RESUMO
Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-ß, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.
Assuntos
Antígeno CD11b/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/imunologia , Receptores Toll-Like/imunologia , Animais , Antígeno CD11b/genética , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/imunologia , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/imunologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores Toll-Like/genéticaRESUMO
OBJECTIVE: To assess the frequency of constipation and its causative factors in 3 different populations, namely, the hospitalized patients admitted at Civil Hospital Karachi, their attendants and medical students. METHOD: A sample size of 200 was divided into 3 groups: hospitalized patients, their attendants and medical students. Frequency of constipation was expected to be greater in patients, so 100 subjects were taken from this population; while from the other 2 populations only 50 subjects were taken. The subjects were diagnosed as constipated on the basis of Rome III criteria for functional constipation and their dietary habits and physical activity were also assessed. RESULTS: The frequency of functional constipation was found to be 53% in hospitalized patients, 52% in their attendants and 34% in medical students. Among the constipated individuals, 50.94% of hospitalized patients, 46.15% of attendants and 29.41% of medical students took laxatives for relief of their symptoms. Constipation was most prevalent among the age group of 18 to 30 years in all the 3 populations. CONCLUSION: Constipation was fairly common in all 3 populations. Male to female ratio is almost equal. Physical inactivity and low fiber intake were prominent risk factors for constipation.
