Lupus erythematosus is a heterogeneous autoimmune condition affecting multiple organs including skin, which remains poorly understood. To investigate pathogenetic processes relevant to cutaneous lupus as compared to systemic disease, we generated genome-wide expression data from lesional and non-lesional skin of chronic cutaneous LE (CCLE) patients. We reveal LE skin-associated transcriptional profiles and identify prominent functional pathways. A subset of CCLE differentially expressed genes (DEGs) was found to overlap with systemic lupus, including those linked to interferon and apoptosis. We identified 13 skin associated transcriptional "hot spots" that represent activated chromosomal regions. Seventeen CCLE DEGs (eight within "hot spots") were found to overlap with previously reported SLE-associated susceptibility loci. Additionally, we identify chromosomal regions not previously associated with lupus, potentially harboring distinct susceptibility loci for CCLE. This study suggests that overlapping as well as distinct genetic factors underlie disease pathogenesis in systemic and cutaneous lupus.
To evaluate pathogenetic mechanisms underlying disease development and progression in the autoimmune skin disease Pemphigus vulgaris (PV), we examined global peripheral blood gene expression in patients and healthy controls. Our goals were to: (1) assign blood gene expression signatures to patients and controls; (2) identify differentially expressed genes (DEGs) and investigate functional pathways associated with these signatures; and (3) evaluate the distribution of DEGs across the genome to identify transcriptional 'hot spots'. Unbiased hierarchical clustering clearly separated patients from human leukocyte antigen (HLA)-matched controls (MCRs; 'disease' signature), and active from remittent patients ('activity' signature). DEGs associated with these signatures are involved in immune response, cytoskeletal reorganization, mitogen-activated protein kinase (MAPK) signaling, oxidation-reduction and apoptosis. We further found that MCRs carrying the PV-associated HLA risk alleles cluster distinctly from unmatched controls (UMCR) revealing an HLA-associated 'control' signature. A subset of DEGs within the 'control' signature overlap with the 'disease' signature, but are inversely regulated in MCR when compared with either PV patients or UMCR, suggesting the existence of a 'protection' signature in healthy individuals carrying the PV HLA genetic risk elements. Finally, we identified 19 transcriptional 'hot spots' across the signatures, which may guide future studies aimed at pinpointing disease risk genes.
Major gaps remain regarding pathogenetic mechanisms underlying clinical heterogeneity in lupus erythematosus (LE). As systemic changes are likely to underlie skin specific manifestation, we analyzed global gene expression in peripheral blood of a small cohort of chronic cutaneous LE (CCLE) patients and healthy individuals. Unbiased hierarchical clustering distinguished patients from controls revealing a "disease" based signature. Functional annotation of the differentially expressed genes (DEGs) highlight enrichment of interferon related immune response and apoptosis signatures, along with other key pathways. There is a 26% overlap of the blood and lesional skin transcriptional profile from a previous analysis by our group. We identified four transcriptional "hot spots" at chromosomal regions harboring statistically increased numbers of DEGs which offer prioritized potential loci for downstream fine mapping studies in the search for CCLE specific susceptibility loci. Additionally, we uncover evidence to support both shared and distinct mechanisms for cutaneous and systemic manifestations of lupus.
Pemphigus vulgaris (PV) is a rare blistering skin disorder characterized by the disadhesion of keratinocytes due to autoantibody attack against epidermal targets including desmoglein (Dsg) 3, Dsg 1 and possibly other adhesion and non-adhesion molecules. The mechanisms leading to immune-mediated pathology in PV are multifactorial and not fully understood. Recently, oxidative stress (antioxidant/oxidant disequilibrium) has been proposed as a contributory mechanism of autoimmune skin diseases, including PV. In this study, we directly assessed oxidative stress via measurement of total antioxidant capacity (TAC) using ELISA in 47 PV patients, 25 healthy controls and 18 bullous pemphigoid (BP) patients. We also performed microarray gene expression analysis on a separate set of 21 PV patients and 10 healthy controls to evaluate transcriptional dysregulation in oxidative stress-related pathways. Our data indicate that there is a significant reduction in TAC levels in PV patients compared with healthy controls, as well as BP patients. Furthermore, PV patients with active disease have significantly lower TAC levels than PV patients in remission. We also find that HLA allele status has a significant influence on oxidative stress. These findings are corroborated by microarray analysis showing differentially expressed genes involved in oxidative stress between the aforementioned groups. Collectively, our findings provide support for a role of oxidative stress in PV. Whether increased oxidative stress leads to disease manifestation and/or activity, or if disease activity leads to increased oxidative stress remains unknown. Future longitudinal studies may help to further elucidate the relationship between PV and oxidative stress.
Selective destruction of epidermal melanocytes is central to vitiligo (VL), a common acquired, autoimmune depigmentory disorder of the skin. Like other autoimmune diseases, the pathogenesis of VL is obscure and both multifactorial and polygenic. The prevailing theory is that VL may be part of an autoimmune diathesis. To evaluate mechanisms underlying disease development and progression, we studied genome-wide gene expression from lesional and non-lesional skin of patients with non-segmental VL. Unbiased clustering and principal components analyses reveals a 'lesional pathology'-based signature. Pathway-based analyses of the differentially expressed genes underscore processes such as melanocyte development and cell cycle as central drivers of the disease state. Interactome analysis identifies several key transcriptional regulators potentially affecting disease pathogenesis both within and 'hidden' from the data set. Finally, two genes within six identified transcriptional 'hot spots' coincide with previous VL-associated genetic elements. The remaining genes in the 'hot spots' offer an additional set of potential disease-linked loci that may help to guide future studies aimed at identifying disease risk genes.
BackgroundSignificant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state.MethodsWe undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy.ResultsUnsupervised clustering methods of the VL-blood dataset demonstrate a “disease-state”-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as “hidden” (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional “hot spot” that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets.ConclusionsWe examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address a major gap in knowledge regarding the systemic changes underlying skin-specific manifestation of vitiligo. Several transcriptional “hot spots” observed in both environments offer prioritized targets for identifying disease risk genes. Finally, within the transcriptional framework of VL, we identify five novel molecules (STAT1, PRKCD, PTPN6, MYC and FGFR2) that lend themselves to being targeted by drugs for future potential VL-therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3510-3) contains supplementary material, which is available to authorized users.
Lupus erythematosus is a chronic autoimmune disorder with a protean clinical manifestation affecting virtually every organ including skin, with tremendous variation between patients. This makes it vital to stratify patients on a molecular basis. We used gene microarray technology for large-scale screening combined with bioinformatics to investigate global patterns of gene expression in cutaneous lupus erythematosus to allow further insights into disease heterogeneity. Unbiased clustering exposed a clear separation between cutaneous lupus erythematosus skin and blood samples. Pathway-based analyses of the differentially expressed genes from sample groups within skin and blood showed prominent apoptosis and interferon response signals. Given their well-known role in systemic lupus, the two processes are potentially critical to cutaneous lupus erythematosus as well. We found both coincident and distinct features between systemic lupus and cutaneous lupus erythematosus, as well as several pathways and processes that are specific to the cutaneous disease that offer potential therapeutic choices in the future. Finally, we identified shared cutaneous lupus erythematosus-skin and -blood transcriptional "hot spots" located on the genome that include several differentially expressed genes previously associated with the systemic disease. The differentially expressed genes included in the hot spots with no systemic lupus associations can potentially be targeted in future studies aimed at identifying risk genes related to cutaneous disease.
We studied genome-wide gene expression from bald and haired scalp of individuals to evaluate pathogenic mechanisms underlying the development and progression of androgenetic alopecia (AGA). Unbiased analyses revealed a "bald pathology" based signature. Ontology enrichment analyses of the differentially expressed genes (DEGs) underscored apoptosis, cell proliferation, perturbed neurological pathways, and WNT signaling as central drivers of the hair loss process. Interactome analysis uncovered several known and novel key transcriptional regulators potentially affecting disease pathogenesis both within and "hidden" from the dataset. One DEG mapped within one of the fourteen identified transcriptionally active "hot spots" across the genome and coincided with a previous AGA-associated gene. The remaining DEGs within the "hot spots" offer an additional set of potential disease linked loci that may help to guide future studies aimed at identifying disease risk genes. Finally, we used in silico analyses to identify five molecular targets for exploration in future AGA therapies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.