RESUMO
The susceptibility to urinary tract infection (UTI) is controlled by the innate immune response and Toll like receptors (TLRs) are the sentinels of this response. If productive, TLR4 signalling may initiate the symptomatic disease process. In the absence of TLR4 signalling the infected host instead develops an asymptomatic carrier state. The activation of mucosal TLR4 is also influenced by the properties of the infecting strain, and pathogens use their virulence factors to trigger 'pathogen-specific' TLR4 responses in the urinary tract but do not respond to the asymptomatic carrier strains in patients with asymptomatic bacteriuria (ABU). The TLR4 dependence has been demonstrated in mice and the relevance of low TLR4 function for protection for human disease was recently confirmed in children with asymptomatic bacteriuria, who expressed less TLR4 than age matched controls. Functional chemokines and functional chemokine receptors are crucial for neutrophil recruitment, and for the neutrophil dependent bacterial clearance. Interleukin (IL)-8 receptor deficient mice develop acute septic infections and chronic tissue damage, due to aberrant neutrophil function. This mechanism is relevant for human UTI as pyelonephritis prone children express low levels of the human CXCL8 (Il-8) receptor, CXC chemokine receptor 1 (CXCR1) and often have heterozygous CXCR1 polymorphisms. This review illustrates how intimately the innate response and the susceptibility to UTI are linked and sophisticated recognition mechanisms that rely on microbial virulence and on host TLR4 and CXCR1 signalling.
Assuntos
Receptores de Interleucina-8A/genética , Receptores Toll-Like/genética , Infecções Urinárias/genética , Animais , Escherichia coli , Infecções por Escherichia coli/imunologia , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Receptores de Interleucina-8A/imunologia , Receptores de Interleucina-8A/metabolismo , Transdução de Sinais/fisiologia , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Sistema Urinário/imunologia , Infecções Urinárias/imunologia , Infecções Urinárias/microbiologiaRESUMO
The neoplastic cells of CLL are able to produce TNF which is known to stimulate the proliferation of CLL cells in an autocrine and paracrine manner. Genetic polymorphism of molecules of the TNF ligand superfamily has been described and certain alleles were suspected to predispose to variant biological responses. Previously, the rare allele TNFB*1 of the TNF-beta/lymphotoxin (LT)-alpha gene (NcoI, asparagine at amino acid position 26) was found to be associated with a stronger LT-alpha response of PBMC in vitro. We now report on a significant increase of the allele TNF1 (TNFA -308 G) of the TNF-alpha promoter/enhancer polymorphism in a group of 73 CLL patients when compared to healthy individuals (RR = 3.18, 95% confidence interval 1.57-8.3; P = 0.006). The allelic distribution of the TNF-beta/LT-alpha NcoI polymorphism did not differ significantly from randomized healthy controls. On the other hand, the frequency of the allele TNFB*2 was increased in CLL patients with advanced clinical stage (P = 0.004). These findings indicate immunogenetic associations involving polymorphisms of cytokine genes serving as paracrine and autocrine growth factors, which thus can contribute to the pathogenesis of the TNF/LT-sensitive haematological malignancy CLL.
Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Linfotoxina-alfa/genética , Polimorfismo Genético , Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Hairy cell leukaemia (HCL) is a rare chronic B lymphoproliferative disorder which can lead to severe pancytopenia and several immunologic abnormalities. The pathogenetic role of tumour necrosis factor (TNF)-alpha in HCL prompted us to study the potential contribution of functionally important genetic polymorphisms of the TNF gene cluster in a large group of patients with HCL. The TNF-alpha (-308 bp) promoter/enhancer point mutation and two polymorphisms located within the first intron of the lymphotoxin (LT)-alpha gene showed neither significant allelic deviation for the patient group nor, after analysis of clinical characteristics such as blood counts, stable or progressive disease or response to therapy.
Assuntos
Leucemia de Células Pilosas/genética , Linfotoxina-alfa/genética , Polimorfismo Genético , Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Alleles of the IL-1 genes are associated with several autoimmune and inflammatory diseases, where they tend to have a role in the severity of the disease rather than in susceptibility to the disease itself. Allele 2 of the variable number tandem repeat (VNTR) polymorphism in the IL-1 receptor antagonist (IL-1ra) gene was the first marker of the IL-1 cluster to be associated in this way with severity of chronic, systemic and local inflammatory diseases. Because of the role that IL-1 also plays in the pathobiology of certain hematopoietic disorders, we aimed at examining the allelic distribution of the IL-1ra VNTR in leukemias, lymphomas and related malignancies. While in patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), multiple myeloma (MM) and related disorders, primary acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and Hodgkin's disease (HD), the allelic distribution of IL-1RN was comparable to that seen in healthy control subjects, in a small group of patients with secondary AML the frequency of the IL-1RN*4 allele appeared to be significantly increased.