclui Retocolite Ulcerativa Idiopática (RCUI) e doença de Crohn (CD). A hiperresponsividade de celulas B e a autoreatividade de células T contribuem para a polarização da resposta imune Th1 em CD e Th2 em RCUI. Sítios polimórficos na região 3'não traduzida do gene HLA-G (completa) e região promotora dos genes IL-10 ( - 1082A/G e - 819C/T) e TNF (completa) foram associados a susceptibilidade a diversas doenças. Estudamos 217 portadores de DII e 249 doadores saudáveis, pareados por sexo e idade. A ascendência africana foi maior em RCUI e caucasiana em DC (p =0,005). Comparados aos controles, o genótipo HLA - G 14bpINS - INS (associado com baixa expressão de HLA - G) (p =0,006) e IL - 10 - 1082G - G (associado com alta expressão de IL - 10) (p =0,030) foram menos frequentes em pacientes com DC, possivelmente contribuindo para a polarização Th1, mas não foram encontradas diferenças nas frequências de TNF. Em RCUI, as frequências do alelo HLA-G +3003C (p =0,015) e genótipo +3003C-T (p =0,003) estavam aumentadas. Apesar da alta frequência do alelo T em africanos, após estratifica rmos por ascendência, o genótipo +3003C - T ainda estava mais frequente em pacientes com ascendência africana (p =0,012)...

Genetic and immunological factors have been associated with inflammatory bowel disease (IBD) pathogenesis, encompassing ulcerative colitis (UC) and Crohn's disease (CD).B cell hyperresponsiveness and T cell auto-reactivity have contributedto a Th1 polarization immune response in CD and a Th2 polarization in UC. Sincepolymorphic sites at the 3’untranslated region (3’UTR)...

Association Between Toll-Like Receptors/CD14 Gene Polymorphisms and Inflammatory Bowel Disease in Korean Population

The innate immune response in patients who develop inflammatory bowel disease (IBD) may be abnormal. However, the exact role of Toll-like receptors (TLRs) / CD14 gene in the pathogenesis of IBD has not been fully elucidated. We aimed to investigate the association between polymorphisms of TLR1, 2, 4, 6, and CD14 gene and susceptibility to IBD in Korean population. A total 144 patients of IBD (99 patients with ulcerative colitis, 45 patients with Crohn's disease) and 178 healthy controls were enrolled. Using a PCR-RFLP, we evaluated mutations of TLR1 (Arg80Thr), TLR2 (Arg753Gln and Arg677Trp), TLR4 (Asp299Gly and Thr399Ile), TLR6 (Ser249Pro) genes and the -159 C/T promoter polymorphism of CD14 gene. No TLR polymorphisms were detected in Korean subjects. T allele and TT genotype frequencies of CD14 gene were significantly higher in IBD patients than in healthy controls. In subgroup analysis, T allelic frequency was higher in pancolitis phenotype of ulcerative colitis. In Korean population, the promoter polymorphism at -159 C/T of the CD14 gene is positively associated with IBD, both ulcerative colitis and Crohn's disease.

La mutación R92Q del gen TNFRSF1A se asocia con manifestaciones extra-intestinales en la enfermedad de Crohn / The TNFRSF1A gene R92Q mutation is associated with extra-intestinal manifestations of Crohn’s disease

It has been suggested that the R92Q mutation of the tumour necrosis factor receptor superfamily 1A (TNFRS1A) gene may be implicated in different inflammatory disorders. The aim of this study was to establish the role of this mutation as a determinant of Crohn`s disease (CD) susceptibility and/or clinical phenotype. One hundred and sixty-five CD patients and 203 healthy controls were prospectively included. The frequency of individuals carrying the R92Q mutation was similar between CD patients (4.24 percent) and controls (4.43 percent) (OR: 0.95; 95 percent CI = 0.34-2.62). In the genotype-phenotype evaluation, the univariate analysis showed that extra-intestinal manifestations were positively associated with the presence of R92Q mutation (p = 0.025; OR: 5.56; 95 percent CI = 1.04-29.6). In the multivariate analysis, presence of R92Q mutation was independently associated to extra-intestinal manifestations of CD, specially cutaneous manifestations (p = 0.02; OR: 5.17, 95 percent CI = 1.07-24.8). The R92Q mutation of TNFRSF1A gene is not a determinant of CD susceptibility, but contributes to the appearance of extra-intestinal manifestations of the disease.

Se ha sugerido que la mutación R92Q del gen de la super-familia del receptor del factor de necrosis tumoral 1A (TNFRS1A) podría estar relacionada con diversos trastornos inflamatorios. El objetivo de este estudio fue determinar el papel de esta mutación como factor determinante de la susceptibilidad y/o fenotipo clínico de la enfermedad de Crohn (EC). Ciento sesenta y cinco pacientes con EC y 203 controles sanos fueron incluidos de manera prospectiva. La frecuencia de individuos portadores de la mutación R92Q fue similar entre los pacientes con EC (4,24 por ciento) y los controles (4,43 por ciento) (OR: 0,95; 95 por ciento IC = 0,34-2,62). En la evaluación genotipo-fenotipo, el análisis univariado indicó que las manifestaciones extra-intestinales estaban relacionadas con la presencia de la mutación R92Q (p = 0,025; OR: 5,56; 95 por ciento IC = 1,04-29,6). En el análisis multivariado, la presencia de la mutación R92Q estuvo relacionada de manera independiente con las manifestaciones extra-intestinales de la EC, especialmente manifestaciones cutáneas (p = 0,02; OR: 5,17, 95 por ciento IC = 1,07-24,8). La mutación R92Q del gen TNFRSF1A no es un factor determinante de susceptibilidad a EC, pero contribuye a la aparición de manifestaciones extra-intestinales de la enfermedad.

Enfermedad inflamatoria intestinal: Una mirada inmunológica: [revisión] / Inflammatory bowel diseases: An immunological approach: [review]

Inflammatory bowel diseases (IBD) are inflammatory diseases with a multifactorial component that involve the intestinal tract. The two relevant IBD syndromes are Crohn's disease (CD) and ulcerative colitis (UC). One factor involved in IBD development is a genetic predisposition, associated to NOD2/CARD15 and Toll-like receptor 4 (TLR4) polymorphisms that might favor infectious enterocolitis that is possibly associated to the development of IBD. The identification of specific immunologic alterations in IBD and their relationship to the etiology of the disease is a relevant research topic. The role of intra and extracellular molecules, such as transcription factors and cytokines that are involved in the inflammatory response, needs to be understood. The relevance of immunologic molecules that might drive the immune response to a T helper (Th) 1, Th 2 or the recently described Th 17 phenotype, has been demonstrated in animal models and clinical studies with IBD patients. CD and UC predominantly behave with a Th 1 and Th 2 immune phenotype, respectively. Recently, an association between CD and Th 17 has been reported. The knowledge acquired from immunologic and molecular research will help to develop accurate diagnostic methods and efficient therapies.

Frequency of three common mutations of CARD15/NOD2 gene in Iranian IBD patients.

BACKGROUND: The CARD15/NOD2 gene, located on the pericentromeric region of chromosome 16 (IBD1) has been reported to have an association with IBD, especially Crohn's disease. Three common mutations of CARD15 are variably associated with Crohn's disease in different ethnic groups. We evaluated the frequency of these mutations (R702W, G908R and 1007fsinsC) in Iranian IBD patients and compared it with the healthy control population. METHODS: One hundred patients with ulcerative colitis, 40 patients with Crohn's disease, and 100 sex- and age-matched controls were enrolled from a tertiary center during a one-year period (2005-2006). The three mutations were assessed in DNA of leukocytes by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: The frequency of R702W mutation was significantly higher in Iranian patients with Crohn's disease (p< 0.001; OR 19.21; 95% CI 4.23-87.32) compared to healthy controls. No association was observed between the other mutations and Crohn's disease and none of these mutations was associated with ulcerative colitis. CONCLUSION: The R702W mutation of CARD15 gene was associated with Crohn's disease in the Iranian population.

Is C3435T Polymorphism of MDR1 Related to Inflammatory Bowel Disease or Colorectal Cancer in Korean? / 대한소화기학회지

BACKGROUND/AIMS: Multidrug resistance 1 (MDR1) gene encodes P-glycoprotein in intestinal epithelium, which serves as a transmembrane efflux pump of various toxins. mdr1 knockout mice develop spontaneous colitis under specific pathogen free conditions. However, it is unclear that C3435T polymorphism of MDR1 is related to ulcerative colitis. Other studies suggest MDR1 may have an important role in colorectal carcinogenesis. Thus, we evaluated whether MDR1 C3435T polymorphism is present in Korean and it is associated with inflammatory bowel disease or colorectal cancer. METHODS: The genotype distributions of the C3435T polymorphism were investigated by PCR-RFLP method in 94 patients with ulcerative colitis, 24 patients with Crohn's disease, 64 patients with colorectal cancer and each of gender-matched controls with equal numbers. RESULTS: There was no significant difference in frequencies of 3435T allele and 3435TT genotype between patients with ulcerative colitis and controls (p=0.443, p=0.194). No significant difference was present in frequencies of 3435T allele and 3435TT genotype between patients with Crohn's disease and controls (p=0.378, p=1.000). There was neither significant difference in frequencies nor 3435T allele or 3435TT genotype between patients with colorectal cancer and controls (p=0.250, p=0.211). C3435T genotype was not associated with the age of onset or other clinical characteristics in patients with ulcerative colitis, Crohn's disease or colorectal cancer. CONCLUSIONS: MDR1 C3435T polymorphism is also present in Korean and the dominant allele is C. However, there is no evidence that C3435T polymorphism of MDRI is associated to inflammatory bowel disease or colorectal cancer in Korean.

prevalence of HLA B27 in inflammatory bowel disease patients in Jordan

To find out the prevalence of Human Leucocyte Antigen B27 [HLA-B27] in inflammatory bowel disease patients in Jordan. Over the last year [2005] all inflammatory bowel disease [IBD] patients attending the gastroenterology outpatient clinic at King Hussein Medical Center[KHMC], were given a questionnaire asking them to report back pain and the characteristics of this pain. The first 60 patients to complain of inflammatory-type back pain [according to the European Spondyloarthropathy Study Group Criteria]; underwent a blood test to check for the presence of HLA-B27 in their blood. At the same time a comparable number of patients not suffering from IBD or any rheumatological disease, were checked for the presence of HLA-B27. Only five patients of the IBD group [4 females and 1 male] showed HLA-B27 positivity. Three patients had ulcerative colitis [UC] and 2 patients had Crohn's disease [CD]. Three of the patients in IBD group had active disease and were on steroids the other two were in remission and were on aminosalicylic acid [5-ASA] only. Three patients of the controlled group [all females] showed HLA-B2 positivity. Two of the patients in the IBD group were of European origin. It is concluded that HLA-B27 is no more common in IBD patients than in the general population of Jordan

El kininógeno de alto peso molecular: su participación en la respuesta inflamatoria y en la angiogénesis. Propiedades y posible aplicación terapéutica / High molecular weight kininogen in inflammation and angiogenesis: a review of its properties and therapeutic applications

The plasma kallikrein-kinin system (KKS) participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion and release of proteases. It has been shown that KKS activation in the systemic inflammatory response syndrome results in decrease of its component plasma proteins. Similar changes have been documented in diabetes, sepsis, children with vasculitis, allograft rejection, disseminated intravascular coagulation, patients with recurrent pregnancy losses, hereditary angioedema, adult respiratory distress syndrome and coronary artery disease. Direct involvement of the KKS in the pathogenesis of experimental acute arthritis and acute and chronic enterocolitis has been documented by previous studies from our laboratory using experimental animal models. It has been found that in HK deficient Lewis rats, experimental IBD was much less severe. We showed a genetic difference in kininogen structure between resistant Buffalo and susceptible Lewis rats, which results in accelerated cleavage of HK and it is responsible for the susceptibility to the inflammatory process in the Lewis rats. It has been demostrated that therapy with a specific plasma kallikrein inhibitor (P8720) modulated the experimental enterocolitis, arthritis and systemic inflammation. Furthermore, it has been shown that a bradykinin 2 receptor (B2R) antagonist attenuates the inflammatory changes in the same animal model. We have showed that a monoclonal antibody targeting HK decreases angiogénesis and arrests tumor growth in a syngeneic animal model. In summary, these results indicate that the plasma KKS plays a central role in the pathogenesis of chronic intestinal inflammation, arthritis and angiogenesis.

Se ha demostrado la participación del sistema plasmático de kalikreína-kininas (KKS) en el proceso inflamatorio, el cual incluye reacciones de daño celular, coagulación y fibrinólisis, formación de kininas, activación del complemento, secreción de citoquinas y liberación de proteasas. El KKS se encuentra activado en el síndrome de respuesta inflamatoria sistémica con una disminución en la concentración plasmática de las proteínas que lo constituyen. También se ha demostrado una activación similar en la diabetes, choque séptico, vasculitis en infantes, enfermedad injerto-huésped, coagulación intravascular diseminada, pacientes con abortos de repetición, angioedema hereditario, el síndrome de estrés respiratorio del adulto y enfermedad coronaria arterial. Mediante el uso de modelos animales experimentales, nuestro laboratorio ha demostrado una participación directa del KKS en la patogénesis de la artritis experimental aguda y la enterocolitis aguda y crónica. Se ha demostrado que en la rata tipo Lewis, cuando es deficiente de kininógeno de alto peso molecular (HK), la enfermedad inflamatoria intestinal es menos severa comparada con la presentada en ratas con niveles normales de HK como la Buffalo. Nosotros mostramos una diferencia entre el gene que codifica la molécula del kininógeno de la rata tipo Buffalo (resistentes) y Lewis (susceptibles), que resulta en un incremento de la actividad proteolítica de kalikreína sobre su substrato HK, lo cual predispone a las ratas Lewis al desarrollo de la enfermedad inflamatoria crónica. Se ha demostrado una disminución en las manifestaciones inflamatorias sistémicas de la enterocolitis y artritis experimental mediante el uso de un inhibidor específico de la kalikreína (P8720). Además, el antagonista del receptor 2 de la bradikinina (BR2) atenuó los cambios inflamatorios en el mismo modelo animal. Asimismo, se ha demostrado que las ratas Lewis deficientes de kininógeno desarrollaron inflamación intestinal sistémica menos severa. Mediante el uso del anticuerpo monoclonal C11C1 contra HK se logró una disminución de la angiogenesis y, consecuentemente, el crecimiento tumoral. En conclusión, los resultados demuestran que el sistema plasmático de KKS desempeña un papel preponderante en la patogénesis de la artritis reumatoide, la enfermedad intestinal crónica y en el proceso angiogénico.

Papel del sistema inmune en el desarrollo de las enfermedades inflamatorias intestinales / Role of the immune system in inflammatory bowel diseases development

Las enfermedades inflamatorias intestinales (EII), entre las que se incluyen a la enfermedad de Crohn (EC) y colitis ulcerosa (CU), son patologías de etiología multifactorial, en las cuales se ha demostrado en los últimos años que el componente genético tiene un papel relevante. La incidencia de estas patologías ha ido en aumento en los países desarrollados y también en Chile. A pesar de los avances en su estudio, la etiología de las EII no está totalmente esclarecida, aunque es posible reconocer factores genéticos, inmunológicos y ambientales en su patogénesis. Entre los posibles mecanismos propuestos la respuesta alterada a antígenos bacterianos cumpliría un papel relevante en un subgrupo de pacientes con EC quienes presentan alguna mutación en los receptores que reconocen patógenos. Esta revisión analiza avances recientes en el conocimiento de las EII y destaca los hallazgos relacionados con alteraciones en los componentes del sistema inmune gastrointestinal y su posible relación con la patogenia de las EII. Un análisis detallado de la interrelación entre los diferentes integrantes del sistema inmune de la mucosa intestinal, tales como las células dendríticas, epiteliales, de Paneth y los linfocitos T y su actividad defectuosa podría brindar nuevas herramientas para el diseño de estrategias experimentales y terapéuticas de las EII.