RESUMO
Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
Assuntos
Endotoxemia/genética , Endotoxemia/imunologia , Glicoproteínas de Membrana/fisiologia , Receptores de Interleucina-1/fisiologia , Seleção Genética , Choque Séptico/genética , Choque Séptico/imunologia , Alelos , Humanos , Imunidade Inata/genética , Leucina/genética , Glicoproteínas de Membrana/genética , Polimorfismo Genético , Receptores de Interleucina-1/genética , Serina/genéticaRESUMO
Between 2004 and 2006, 50 radical prostatectomies were performed in our department, 46 of them through a laparoscopic approach addressed to early stage cancer (T1a,b,c and T2a,b,c N0 M0). We present the case of a 63 year old patient, who was initially diagnosed with prostate cancer in T1bN0M0 stage, Gleason score 8 and later presented atypical hepatic and trocar site metastases. This particular evolution of the case can be explained by the high value of the Gleason score and by the extension into microvessels observed on the sample prelevated by prostatectomy. The rarity of this atypical metastases and its association, the diagnostic and therapy problems are the reasons for the detailed presentation of this case.
Assuntos
Adenocarcinoma , Carcinoma in Situ , Neoplasias Hepáticas/secundário , Neoplasias da Próstata , Neoplasias Cutâneas/secundário , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Carcinoma in Situ/patologia , Carcinoma in Situ/cirurgia , Seguimentos , Humanos , Laparoscopia , Fígado/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Próstata/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Instrumentos Cirúrgicos , Fatores de Tempo , Ressecção Transuretral da Próstata , UltrassonografiaRESUMO
Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.