Psoriasis Susceptibility Locus Research Articles

Genetic Validation of Psoriasis Phenotyping in UK Biobank Supports the Utility of Self-Reported Data and Composite Definitions for Large Genetic and Epidemiological Studies

Genetic Validation of Psoriasis Phenotyping in UK Biobank Supports the Utility of Self-Reported Data and Composite Definitions for Large Genetic and Epidemiological Studies

Role of tyrosine kinase 2 signals during progression of psoriasis

Psoriasis is a skin disease characterized by scaly erythema, parakeratosis, and epidermal hyperplasia. Application of imiquimod (IMQ), a ligand for Toll-like receptor 7, produces a mouse model for psoriasis. IMQ application induces scaling, erythema, and thickness in skin lesions, and the symptoms are milder in interleukin-23 p19 (Il23p19)-deficient and Il17a-deficient mice than in wild-type mice; this suggests that the interleukin-23 (IL-23)/T helper 17 (Th17) axis and Th17 cell-secreting cytokines play essential roles in the IMQ-induced psoriasis model. It is notable that a genome-wide association study identified the human tyrosine kinase 2 (TYK2) gene within the psoriasis susceptibility locus. After IMQ application, mice lacking Tyk2, a mouse homologue of the human TYK2 gene, exhibited significantly lower symptom scores of psoriasis and diminished inflammatory cell infiltration in the skin lesions. Tyk2-deficient mice also failed to increase CD4+IL-17+ or CD4+ interferon-γ+ (IFN-γ+) T cells in the draining lymph nodes or to produce Th17 cell-related cytokines after IMQ application. Furthermore, Tyk2 deficiency led to diminished skin inflammation induced by IL-23 and IL-22 injections. These results indicate that Tyk2-mediated signals in mice contribute to multiple steps of immune and inflammatory responses during the development of psoriasis; therefore, TYK2 targeting may be a promising strategy to treat patients with psoriasis. Recent clinical trials have shown that TYK2 inhibitors have a high overall response rate with good tolerability in the management of psoriasis. This review describes the fundamental mechanisms of Tyk2 inhibition in immune/inflammatory diseases.

Research Progress of Genomic Variation in Psoriasis

As a typical representative of global complex diseases, psoriasis has attracted widespread attention because of its high heritability, heterogeneity, and incidence. Environmentally induced activation of the inflammatory–immune axis in patients with psoriasis relies on genetic regulation of genomic variation. The heritability of psoriasis exceeds 80%, and research of genomic variation in psoriasis is of great significance to the interpretation of the biological pathogenesis of the disease. The development of genome-wide association studies (GWASs) has provided a powerful means for the capture of psoriasis susceptibility genes. More than 100 psoriasis susceptibility loci have been captured, enabling humans to gain a breakthrough understanding of the genetics and traits of psoriasis. With the advancement of research methods, increasingly more genetic methodologies are being used to capture the locations and types of variants outside the scope of GWAS scanning, making up for the inclinations and deficiencies of traditional GWAS capture of gene loci in a more detailed manner. This review covers several decades of research on genomic variation in psoriasis, including GWASs in psoriasis, the capture of functional gene variant types, and the translation of genomic variation into precision medicine; summarizes the research progress of genomic variation in psoriasis; and provides a theoretical reference for future genetic-based research of the mechanisms underlying psoriasis.

Diagnostic Test Accuracy of Genetic Tests in Diagnosing Psoriasis: A Systematic Review.

The pathogenesis of psoriasis involves the interaction of several environmental and genetic factors. Predicting the disease risk cannot depend on individual genetic alleles. Consequently, some studies have evaluated the use of genetic risk scores that combine several psoriasis susceptibility loci to increase the accuracy of predicting/diagnosing the disease. This meta-analysis summarizes the evidence regarding using genetic risk scores (GRS) in the diagnosis or prediction of psoriasis. A search of MEDLINE/PubMed, the Latin American Caribbean Health Sciences Literature (LILACS) database, Cochrane Library, Scopus, Web of Science, and ProQuest was conducted in July 2022. The primary objective was to record the area under the curve (AUC) for GRS of psoriasis. Secondary objectives included characteristics of studies and patients. The risk of bias (ROB) was assessed using the PROBAST tool. Five studies fulfilled the eligibility criteria of this review. None of the studies described the clinical criteria (reference standard) that were employed to diagnose psoriasis. The AUCs of the 11 GRS models ranged from 0.6029-0.8583 (median: 0.75). Marked heterogeneity was detected (Cochran Q: 1250.051, p < 0.001, and I2 index: 99.2%). So, pooling of the results of the included studies was not performed. The ROB was high for all studies and clinical application was not described. Genetic risk scores are promising tools for the prediction of psoriasis with fair to good accuracy. However, further research is required to identify the most accurate combination of loci and to validate the scores in variable ethnicities.

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a posttranslational regulator of the LDL receptor (LDLR). Recent studies have proposed a role for PCSK9 in regulating immune responses. Using RNA-Seq–based variant discovery, we identified a possible psoriasis-susceptibility locus at 1p32.3, located within PCSK9 (rs662145 C > T). This finding was verified in independently acquired genomic and RNA-Seq data sets. Single-cell RNA-Seq (scRNA-Seq) identified keratinocytes as the primary source of PCSK9 in human skin. PCSK9 expression, however, was not uniform across keratinocyte subpopulations. scRNA-Seq and IHC demonstrated an epidermal gradient of PCSK9, with expression being highest in basal and early spinous layer keratinocytes and lowest in granular layer keratinocytes. IL36G expression followed the opposite pattern, with expression highest in granular layer keratinocytes. PCSK9 siRNA knockdown experiments confirmed this inverse relationship between PCSK9 and IL36G expression. Other immune genes were also linked to PCSK9 expression, including IL27RA, IL1RL1, ISG20, and STX3. In both cultured keratinocytes and nonlesional human skin, homozygosity for PCSK9 SNP rs662145 C > T was associated with lower PCSK9 expression and higher IL36G expression, when compared with heterozygous skin or cell lines. Together, these results support PCSK9 as a psoriasis-susceptibility locus and establish a putative link between PCSK9 and inflammatory cytokine expression.

Psoriasis: An Immunogenetic Perspective.

Psoriasis is an erythematous-squamous dermatosis with a polygenic inheritance history. Both environmental and genetic factors play a role in the etiology of the disease. Over the past two decades, numerous linkage analyzes and genome-wide association studies have been conducted to investigate the role of genetic variation in disease pathogenesis and progression. To date, >70 psoriasis susceptibility loci have been identified, including HLA-Cw6, IL12B, IL23R, and LCE3B/3C. Some genetic markers are used in clinical diagnosis, prognosis, treatment, and personalized new drug development that can further explain the pathogenesis of psoriasis. This review summarizes the immunological mechanisms involved in the etiopathogenesis of psoriasis and recent advances in susceptibility genes and highlights new potential targets for therapeutic intervention.

200 Genome-wide analysis of long non-coding RNA expression profiles in keratinocytes from psoriasis skin

Psoriasis is a common, chronically relapsing inflammatory skin disease, affecting the patients’ life quality substantially. Psoriasis has a strong genetic background and a large number of genetic susceptibility loci have been identified. In psoriatic plaques, keratinocytes, the major cell type in the epidermis, undergo hyperproliferation and aberrant differentiation. The regulation of these processes in keratinocytes is not fully understood. Long non-coding RNAs are >200 nucleotide long transcripts, which do not code for protein but regulate other genes. Little is known about their involvement in epidermal alterations in psoriasis. In this study, we aimed to explore the potential contribution of long non-coding RNAs to epidermal alterations in psoriasis. In order to detect changes in the non- coding epidermal transcriptome, keratinocytes were sorted from skin biopsies collected from healthy skin of volunteers as well as from non-lesional and lesional skin of patients with psoriasis. Affymetrix Human Transcriptome Array 2.0 platform was used to identify differentially expressed lncRNAs. Microarray analysis identified 43 lncRNAs that were significantly up-regulated and 37 lncRNAs that were down-regulated in keratinocytes from psoriasis lesional skin as compared to healthy skin. 65 lncRNAs were deregulated in the lesional skin when compared with non-lesional skin. Analysis of overlap between the genomic loci coding for lncRNAs and known psoriasis susceptibility regions identified several lncRNAs, which are localized in genomic regions in the vicinity of known psoriasis susceptibility loci. We identified the LINC00958 as a lncRNA to be overexpressed in keratinocytes from psoriasis lesional skin, as compared with non-lesional and healthy skin. We have confirmed its overexpression in keratinocytes of psoriasis skin by qPCR and RNAscope in situ hybridization. Our results suggest that lncRNAs may contribute to epidermal dysfunction in psoriatic skin and that lncRNA modulation may be a novel treatment option for psoriasis in the future.

Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology.

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

Pediatric psoriasis induced by HLA-B46-Cw1 haplotype: A retrospective study of psoriasis onset after hematopoietic stem cell transplantation.

Genome-wide association studies have identified more than 60 susceptibility loci for psoriasis, highlighting the role of genetics in psoriasis development. Although the HLA region is suggested as the most prominent susceptibility locus, the role of the HLA haplotype in the development of psoriasis is unclear. The aim of this study is to investigate how HLA haplotype changes affect the onset of psoriasis and which HLA haplotypes are associated with the development of psoriasis. A longitudinal, retrospective case series study of children was conducted at Tohoku University Hospital in Japan, between November 1981 and October 2020. We evaluated a total of 378 pediatric patients who underwent hematopoietic stem cell transplantation in the Department of Pediatrics. The background of these patients and their HLA haplotypes before and after transplantation was assessed. Among the 378 cases, aged 0-22years old (median age 6) identified, 117 cases received autologous transplantation, 260 cases received allogeneic transplantation, and one case received syngeneic transplantation. Only two cases developed de novo psoriasis, and these cases had acquired HLA-B46-Cw1 after allogeneic transplantation. Others who had HLA-B46-Cw1 before and after allogeneic transplantation did not develop psoriasis. Our findings suggest that the HLA-B46 and HLA-Cw1 combination contributes to the development of psoriasis in this Asian population.

Single cell transcriptional zonation of human psoriasis skin identifies an alternative immunoregulatory axis conducted by skin resident cells

Psoriasis is the most common skin disease in adults. Current experimental and clinical evidences suggested the infiltrating immune cells could target local skin cells and thus induce psoriatic phenotype. However, recent studies indicated the existence of a potential feedback signaling loop from local resident skin cells to infiltrating immune cells. Here, we deconstructed the full-thickness human skins of both healthy donors and patients with psoriasis vulgaris at single cell transcriptional level, and further built a neural-network classifier to evaluate the evolutional conservation of skin cell types between mouse and human. Last, we systematically evaluated the intrinsic and intercellular molecular alterations of each cell type between healthy and psoriatic skin. Cross-checking with psoriasis susceptibility gene loci, cell-type based differential expression, and ligand-receptor communication revealed that the resident psoriatic skin cells including mesenchymal and epidermis cell types, which specifically harbored the target genes of psoriasis susceptibility loci, intensively evoked the expression of major histocompatibility complex (MHC) genes, upregulated interferon (INF), tumor necrosis factor (TNF) signalling and increased cytokine gene expression for primarily aiming the neighboring dendritic cells in psoriasis. The comprehensive exploration and pathological observation of psoriasis patient biopsies proposed an uncovered immunoregulatory axis from skin local resident cells to immune cells, thus provided a novel insight for psoriasis treatment. In addition, we published a user-friendly website to exhibit the transcriptional change of each cell type between healthy and psoriatic human skin.

005 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel psoriasis susceptibility locus

005 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a novel psoriasis susceptibility locus

Assay for Transposase-Accessible Chromatin Using Sequencing Analysis Reveals a Widespread Increase in Chromatin Accessibility in Psoriasis

Psoriasis is a complex chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and disordered immune response; however, its exact etiology remains unknown. To better understand the regulatory network underlying psoriasis, we explored the landscape of chromatin accessibility by assay for transposase-accessible chromatin using sequencing (ATAC-seq) on 15 psoriatic, 9 nonpsoriatic, and 19 normal skin tissues, and the chromatin accessibility data were integrated with genomic, epigenomic, and transcriptomic datasets. We identified 4,915 genomic regions that displayed differential accessibility in psoriatic samples compared with both nonpsoriatic and normal samples, nearly all of which exhibited increased accessibility in psoriatic skin tissue. These differentially accessible regions (DARs) tended to be more hypomethylated and correlated with the expression of their linked genes, which comprised several psoriasis susceptibility loci. Analyses of the DAR sequences showed that they were most highly enriched for FRA1/AP-1 transcription factor DNA-binding motifs. We also found that AIM2, which encodes an important inflammasome component that triggers skin inflammation, is a direct target of FRA1/AP-1. Our study provided clear insights and resources for an improved understanding of the pathogenesis of psoriasis. These disease-associated accessible regions might serve as therapeutic targets for psoriasis treatment in the future.

Identification of protein/mRNA network involving the PSORS1 locus gene CCHCR1 and the PSORS4 locus gene HAX1

CCHCR1 (Coiled-Coil alpha-Helical Rod 1), maps to chromosomal region 6p21.3, within the major psoriasis susceptibility locus PSORS1. CCHCR1 itself is a plausible psoriasis candidate gene, however its role in psoriasis pathogenesis remains unclear. We previously demonstrated that CCHCR1 protein acts as a cytoplasmic docking site for RNA polymerase II core subunit 3 (RPB3) in cycling cells, suggesting a role for CCHCR1 in vesicular trafficking between cellular compartments.Here, we report a novel interaction between CCHCR1 and the RNA binding protein HAX1. HAX1 maps to chromosomal region 1q21.3 within the PSORS4 locus and is over-expressed in psoriasis. Both CCHCR1 and HAX1 share subcellular co-localization with mitochondria, nuclei and cytoplasmic vesicles as P-bodies. By a series of ribonucleoprotein immunoprecipitation (RIP) assays, we isolated a pool of mRNAs complexed with HAX1 and/or CCHCR1 proteins. Among the mRNAs complexed with both CCHCR1 and HAX1 proteins, there are Vimentin mRNA, previously described to be bound by HAX1, and CAMP/LL37 mRNA, whose gene product is over-expressed in psoriasis.

Mapping DNA interaction landscapes in psoriasis susceptibility loci highlights KLF4 as a target gene in 9q31

BackgroundGenome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA and instead are enriched in cell type- and stimulation-specific gene regulatory regions.ResultsHere, we use a disease-focused Capture Hi-C (CHi-C) experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (> 500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis-associated enhancer upregulates KLF4 and its downstream targets, relevant to skin cells and apoptosis.ConclusionsThis approach utilises multiple functional genomic techniques to follow up GWAS-associated variants implicating relevant cell types and causal genes in each locus; these are vital next steps for the translation of genetic findings into clinical benefit.

Next-Generation Sequencing Identifies the Keratinocyte-Specific miRNA Signature of Psoriasis

Next-Generation Sequencing Identifies the Keratinocyte-Specific miRNA Signature of Psoriasis

Combining Understanding of Immunological Mechanisms and Genetic Variants Toward Development of Personalized Medicine for Psoriasis Patients.

Psoriasis is multifactorial disease with complex genetic predisposition. Recent advances in genetics and genomics analyses have provided many insights into the relationship between specific genetic predisposition and the immunopathological mechanisms driving psoriasis manifestation. Novel approaches which utilize array-based genotyping technologies such as genome-wide association studies and bioinformatics tools for transcriptomics analysis have identified single nucleotide polymorphisms, genes and pathways that are associated with psoriasis. The discovery of these psoriasis-associated susceptibility loci, autoimmune targets and altered signaling pathways have provided opportunities to bridge the gap of knowledge from sequence to consequence, allowing new therapeutic strategies for the treatment of psoriasis to be developed. Here, we discuss recent advances in the field by highlighting how immune functions associated with psoriasis susceptibility loci may contribute to disease pathogenesis in different populations. Understanding the genetic variations in psoriasis and how these may influence the immunological pathways to cause disease will contribute to the efforts in developing novel and targeted personalized therapies for psoriasis patients.

Investigation of Psoriasis Susceptibility Loci in Psoriatic Arthritis and a Generalized Pustular Psoriasis Cohort.

Psoriasis is a common skin disease affecting 1-3% of the population (Gelfand etal., 2005; Ferrándiz etal., 2001). Approximately 30% of patients with psoriasis develop psoriatic arthritis (PsA), an inflammatory arthritis associated with psoriasis (Haroon etal., 2013; Prey etal., 2010). Generalized pustular psoriasis (GPP) affects about 1.3% of psoriasis patients. Recently, numerous novel susceptibility loci for psoriasis vulgaris (PsV) have been discovered thorough the application of genome-wide association studies (GWASs). Among them, the major histocompability complex is the locus with the strongest effect. Outside the major histocompability complex region, the novel susceptibility loci of PsV can be incorporated into an integrated pathogenic model comprising distinct signaling networks affecting skin barrier function, innate immune responses involving NF-κB signaling, and adaptive immune responses involving CD8 T cells and IL-23/IL-17-mediated lymphocyte signaling. Compared with PsV, only three GWASs were performed in PsA (Ellinghaus etal., 2012; Hüffmeier etal., 2010; Stuart etal., 2015), accompanied with other candidate gene studies, most of the PsA susceptibility loci have been proved to be associated with PsV. However, the genetic study of GPP is quite different. Up to now, IL36RN is the only associated gene of GPP that has been widely verified. The data are based on homozygosity mapping and direct sequencing in consanguineous Tunisian multiplex families with autosomal recessive GPP (Marrakchi etal., 2011). Some researchers suggested that GPP and PsV are etiologically distinct clinical entities (Capon, 2013), challenging the traditional understanding of psoriasis. The percentages of IL36RN-negative patients have been reported to range from 51% (Li etal., 2013) to 84% (Setta-Kaffetzi etal., 2013), implying that additional risk loci, genetic interactions, and other factors may account for the other GPP cases. Recently, more than 10 GWASs of PsV have identified a number of susceptibility loci, making PsV GWASs a rich source of potential risk loci for other subtypes of psoriasis. Here, we use information emerging form PsV GWASs to make inferences about the genetic etiology of PsA and GPP in a Chinese population.

Expanded Genome-Wide Association Study Meta-Analysis of Psoriasis Expands the Catalog of Common Psoriasis-Associated Variants.

Psoriasis is a complex immune-mediated disease of skin and joints with a prevalence of about 2%. Previous genetic association studies have identified more than 60 psoriasis susceptibility loci, 47 of which were identified in Caucasians. To further understand the genetic architecture of this disease, we conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts (seven GWAS and one Immunochip dataset), with a combined effective sample size of more than 39,000 individuals. Approximately half (n= 22) of the 47 European-origin loci were identified in cohorts containing a large proportion (≥50%) of samples genotyped using the Immunochip (Bowes etal., 2015; Stuart etal., 2015; Tsoi etal., 2012a, 2015), a platform that focuses on genetic variants from promising signals identified in previous association studies of autoimmune diseases (Stuart etal., 2015). However, restricting analysis to markers genotyped (∼110,000) (Tsoi etal., 2012b) or well-imputed (∼700,000) (Tsoi etal., 2015) on the Immunochip limits exploration of the full genome for susceptibility loci.

Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease

The CARD: BCL10: MALT1 (CBM) complex is an essential signaling node for maintaining both innate and adaptive immune responses. CBM complex components have gained considerable interest due to the dramatic effects of associated mutations in causing severe lymphomas, immunodeficiencies, carcinomas and inflammatory disease. While MALT1 and BCL10 are ubiquitous proteins, the CARD-containing proteins differ in their tissue expression. CARD14 is primarily expressed in keratinocytes. The CARD14-BCL10-MALT1 complex is activated by upstream pathogen-associated molecular pattern-recognition in vitro, highlighting a potentially crucial role in innate immune defense at the epidermal barrier. Recent findings have demonstrated how CARD14 orchestrates activation of the NF-κB and MAPK signaling pathways via recruitment of BCL10 and MALT1, leading to the upregulation of pro-inflammatory genes encoding IL-36γ, IL-8, Ccl20 and anti-microbial peptides. Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus PSORS2, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders. Recent publications of mouse models also helped to better understand the physiological contribution of CARD14 to psoriasis pathogenesis. In this review, we summarize the clinical, genetic and functional aspects of human and murine CARD14 mutations and their contribution to psoriatic disease pathogenesis.

Human Leukocyte Antigen-Class I Alleles and the Autoreactive T Cell Response in Psoriasis Pathogenesis.

Psoriasis is a complex immune-mediated inflammatory skin disease characterized by T-cell-driven epidermal hyperplasia. It occurs on a strong genetic predisposition. The human leukocyte antigen (HLA)-class I allele HLA-C*06:02 on psoriasis susceptibility locus 1 (PSORS1 on 6p21.3) is the main psoriasis risk gene. Other HLA-class I alleles encoding HLA molecules presenting overlapping peptide repertoires show associations with psoriasis as well. Outside the major histocompatibility complex region, genome-wide association studies identified more than 60 psoriasis-associated common gene variants exerting only modest individual effects. They mainly refer to innate immune activation and the interleukin-23/Th/c17 pathway. Given their strong risk association, explaining the role of the HLA-risk alleles is essential for elucidating psoriasis pathogenesis. Psoriasis lesions develop upon epidermal infiltration, activation, and expansion of CD8+ T cells. The unbiased analysis of a paradigmatic Vα3S1/Vβ13S1-T-cell receptor from a pathogenic epidermal CD8+ T-cell clone of an HLA-C*06:02+ psoriasis patient had revealed that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation, and it identified a peptide form ADAMTS-like protein 5 as an HLA-C*06:02-presented melanocyte autoantigen. These data demonstrate that psoriasis is an autoimmune disease, where the predisposing HLA-class I alleles promote organ-specific inflammation through facilitating a T-cell response against a particular skin-specific cell population. This review discusses the role of HLA-class I alleles in the pathogenic psoriatic T-cell immune response. It concludes that as a principle of T-cell driven HLA-associated inflammatory diseases proinflammatory traits promote autoimmunity in the context of certain HLA molecules that present particular autoantigens.