Genetic Basis of DAF-12/Vitamin D Receptor (VDR) in Autoimmune Immunity, Autoimmune Diseases and Associated Cancers

Abstract

Copyright: © 2013 Zhang Y. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Along with ageing, there is an increased risk for autoimmune diseases and/or cancers and no one is sure what causes such outcome. The vitamin D supplementation in the management of patients with rheumatic diseases and its controversary [1]. Indeed, the beneficial effects of vitamin D on Autoimmune Diseases (ADs) and cancers remain uncertain [1,2]. However, for the presence/absence of Vitamin D Receptor (VDR) within muscle [1], VDR might be transiently stable, similar to nuclear hormone receptor DAF-12, most closely-related to vertebrate VDR in nematode Caenorhabditis elegans [3-5]; thus some findings may be inconsistent even exacerbated with different genetic backgrounds. DAF-12 has its involvement in ageing and longevity [6-8]. Currently, the Rheumatoid Arthritis (RA) therapy is with a failure of anti-TNF therapy alone, but a better inhibition of human Th17-mediated synovial inflammation has been obtained alongside 1,25(OH)2D3−an active vitamin D metabolite [5]. Interestingly, human Matrix Metallopeptidase 3 (MMP3) gets involved in this processing and its homologue H36L18.1 as direct target candidate of DAF-12//VDR [3]. The highly-conserved targets (e.g. MMP3) of DAF-12/VDR [3] may be extrapolated to have synergic functions with its other evolutionarily“fresh” targets (e.g. IL-6) [9,10]. Unless we truly understand such processes, some controversies may remain and precise therapies could hardly be developed to correct harmful cell behaviours in cancer or autoimmune diseases (ADs) [2,11]. Strikingly, one Genome-Wide Assocaition Study (GWAS) suggests that one allelic VDR variant may link to clinical autoimmune antibodies including anti-p150(TRIM33/ TIF-1γ)/p140(TRIM24/TIF-1α) [9], whose natural auto-antigens may be related to protein products encoded by TIF-1γ/α, their homologues flt-1 and nhl-2 as direct targets of DAF-12/VDR [3]. Our ChIP-chip screening for DAF-12/VDR target genes [3] actually revealed many overlaps with validated homologues identified in human VDR studies and significantly enriched near genes that are pathologically associated with ADs and cancer [12]. Further, genes near these DAF-12 binding sites include an extensive network of autophagy-related genes, interconnected microRNAs, longevity factors, genes homologous to cellular reprogramming and carcinogenesis in mammals [3,13], etc. (Figure 1, and Zhang Y, AR which may cause diseases such as myositis, RA (Figure 1, and Zhang Y, A&R, comments in preparation). Genetically and/or physically, most of these targets intertwine in functional clusters/networks. Moreover, DAF-12/VDR acts as a capacitor to buffer internal/external challenges via multiple regulatory systems [3]. As a functional equivalent, human VDR may buffer detrimental effects of mutations of its targets, i.e. compensate to such mutations and ensure normal health. Environmental fluctuations, such as vitamin D deficiency and/ or a lack of UVB, likely enhance weaker phenotypes of mutations from VDR targets in patients, such synergic effects eventually lead to ADs and/or cancer. Data are waiting for completely clarifying these issues, but we predict, dys-expression of a subset of human VDR targets may cause cell-attractors shift, break down robustness of health, thus lead to ADs and carcinogenesis [13,16] (Figure 1). Other VDR targets function in response to danger signals, including hmgb1/hmg-1.2, grp78/hsp-3, hsp90/daf-2 [3]. Finally, VDR malfunction may result in over-expressions of reprogramming factors such as c-myc [17], lin-28 [3], and reprogram cells to cancerous stemlike [13,16] and/or immunogenic [18].