TNF block haplotypes reveal diverse pathways between TNF and disease: Implications for understanding neuropathy in HIV patients

Abstract

The region spanning the tumor necrosis factor (TNF) cluster in the human major histocompatibility complex (MHC) has been implicated in susceptibility to numerous immunopathological and inflammatory diseases. However, strong linkage disequilibrium in the region creates conserved TNF block haplotypes; hampering identification of specific polymorphisms responsible for disease phenotypes. Here we review studies investigating TNF block haplotypes and their links with cytokine production and inflammatory disease risk.Recent work has done much to characterize TNF block haplotypes in different ethnicities and their associations with the larger overall structure of MHC ancestral haplotypes. There have also been studies examining the effects of TNF block haplotypes on levels of inflammatory cytokine production, with others investigating haplotype association with diseases risk. Carriage of specific TNF block haplotypes have been associated with increased risk of Type II Diabetes, Chronic Venous Leg Ulceration and Nucleoside Reverse Transcriptase-associated Sensory Neuropathy, all conditions where the underlying pathogenesis lies in a dysregulated inflammatory response. Despite this, no one haplotype was associated with susceptibility to all these diseases, inferring the TNF block region is involved in the multiple pathways of inflammatory dysregulation leading to disease phenotype.The central MHC on human chromosome 6 spans more than 700 kilobases of DNA and contains in excess of 60 genes, making it one of the most gene-dense regions in the human chromosome. A number of diseases, many of them immunopathological in character, have been associated with variations in MHC genes marked by alleles of the HLA loci. It is thought that whilst there are associations with the HLA class II region of the MHC there are also genes within the central MHC which act in conjunction with the class II genes to mediate susceptibility to these diseases. Some of the genes within the central MHC are well known and characterised. These include the complement genes, the heat shock protein 70 (HSP70) cluster and the tumour necrosis factor (TNF) cluster. Disease pathogenesis may most obviously be influenced by the gene encoding TNF-a.TNF-a confers both protection against infections, but is also implicated in pathological conditions, such as transplant rejection, septic shock, viral replication, rheumatoid arthritis, bacterial infections and Type 1 Diabetes Mellitus (T1DM) depending on the timing, localization and extent of release (reviewed in [1]). Hence anti-TNFa antibodies (Infliximab) are effective in treating rheumatoid arthritis and Crohn's disease [2], but promote more severe tuberculosis [3]. Inflammatory diseases such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and T1DM show a potential association with TNFa levels [4]. This pro-inflammatory cytokine is an essential component of inflammatory and immune responses, but may be harmful in excess.An interesting example is the 8.1 ancestral haplotype (AH) [HLA -A1, B8, TNFA-308*2, DR3, DQ2]. The broad spectrum of diseases affected by this haplotype [eg: IgA deficiency, T1DM, rapid HIV disease, inclusion body myositis, coeliac disease, myasthenia gravis, Graves disease] suggests it has non-specific immunomodulatory effects. Although the disorders are triggered by different genetic and environmental stimuli and have diverse manifestations, they all involve elevated levels of inflammatory mediators (eg: TNFa). However other diseases with an immunopathological basis associate with other TNF haplotypes [5].Unfortunately the precise gene(s) or polymorphism(s) responsible for these complex disease phenotypes remain unknown, because linkage disequilibrium (LD) creates conserved haplotypes within and across the MHC. Comparisons between haplotypes associated with a disease in multiple ethnic populations may narrow the list of candidate polymorphisms that warrant more detailed study. © 2012 by Nova Science Publishers, Inc. All rights reserved.