RESUMO
Tumor necrosis factor (TNF) is a critical mediator of host defense against infection but may cause severe pathology when produced in excess. Individuals vary in the amount of TNF produced when their peripheral blood mononuclear cells are stimulated in vitro, and family studies indicate that much of this variability is genetically determined. Since the TNF response to infection is partly regulated at the transcriptional level, TNF promoter polymorphisms have been the subject of intense interest as potential determinants of disease susceptibility. A single nucleotide polymorphism at nucleotide -308 relative to the transcriptional start site has been associated with susceptibility to severe malaria, leishmaniasis, scarring trachoma, and lepromatous leprosy. Some experimental data indicate that this polymorphism acts to upregulate TNF transcription, but this remains controversial. Detailed analysis of multiple genetic markers at this locus and more sophisticated investigations of TNF transcriptional regulation, in different cell types and with a wide range of stimuli, are required to understand the molecular basis of these disease associations.
Assuntos
Predisposição Genética para Doença/genética , Variação Genética , Infecções/genética , Fator de Necrose Tumoral alfa/genética , Estudos de Casos e Controles , Regulação da Expressão Gênica , Frequência do Gene , Ligação Genética , Genótipo , Infecções por HIV/genética , Antígeno HLA-DR3/genética , Humanos , Infecções/metabolismo , Leishmaniose Mucocutânea/genética , Hanseníase/genética , Linfotoxina-alfa/genética , Complexo Principal de Histocompatibilidade/genética , Malária/genética , Complicações Pós-Operatórias , Sepse/genética , Transcrição Gênica , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
Genetically determined differences in immune responses to environmental agents may underlie susceptibility to many autoimmune and infectious diseases. Leprosy provides an example of a polarity in the type of immune response made to an infectious agent, and there is evidence that the major histocompatibility complex is genetically linked to leprosy type. It was found that HLA-DR2 is associated with both tuberculoid and lepromatous types of leprosy; however, a variant at position -308 of the promoter of the neighboring tumor necrosis factor (TNF) gene was increased in frequency in lepromatous (odds ratio = 3.0, P = .02) but not tuberculoid leprosy. Some studies have found higher serum levels of TNF in lepromatous than tuberculoid leprosy, and high TNF levels are found in malaria and leishmaniasis, which are also associated with this TNF allele. It is speculated that this association reflects genetic variability in cytokine production, which influences the immune response to and clinical outcome of leprosy.