The immunogenetics of Psoriasis: A comprehensive review.
Journal: 2016/August - Journal of Autoimmunity
ISSN: 1095-9157
Abstract:
Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL, TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN, SOCS1). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. However, many of the genetic findings involve immune genes with less clear roles in psoriasis pathogenesis. This is particularly the case for those genes involved in innate immunity and negative regulation of immune specific pathways. It is possible that risk alleles of these genes decrease the threshold for the initial activation of the innate immune response. This could then lead to the onslaught of the pathogenic adaptive immune response known to be active in psoriatic skin. However, precisely how these various genes affect immunobiology need to be determined and some are speculated upon in this review. These novel genetic findings also open opportunities to explore novel therapeutic targets and potentially the development of personalized medicine, as well as discover new biology of human skin disease.
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J Autoimmun 64: 66-73

The Immunogenetics of Psoriasis: A Comprehensive Review

1. Introduction

Psoriasis is a chronic, inflammatory skin disease, characterized by raised, red scaly plaques [1]. This disease affect affects about 2-3% of the world-wide population, although it is more prevalent in American, Canadian, and European populations [2]. Psoriasis is also associated with several comorbidities, suggesting that the underlying pathogenesis of the disease is more than “skin deep” [3].

Psoriasis arises through chronic interactions between hyper-proliferative keratinocytes and infiltrating, activated immune cells. Initially, psoriasis was considered solely to be due to dysfunction of limiting keratinocyte proliferation [4]. Infiltration of immune cells was noticed, but not considered to be key in pathogenesis, but rather just a consequence of the hyper-proliferating keratinocytes. However, the critical role of the immune system in psoriasis pathogenesis was discovered when administration of immune suppressive agents, such as cyclosporine, denileukin diftitox, and alefacept, proved successful in ameliorating disease [5-8]. Over the next several years, the cellular and molecular contributions to the overactive immune response were further elucidated. It was found that T-cells, particularly those with Th1 and Th17 polarization, are heavily present in psoriatic lesions [1, 9]. Additionally, TNFα and iNOS producing inflammatory DCs (TIP-DCs), massively infiltrate psoriatic skin, and these TIP-DCs have the ability to polarize T-cells to Th1 and Th17 fates [4, 10, 11]. Lastly, psoriatic skin is infiltrated by a myriad of other immune cells including macrophages and innate immune cells, as well as an increased amount of endothelial cells (angiogenesis); these other cell types may certainly also play a role in psoriasis pathogenesis [1].

Similar to other autoimmune diseases, the genetics of psoriasis is complex and multifactorial. There is clear evidence of an important genetic component to psoriasis. This is supported by both twin and family studies [12]. The concordance rate of monozygotic twins is approximately 70% and for dizygotic twins is about 20% [13].

Areas of chromosomes which were thought to harbor psoriasis genes were initially entitled PSORS (psoriasis-susceptibility) loci. There are at least 12 different PSORS loci that were mainly identified through linkage analysis of multiply affected psoriasis families [1]. However, the gene or gene(s) for most PSORS loci that are responsible for susceptibility is not known. In recent years, our understanding of psoriasis pathogenesis has been enriched by genome-wide association studies (GWAS) where large cohorts of psoriasis cases and matched controls have been typed for single nucleotide polymorphisms (SNPs) and tested for a statistically significant excess of one SNP allele in cases versus controls. These studies have revealed over 50 regions associated with psoriasis risk and within some of these regions there is more than one independent susceptibility factor. In all of these studies, a dominant function of a significant percentage of these genes is related to the immune system. Here we summarize what is currently known about the immunogenetics of psoriasis pathogenesis.

2. Antigen presentation

The first gene that was discovered to be significantly associated with psoriasis susceptibility was HLA-Cw6, which is located at PSORS1 at chromosomal position 6p21.3 [13, 14]. HLA-Cw6 is found in about 4-16% of healthy controls [15] and in about 20%-to over 50% of psoriasis cases, depending on the population being studied. HLA-Cw6 encodes a major histocompatibility complex I (MHCI) allele. MHCI molecules are present on almost all nucleated cells and are key molecules for immune surveillance since they present intracellular peptides (both self and non-self peptides) to the immune system. MHCI is also critical for CD8+ T-cells priming and subsequent cytolytic targeting of cells. This finding supported the important role of T-cells in the pathogenesis of psoriasis.

HLA-Cw6 is not the only antigen presentation associated molecule associated with psoriasis. A recent GWAS also revealed a role of the ERAP1 loci in and this was enriched in individuals carrying the HLA-Cw6 mutation [16, 17]. ERAP1 (endoplasmic reticulum aminopeptidase 1) plays a role in processing of peptides for loading onto MHC class I. Due to these associations, it could be postulated that psoriasis is caused by a T-cell mediated reaction to an auto-antigen, one that is most easily presented on HLA-Cw6 and via processing by particular mutations in ERAP1. Additionally, ERAP2 is also a likely candidate gene of a PSORS locus at chromosomal position 5q15 [18]. However, despite these associations of psoriasis with the MHCI allele HLA-Cw6 and MHCI processing enzymes, we still do not have a confirmed “auto-antigen”. Additionally, it has been determined through deep sequencing of the T-cell repertoire that the T-cell infiltrate is highly polyclonal, and is not dominated by a heavy clonal expansion of a particular T-cell responding to a specific epitope (JLH and JGK, unpublished results).

Although more related to the innate immune response, MICA (MHC class I polypeptide-related sequence A) is also associated with psoriasis [19]. Expression of MICA is thought to mainly be stress-induced and is a ligand for NKG2D, an activating receptor found on natural killer (NK) cells, NKT-cells, and T-cells [20]. Although the exact role of NK and NKTs cells in psoriasis have not been thoroughly explored, these innate immune cells can make several inflammatory cytokines that are known to be increased in psoriasis lesions, such as TNFα, IFNγ, and IL-22.

3. The IL12/23 axis

As a specific auto-antigen in psoriasis proved troubling to identify, attention turned to elucidation of exactly how the immune system was responding in psoriatic lesions. It was first revealed that IFNγ producing T-cells are massively increased in psoriatic lesions [21]. Dendritic cells can instruct T-cells during priming to adopt a Th1 fate through secretion of the cytokine IL-12. IL-12 is composed of two subunits, p35 and p40. It was found that p40 expression is increased in psoriasis. Therefore targeting of the IL-12/IFNγ/Th1 axis was the next logical step in disease treatment. However, treatment with anti-IFNγ proved disappointing in preliminary clinical trials [22], resulting in the need for a deeper look into psoriasis pathogenesis. It was not until several years later, with the discovery of the Th17 subset and the key Th17 polarizing cytokine IL-23, that a role for the Th17 axis in psoriasis became apparent [23, 24]. IL-23 and IL-12 share the common p40 subunit; however IL-23 is produced by the combination of p40 with the p19 subunit [25] (Figure 1). Although expression of p35 is not increased in psoriasis, expression of both p40 and p19 are drastically increased in psoriasis lesions, and subsequently there is increased expression of biologically active IL-23 in psoriatic lesional skin.

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The IL-23 axis genes associationed with psoriasis

IL-12 and IL-23 share both a common subunit (p40), as well as a common chain in their heterodimeric receptor, IL-12RB1. Both cytokines signal though JAK-STAT signaling. However, IL-12 is composed of p35 and p40, whereas IL-23 is composed of p19 and p40. The IL-12 receptor is composed of IL-12RB1 and IL-12R2, whereas the IL-23 receptor is composed of IL-12RB1 and IL-23R. Lastly, IL-12 signaling culminates in activation of STAT4, whereas IL-23 signaling results in activation of STAT3. Components underlined and bolded represent the protein products of genes found to have associations with psoriasis; specific details are provided to the right of the diagram. Although psoriasis was initially considered to be a Th1 mediated disease (and thus would have large contributions of the IL-12 axis), it is now well understood that the disease is mainly mediated through the IL-23 driven Th17 response. In summary, many components of the IL-23 axis have genetic associations with psoriasis, including the IL-23 cytokine itself, the IL-23 receptor, and downstream signaling through the IL-23 receptor.

The immunogenetic association of IL-23 with psoriasis has proven quite strong. There have been several SNPs identified in genomic regions harboring genes for both subunits of the IL-23 cytokine: IL12Bp40 and IL23Ap19 [26] and coding SNPs in the IL-23 receptor (IL23R) that are associated with psoriasis [26-28]. The most consistently associated SNP within IL23R encodes a R381Q amino acid substitution, where the rarer Q allele results in decreased IL-23 signaling and is therefore protective against several autoimmune diseases, including psoriasis [29].

The IL-23 receptor is a heterodimeric receptor, composed of IL-12RB1 and IL-23R. These receptor components lack intrinsic signaling activity, and signal through the interactions with downstream molecules. IL-12B1 requires Tyk2 for signaling, whereas IL-23R requires Jak2 [30, 31]. GWAS studies of psoriasis have found associations with TYK2 [16], as well as an association of JAK2 with both psoriasis and Crohn’s disease [32]. Additionally, GWAS studies have found psoriasis associations with mutations in STAT3 (signal transducer and activator of transcription 3), a key molecule for downstream signaling through several cytokines, one of which is IL-23 [33].

The importance of IL-23 in psoriasis pathogenesis has been further confirmed by the recent major success of targeting this cytokine in treatment of psoriasis [34-36]. Monoclonal antibody treatment targeting both the common p40 subunit and the IL-23 specific p19 subunit have demonstrated outstanding clinical efficacy. In conjunction with the heavy genetic link to the IL-23 cytokine components and the IL-23 receptor, the transcripts of all three of these products are also significantly increased in psoriatic lesional skin [1]. Thus, the genetics, the transcriptomics, and the clinical success of blocking this cytokine all point towards a key role of IL-23 in psoriasis pathogenesis. In turn, IL-23 regulates activation and expansion of Th17 T-cells that are defined by production of IL-17A and IL-17F, and as discussed below in section 4, the pathogenic activity of IL-17 in psoriasis vulgaris is now well defined.

4. T-cell polarization

As mentioned in section 1, the critical role of T-cells in psoriasis was initially discovered by observing the improvement in disease when general T-cell suppressive agents were utilized. T-cells can be subdivided into two classes: CD8+ cytotoxic T-cells and CD4+ helper T-cells, both which are found to be increased in psoriatic lesional skin. Regarding CD4+ T-helper cells, this cell type can be polarized to different fates depending on the needs of the immune response. Initially, CD4+ T-helper cell fates were considered to be one of two-options: Th1 and Th2. Th1 T-cells produce IFNγ and are important for eliciting anti-viral immune responses. Th2 cells produce IL-4 and IL-5 and are critical for anti-microbial responses. Additionally, it was thought that allergies and autoimmune/auto-inflammatory diseases could also be characterized by the Th1 and Th2 paradigm. However in recent years, this simple dichotomy has transformed into a complex array of phenotypes which a CD4+ T-cell can acquire, including T-reg (regulatory T-cell), Th17, Th22, and Th9 T cells, to name a few. As described in section 3, psoriasis now is considered to be a disease mainly mediated by T-cells polarized to a Th17 fate, i.e. T-cells producing the cytokines, IL-17. The importance of IL-17 in psoriasis pathogenesis has been confirmed by the success of treatments targeting either the IL-17 cytokine directly (i.e. Secukinumab, Bimekizumab, and Ixelkizumab) or blocking the IL-17R (i.e. Broadalumab) [37].

Several genetic associations with psoriasis have been found in critical genes for T-cell development and polarization (Figure 2). One of these genes is RUNX3, which encodes a transcription factor in the Runt-domain containing family. RUNX3 is important for CD8+ T-cell development, promotion of Th1 polarization, and possibly Th17 polarization as well [38, 39]. There are also psoriasis-associated mutations in RUNX1, another transcription factor in the Runt-domain containing family [18]. RUNX1 plays an important role in normal hematopoiesis and has mainly been investigated regarding its’ dysregulation in leukemia and other hematopoietic cancers [40]. RUNX1 is expressed in naïve CD4+ T-cells and is rapidly downregulated upon TCR stimulation [39]. It can also be upregulated following Th2 polarizing conditions, but contradictorily, it also suppresses expression of the master Th2 transcription factor GATA3 and the key Th2 cytokine, IL-4 [39]. RUNX1 additionally plays a role in the development and the immunosuppressive ability of T-regs [39, 41-43]. However, exactly how these psoriasis-associations at the RUNX3 and RUNX1 loci contribute to psoriasis have not been explored. It is possible that a disruption in the balance of RUNX1 and RUNX3, through gain-of-function mutations in RUNX3 and/or reduction-of-function mutations in RUNX1, predisposes T-cells to a Th17 phenotype in psoriasis patients. However, besides modulating T-cell polarization and function, RUNX1 and RUNX3 may also modulate the activity of other immune cells, such as NK cells or DCs [39]. Furthermore, a psoriasis-associated SNP residing between the genes SLC9A3R1 and NAT9 results in loss of a RUNX1 binding site, supporting that either alterations in RUNX1 itself or its potential binding sites may play a role in psoriasis susceptibility [44].

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T-cell polarization genes associated with psoriasis

Massive T-cell infiltration is a hallmark of psoriasis and both CD8+ and CD4+ T-cells have increased prevalence in lesional skin. In response to cytokine signaling during the elicitation of inflammation, T-cells (particularly CD4+T-cells), have the plasticity to acquire unique phenotypes. Many cellular factors play important roles in this phenotype determination. Psoriasis is characterized by a predominantly Th1 and Th17 infiltrate, although the latter is considered to be the key pathogenic response. Many factors which control T-cell polarization and fate have genetic associations with psoriasis. These include both genes associated with Th1 and Th17 phenotypes (RUNX1 and STAT3) and T-reg and Th2 phenotypes (RUNX1, IL4, and IL13). As T-cell polarization is a delicate balance of signals that determine the T-cell’s fate, both gain-of-function (i.e. RUNX1 and STAT3) and loss-of-function mutations (i.e. RUNX1, IL4, and IL13) may both contribute to disease susceptibility.

As described in section 3, association with a region harboring STAT3 has also been found in psoriasis GWAS [33]. In psoriatic lesions, STAT3 is found in a phosphorylated and activated state [45]. STAT3 is important in the signaling cascades of several cytokines, such as IL-6, IL-10, IL-22, and IL-23. Because STAT3 is required for signaling through the IL-23R, it is essential for Th17 polarization [46]. It is possible that psoriasis-associated mutations in STAT3 decrease the threshold of IL-23 signaling required to elicit Th17 polarization. However, activation of STAT3 in psoriasis may also play a role in non-hematopoietic cells, as STAT3 signaling can directly modulate epidermal hyperplasia as well [47].

Another gene with function in T-cell biology that has recently been identified as a locus receiving genome-wide significance for association with psoriasis is TAGAP (T-cell activation RhoGTPase activating protein). TAGAP is expressed in activated T-cells, however the exact role of this protein in T-cell biology has not been explored [48]. Several other immune mediated diseases have also noted associations of TAGAP SNPs with disease susceptibility, including Crohns disease, celiac disease, multiple sclerosis, and rheumatoid arthritis [49-52].

Interestingly, association with a region harboring Th2 associated genes, specifically IL4, IL5 and IL13, in a region of chromosome 5q31 that harbors genes for multiple cytokines, has also been found in psoriasis patients [53]. However, given that these cytokines do not play a role in psoriasis pathogenesis and are not detected in psoriatic skin, this association is likely to result in decreased activity of these cytokines, although this has not been shown experimentally. T-cell polarization is a delicate balance, and often a molecular “push” towards a certain T-helper phenotype will inhibit T-helper cell polarization to other fates. Several studies have demonstrated epigenetic changes in the promoter regions of key Th2 and T-regulatory phenotype genes when T-cells are pushed towards a Th1 fate, and vice-versa [54, 55]. In the case of this association at chromosome 5q31 and one possible causative SNP (rs20541; Q144R of IL13), the Q allele is protective for psoriasis, but is a risk allele for asthma [56]. Reduced functionality of the Th2-associated SNPs may more easily allow T-cells to adopt an alternate outcome, such as the Th1 polarized cells found heavily in psoriasis, or more importantly, the pathogenic Th17 cell fate.

5. Innate immunity

Although the critical role of the adaptive immune system and Th17 polarized memory T-cells in psoriasis pathogenesis is difficult to refute, recent data also suggests an important role of the innate immune system in psoriasis susceptibility. These ideas are not mutually exclusive, as initial activation of the innate immune system is required for the subsequent onslaught of the adaptive response. Although the protein products of these innate immune genes are not currently key therapeutic targets in psoriasis, they may represent a predisposition for immune activation. In other words, psoriasis associations at loci harboring these innate immune genes may decrease the threshold needed to initiate the pathogenic adaptive immune response.

Many genes in the NF-κB pathway are associated with psoriasis [57] (Figure 3). NF-κB is a key transcription factor in immune responses, and plays an important role in almost every immune cell type [58]. NF-κB is held in the cytoplasm of the cell, bound to its’ inhibitor, IκB [59]. Many cellular receptors of immune signaling include innate immune pattern recognition receptors and cytokine receptors, such as TNFα. Upon initiation of NF-κB signaling, IκB is phosphorylated by IκB kinase (IKK) and subsequently targeted for proteosomal degradation. The degradation of IκB releases NF-κB for translocation to the nucleus and subsequent induction of inflammatory gene expression [59].

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Multiple genes in the NF-κB pathway are associated with psoriasis

The NF-κB pathway is a critical pathway in elicitation of immune responses. Although psoriasis is considered a disease of an overactive adaptive immune response, as evidenced by the massive infiltration of T-cells and the success of treatment based upon elimination of these pathogenic T-cells, innate pathways may still play a central role in disease. Genetic associations with psoriasis have been found in both components that activate and components that repress the NF-κB pathway. It is likely that gain-of-function mutations in NF-κB activating components (left) and loss-of-function mutations in NF-κB inhibitory components (right) decreased the threshold for immune activation and the subsequent onset of psoriasis. Specific details regarding mutations and the functional consequences are provided near the corresponding gene.

NF-κB is a dimeric transcription factor, which can be composed of combinations of several different subunits, p50, p52, RelA(p65), c-Rel, and Rel-B. Expression of different subunits vary depending on cell type. The NF-κB pathway is well known to be activated in psoriatic lesional skin, and is reduced upon successful treatment [57, 60]. SNPs within a region harboring a gene for one of the NF-κB components, c-Rel, are associated with psoriasis susceptibility [61]. C-Rel can also directly regulate keratinocyte growth and cell cycle progression [39, 62].

A SNP within TRAF3IP2 (TRAF3 interacting protein 2, also known as Act1) is also associated with psoriasis [63, 64]. TRAF3IP2 interacts with TRAF6 and is important for NF-κB activation downstream of IL-17 receptor signaling [64-66]. TRAF3IP2 is also important for CCL20 production from keratinocytes in response to IL-17 [67]. A coding alteration in TRAF3IP2 is associated with both psoriasis vulgaris and psoriatic arthritis. This likely results in increased activation of NF-κB and heightened production of inflammatory products [65].

CARD-proteins are scaffolding proteins important in activation of NF-κB [68]. CARD-proteins have specific cellular distribution, with CARD9 being predominantly in myeloid cells, CARD10 in non-hematopoietic cells, and CARD11 in hematopoietic cells [68]. CARD14, a less investigated member of the CARD-family, was recently described to be the causative gene at PSORS2 [69, 70]. In this instance, rare gain-of-function, highly penetrant dominantly acting mutations lead to psoriasis with or without psoriatic arthritis. In one case a de-novo mutation in CARD14 lead to generalized pustular psoriasis. A coding SNP in CARD14 described in this earlier study (R820W) was found to be associated with psoriasis at genome-wide significance in a subsequent meta-GWAS study [33]. Although CARD14 was initially described to be expressed in placental and mucosal tissue [71], recently CARD14 was found to be expressed in keratinocytes and endothelial cells [69, 72]. Psoriasis associated mutations in CARD14 result in increased NF-κB signaling, and production of several inflammatory cytokines and chemokines in both keratinocytes and endothelial cells [70, 72]. This suggests that CARD14 mutations increase the ability of both keratinocytes and endothelial cells to recruit and activate immune cells. CARD14 is one of only two genes in which a rare mutation can independently result in psoriasis; the other is IL36RN, which is mutated in pustular psoriasis and will be discussed in section 6 about negative regulators [1].

Interestingly, some of the more recent innate immune gene associations with psoriasis have been found in interferon and anti-viral response genes. These genes are DDX58 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 58), which encodes the protein RIG-I, and IFIH1, which encodes the protein MDA5. Both RIG-I and MDA5 are intracellular, innate immune sensors, critical for detection of double stranded RNAs. RIG-I specifically recognizes shorter RNAs containing 5’ triphosphate moieties and blunt-end base pairing at the 5’ end, whereas MDA5 is thought to recognize longer RNA structures [73]. Both are important for recognition of dsRNA viruses or viruses that utilize dsRNA intermediates of replication, and the subsequent elicitation of a type-I interferon response [73, 74]. RIG-I can also detect DNA viruses and bacterial RNAs [73]. Activation of RIG-I or MDA5 results in gene expression changes mainly mediated by IRF3 and NF-κB [74]. Induction of type-I interferons, as well as other innate inflammatory and anti-microbial molecules, is a common outcome of RIG-I and MDA5 activation [74], and it known that expression of type-I interferons and downstream products of type-1 interferons are increased in psoriatic lesions [75-77].

Although it is not clear how DDX58 and IFIH1 mutations predispose to psoriasis, there have been a few studies that have investigated these genes in relation to psoriasis. Two cytokines heavily present in psoriasis, TNFα and/or IFNγ, can increase expression of RIG-I and MDA5 expression in keratinocytes [78, 79]. Additionally, RIG-I and MDA5 have increased expression in psoriasis lesional skin [79, 80]. Upon successful treatment of psoriatic lesions, using narrow band-ultra violet B (NB-UVB), expression of RIG-I and MDA5 are decreased [79]. A third GWAS hit was recently found in another potential innate, type-I interferon inducing gene, RNF144 [81], supporting the role of mutations in this pathway in psoriasis susceptibility. Lastly, two rare SNPs in MDA5, likely leading to reduced functionality of the protein, are associated with a decreased risk of psoriasis [82].

Although classically thought to be important for sensing pathogens, these innate pattern-recognition receptors may bind self-derived molecules that have increased presence in psoriatic skin. SRSF1 (serine/arginine rich splicing factor 1) can interact with RIG-I, resulting in the ability of cytosolic DNA to elicit RIG-I mediated-production of type I interferons [83]. Some recent studies have shown that plasmacytoid DCs and myeloid DCs can respond to self-DNA and LL37 complexes, via TLR7 and TLR8, respectively [84]. In conclusion, mutations in innate pattern recognition receptors, such as RIG-I and MDA5, might have a decreased threshold for triggering by either self- or non-self stimuli, and be a key initiating step in lesion development.

6. Negative regulators

Most biological systems have mechanisms to maintain homeostasis, and the immune system is no exception. There are several immune suppressive cytokines (i.e. IL-10), cell surface signaling molecules (CTLA-4), secreted soluble receptors and natural receptor antagonists involved in suppression of immune responses. As psoriasis is a disease of an overactive immune response, it is not unexpected that mutations in genes important for maintaining homeostasis might be associated with disease susceptibility.

Several genes involved in downregulation of the NF-κB pathway have been found to have genetic associations with psoriasis. These include TNIP1 (TNFAIP3 interacting protein 1, annexin A6), TNFAIP3 (tumor necrosis factor, alpha-induced protein 3, also known as A20), NFKBIA (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), and ZC3H12C (zinc finger, DHHC-type containing 23) [18, 33, 85].

TNIP1 and TNFAIP3 work together in inhibition of NF-κB signaling, via prevention of NEMO polyubiquination and subsequent degradation of the NF-κB inhibitor, IκB [86, 87]. Both TNIP1 and TNFAIP3 have been found as susceptibility loci for not only psoriasis [16, 17, 27, 88], but also SLE and rheumatoid arthritis [89-91]. TNIP1 inhibits NF-κB signaling through several receptors, including the TNFα receptor, the EGF receptor, and Toll-like receptors [86, 92]. TNIP1 can also inhibit PPAR signaling [93] and may protect cells from apoptosis [86]. A noncoding variant of TNIP1 is associated with psoriasis, suggesting that reduced ability to suppress NF-κB signaling is important in elicitation of psoriasis [14]. It was also found that TNIP1 has an altered methylation pattern in psoriasis patients, which would correlate with the observation that it is up-regulated in psoriatic skin [94]. NFKBIA, which encodes the protein IκBα, is an inhibitor of NF-κB signaling. It does this by sequestering of NF-κB dimers in the cytosol in the absence of inflammatory stimuli [95].

ZC3H12C is important in suppressing NF-κB signaling and pro-inflammatory gene expression in endothelial cells [96]. This finding that ZC3H12C is able to inhibit vascular inflammation is interesting considering the cardiovascular comorbidities with psoriasis. Therefore, similar to gain-of-function psoriasis-associated mutations in CARD14, loss-of-function psoriasis-associated variants in ZC3H12C within endothelial cells may result in overactive NF-κB signaling, resulting in the heightened ability of both dermal and non-dermal endothelial cells to produce inflammatory molecules. ZC3H12C is also expressed in macrophages and although the exact role of this gene in macrophages has not been explored, it was found that a member of the same family, ZC3H12A, inhibits the ability of macrophages to produce nitric oxide species after LPS stimulation [97]. As psoriatic lesional skin contains an abundance of myeloid cells expressing iNOS, it may be possible that psoriasis-associated mutations in ZC3H12C result in heightened nitric oxide production.

As mentioned in section 5, one of the few genes with highly penetrant mutations leading to psoriasis is IL36RN; mutations in this gene were first found in two families with severe generalized pustular psoriasis [98, 99]. IL36RN encodes the IL-36Ra, an anti-inflammatory protein that is a natural antagonist for IL-1F9. These mutations in result in reduced activity of the protein, and subsequent unopposed affects of the inflammatory cytokine IL-1F9. As a consequence, NF-κB regulated cytokines are highly increased in individuals with IL36RN mutations.

SOCS proteins are critical in limiting STAT-mediated signaling, such as the downstream signaling activated through cytokine receptors [100]. SOCS1 (suppressor of cytokine signaling 1) is rapidly upregulated upon signaling through type I and II cytokine receptors, including IFNγ [101]. SOCS1 contains a kinase inhibitory region (KIR), which binds to JAKs and inhibits further cell signaling [102]. SOCS1 can also bind to proteins and target them for proteosomal degradation [100]. GWAS have shown that SOCS1 is an independent predisposing locus for psoriasis in European populations [18]. SOCS1 is known to be important in suppressing a Th1/IFNγ response although how SOCS1 alterations contribute to psoriasis is not immediately obvious, SOCS1−/− CD4+ T-cells have suppressed Th17 polarization [102], so the biological consequences of psoriasis mutations in SOCS1, including its signaling pathway in healthy and psoriatic skin need to be further investigated.

In general, the failure of inflammation to resolve in psoriasis has been much less studied than the mechanisms that actively contribute to the inflammation. These genetic examples demonstrate the importance of negative regulators in controlling inflammation in psoriasis. Mutations in these negative regulators likely result in reduced ability to control inflammation and may play as important a role as those mutations resulting in overactive immune responses.

7. Immune genes with less-well established links to psoriasis pathogenesis

As described through this review, many of the immune genes implicated by genetic associations in psoriasis have a relatively obvious rationale regarding how they might predispose to disease. However, the causative variants responsible for these variants have not been identified in the majority of cases, so confirmation of both the gene/s within an associated interval, and how the variant leads to disease, will await future studies. There are additional immune related genes in which an association to psoriasis has been made, but the link between mutations in these genes and psoriasis susceptibility is less clear. These include NOS2A (nitric oxide synthase 2, inducible) and IL28RA (interleukin-28 receptor alpha) [88].

NOS2A is one gene that can correctly classify psoriasis versus eczema, with NOS2A expression being specifically only enhanced in psoriasis [103, 104]. NOS2A is upregulated in many cancers, including prostate and breast cancers [105-107]. NOS2 is also important in the immune response to several pathogens. However, it is unclear how NOS2A mutations might contribute to psoriasis susceptibility. NOS2A expression can be induced by IFNγ, a cytokine heavily present in psoriatic lesions, and the products of NOS2A can upregulate several inflammatory molecules known to be increased in psoriasis, such as S100A8, IL-6, and IL-8 [108]. NOS2 is also important for the de novo induction and stability of human Th17 cells in from cancer patients [109]. This last finding merits further investigation, and may be a clue to the role of NOS2A mutations in psoriasis predisposition.

IL28RA is a member of the class II cytokine receptor family. It can dimerize with IL-10RB, which forms the receptor for the three cytokines IL-28A, IL-28B, and IL-29. These three cytokines are also known at type III interferons (IFNλ) [110]. IFNλ, as with the other interferons, are important for the immune response to viruses and stimulates similar signaling cascades, i.e. Jak-STAT signaling [110, 111]. However, one interesting feature of IFNλ is the restriction of IFNλ-receptors (such as IL28A) to mainly cells of epithelial origin [112]. Therefore, psoriasis associated mutations in IL28RA may increase the responsiveness of the skin to IFNλ, and contribute to elicitation of inflammation.

Although they do not encode proteins, microRNAs may also play a role in the immunogenetics of psoriasis [113, 114]. The rs2910164 SNP of miR-146a was associated with an increased risk of psoriasis in one study [115]. This microRNA targets the EGFR (epidermal growth factor receptor) transcript. The rs2910164 SNP was found to decrease the ability of this miR-146a to suppress EGFR expression, and EGFR expression is known to be elevated in lesional skin [116]. Alternatively, it is possible that any of the SNPs mentioned above in protein-coding immune genes may destroy, alter, or even create miRNA targeting-sites for that transcript [114].

8. Conclusions

Psoriasis is a complex, multi-factorial autoimmune disease, with many complex immunogenetic contributions. Despite our increase in knowledge about disease pathogenesis and the identification of predisposing genetic risk factors in the form of SNPs, there are many unanswered questions. Most GWAS findings are in noncoding DNA, and the causative variants still need to be identified. Changes in noncoding DNA could certainly modulate splicing of the pre-mRNA transcript, but a specific understanding on the effects of these psoriasis-associated mutations on the protein and subsequent biological function still need to be addressed. Until this is achieved, it will not be easy to interpret GWAS associations and how this modulates not only the immune system, but also other cells and tissues. Additionally, many of these immunological gene associations are shared with other autoimmune diseases; specific examples were highlighted throughout the article. There are many immunogenetic associations shared between psoriasis vulgaris and psoriatic arthritis, with most psoriasis vulgaris loci being shared with psoriatic arthritis [117].

Gaining a better understanding of how these gene associations predispose to psoriasis will likely shed light on their role in predispositions to other autoinflammatory and autoimmune diseases, as well as the psoriasis associated comorbidities. Several of the genetic predispositions, such as CARD14 and ZC3H12C, were found to not only potentially alter immune cell or keratinocyte behavior, but also the biology of the vasculature. These mutations might therefore play a role in the cardiovascular comorbidities associated with psoriasis, and may also highlight a need to monitor cardiovascular health more closely in these individuals.

Enhanced understanding of the underlying biology of these immunogenetic associations with psoriasis may generally improve treatment of patients. Although we consider all of these psoriasis-associated mutations as eliciting the same disease (i.e. psoriasis vulgaris), it is interesting to speculate that in fact these are distinct diseases. In fact, we may eventually describe a person with psoriasis as having, for example, “CARD14-associated psoriasis”. Although the disease may manifest similarly, the underlying initiators may be distinct. Those whom have psoriasis elicited by particular mutations may more likely benefit from particular treatments over others. Indeed, those with polymorphisms in TNF-related genes, such as TNFAIP3, are associated with a better response to anti-TNFα therapy [118, 119]. It is not unreasonable to speculate that in the future, personalized medicine and specific immunomodulatory treatment will be based upon genetic alterations in particular immune genes.

Acknowledgments

Funding Sources: JLH was supported by NIH 1R01AR060222 and The Robertson Therapeutic Development Fund. AMB is supported by R01AR050266.

The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY 10065, USA
Dermira, Inc. Menlo Park, CA, 94025, USA
National Heart and Lung Institute, Imperial College, London SW3 6LY, UK
Corresponding author: Dr. Anne Bowcock, National Heart and Lung Institute, Imperial College, London, SW3 6LY, United Kingdom; ku.ca.lairepmi@kcocwob.A
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Abstract

Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL, TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN, SOCS1). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. However, many of the genetic findings involve immune genes with less clear roles in psoriasis pathogenesis. This is particularly the case for those genes involved in innate immunity and negative regulation of immune specific pathways. It is possible that risk alleles of these genes decrease the threshold for the initial activation of the innate immune response. This could then lead to the onslaught of the pathogenic adaptive immune response known to be active in psoriatic skin. However, precisely how these various genes affect immunobiology need to be determined and some are speculated upon in this review. These novel genetic findings also open opportunities to explore novel therapeutic targets and potentially the development of personalized medicine, as well as discover new biology of human skin disease.

Keywords: Psoriasis, genetics, immunology, Th17-axis, innate immunity, negative regulators
Abstract
Highlights

Footnotes

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Financial Disclosures: All authors have no conflicts of interest. JLH is currently employed by Dermira, Inc.

Footnotes

REFERENCES

REFERENCES

References

  • 1. Lowes MA, Suarez-Farinas M, Krueger JGImmunology of psoriasis. Annual review of immunology. 2014;32:227–55.[Google Scholar]
  • 2. Perera GK, Di Meglio P, Nestle FOPsoriasis. Annual review of pathology. 2012;7:385–422.[PubMed][Google Scholar]
  • 3. Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, et al Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. The Journal of investigative dermatology. 2010;130:1785–96.[PubMed][Google Scholar]
  • 4. Di Cesare A, Di Meglio P, Nestle FOThe IL-23/Th17 axis in the immunopathogenesis of psoriasis. The Journal of investigative dermatology. 2009;129:1339–50.[PubMed][Google Scholar]
  • 5. Colombo MD, Cassano N, Bellia G, Vena GACyclosporine regimens in plaque psoriasis: an overview with special emphasis on dose, duration, and old and new treatment approaches. TheScientificWorldJournal. 2013;2013:805705.[Google Scholar]
  • 6. Ellis CN, Krueger GGTreatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. The New England journal of medicine. 2001;345:248–55.[PubMed][Google Scholar]
  • 7. Mueller W, Herrmann BCyclosporin A for psoriasis. The New England journal of medicine. 1979;301:555.[PubMed][Google Scholar]
  • 8. Gottlieb SL, Gilleaudeau P, Johnson R, Estes L, Woodworth TG, Gottlieb AB, et al Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nature medicine. 1995;1:442–7.[PubMed][Google Scholar]
  • 9. Lowes MA, Bowcock AM, Krueger JGPathogenesis and therapy of psoriasis. Nature. 2007;445:866–73.[PubMed][Google Scholar]
  • 10. Lowes MA, Chamian F, Abello MV, Fuentes-Duculan J, Lin SL, Nussbaum R, et al Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a) Proceedings of the National Academy of Sciences of the United States of America. 2005;102:19057–62.[Google Scholar]
  • 11. Zaba LC, Krueger JG, Lowes MAResident and "inflammatory" dendritic cells in human skin. The Journal of investigative dermatology. 2009;129:302–8.[Google Scholar]
  • 12. Wuepper KD, Coulter SN, Haberman APsoriasis vulgaris: a genetic approach. The Journal of investigative dermatology. 1990;95:2S–4S.[PubMed][Google Scholar]
  • 13. Bowcock AMThe genetics of psoriasis and autoimmunity. Annual review of genomics and human genetics. 2005;6:93–122.[PubMed][Google Scholar]
  • 14. Elder JTPSORS1: linking genetics and immunology. The Journal of investigative dermatology. 2006;126:1205–6.[PubMed][Google Scholar]
  • 15. Gourraud PA, Khankhanian P, Cereb N, Yang SY, Feolo M, Maiers M, et al HLA diversity in the 1000 genomes dataset. PloS one. 2014;9:e97282.[Google Scholar]
  • 16. Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, et al A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nature genetics. 2010;42:985–90.[Google Scholar]
  • 17. Sun LD, Cheng H, Wang ZX, Zhang AP, Wang PG, Xu JH, et al Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nature genetics. 2010;42:1005–9.[Google Scholar]
  • 18. Yin X, Low HQ, Wang L, Li Y, Ellinghaus E, Han J, et al Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility. Nature communications. 2015;6:6916.[Google Scholar]
  • 19. Okada Y, Han B, Tsoi LC, Stuart PE, Ellinghaus E, Tejasvi T, et al Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. American journal of human genetics. 2014;95:162–72.[Google Scholar]
  • 20. Gonzalez S, Lopez-Soto A, Suarez-Alvarez B, Lopez-Vazquez A, Lopez-Larrea CNKG2D ligands: key targets of the immune response. Trends in immunology. 2008;29:397–403.[PubMed][Google Scholar]
  • 21. Lew W, Bowcock AM, Krueger JGPsoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and "Type 1" inflammatory gene expression. Trends in immunology. 2004;25:295–305.[PubMed][Google Scholar]
  • 22. Harden JL, Johnson-Huang LM, Chamian MF, Lee E, Pearce T, Leonardi CL, et al Humanized anti-IFN-gamma (HuZAF) in the treatment of psoriasis. The Journal of allergy and clinical immunology. 2015;135:553–6.[PubMed][Google Scholar]
  • 23. McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, et al The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nature immunology. 2009;10:314–24.[Google Scholar]
  • 24. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt ACirculating Th17, Th22, and Th1 cells are increased in psoriasis. The Journal of investigative dermatology. 2010;130:1373–83.[Google Scholar]
  • 25. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13:715–25.[PubMed][Google Scholar]
  • 26. Nair RP, Ruether A, Stuart PE, Jenisch S, Tejasvi T, Hiremagalore R, et al Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. The Journal of investigative dermatology. 2008;128:1653–61.[Google Scholar]
  • 27. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, et al Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nature genetics. 2009;41:199–204.[Google Scholar]
  • 28. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, et al A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. American journal of human genetics. 2007;80:273–90.[Google Scholar]
  • 29. Di Meglio P, Di Cesare A, Laggner U, Chu CC, Napolitano L, Villanova F, et al The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PloS one. 2011;6:e17160.[Google Scholar]
  • 30. Zou J, Presky DH, Wu CY, Gubler UDifferential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases. The Journal of biological chemistry. 1997;272:6073–7.[PubMed][Google Scholar]
  • 31. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, et al A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002;168:5699–708.[PubMed][Google Scholar]
  • 32. Ellinghaus D, Ellinghaus E, Nair RP, Stuart PE, Esko T, Metspalu A, et al Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. American journal of human genetics. 2012;90:636–47.[Google Scholar]
  • 33. Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nature genetics. 2012;44:1341–8.[Google Scholar]
  • 34. Sofen H, Smith S, Matheson RT, Leonardi CL, Calderon C, Brodmerkel C, et al Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. The Journal of allergy and clinical immunology. 2014;133:1032–40.[PubMed][Google Scholar]
  • 35. Kopp T, Riedl E, Bangert C, Bowman EP, Greisenegger E, Horowitz A, et al Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature. 2015;521:222–6.[PubMed][Google Scholar]
  • 36. Papp K, Thaci D, Reich K, Riedl E, Langley RG, Krueger JG, et al Tildrakizumab (MK-3222), an Anti-IL-23p19 Monoclonal Antibody, Improves Psoriasis in a Phase 2b Randomized Placebo-Controlled Trial. The British journal of dermatology. 2015[PubMed][Google Scholar]
  • 37. Chiricozzi A, Krueger JGIL-17 targeted therapies for psoriasis. Expert opinion on investigational drugs. 2013;22:993–1005.[PubMed][Google Scholar]
  • 38. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KMTranscription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nature immunology. 2007;8:145–53.[PubMed][Google Scholar]
  • 39. Wong WF, Kohu K, Chiba T, Sato T, Satake MInterplay of transcription factors in T-cell differentiation and function: the role of Runx. Immunology. 2011;132:157–64.[Google Scholar]
  • 40. Faridi F, Ponnusamy K, Quagliano-Lo Coco I, Chen-Wichmann L, Grez M, Henschler R, et al Aberrant epigenetic regulators control expansion of human CD34+ hematopoietic stem/progenitor cells. Frontiers in genetics. 2013;4:254.[Google Scholar]
  • 41. Ono M, Yaguchi H, Ohkura N, Kitabayashi I, Nagamura Y, Nomura T, et al Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature. 2007;446:685–9.[PubMed][Google Scholar]
  • 42. Bruno L, Mazzarella L, Hoogenkamp M, Hertweck A, Cobb BS, Sauer S, et al Runx proteins regulate Foxp3 expression. The Journal of experimental medicine. 2009;206:2329–37.[Google Scholar]
  • 43. Kitoh A, Ono M, Naoe Y, Ohkura N, Yamaguchi T, Yaguchi H, et al Indispensable role of the Runx1-Cbfbeta transcription complex for in vivo-suppressive function of FoxP3+ regulatory T cells. Immunity. 2009;31:609–20.[PubMed][Google Scholar]
  • 44. Helms C, Cao L, Krueger JG, Wijsman EM, Chamian F, Gordon D, et al A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nature genetics. 2003;35:349–56.[PubMed][Google Scholar]
  • 45. Andres RM, Hald A, Johansen C, Kragballe K, Iversen LStudies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity. Experimental dermatology. 2013;22:323–8.[PubMed][Google Scholar]
  • 46. Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, et al Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol. 2007;179:4313–7.[PubMed][Google Scholar]
  • 47. Tarutani M, Nakajima K, Takaishi M, Ohko K, Sano SEpidermal hyperplasia induced by Raf-MAPK signaling requires Stat3 activation. Journal of dermatological science. 2013;72:110–5.[PubMed][Google Scholar]
  • 48. Mao M, Biery MC, Kobayashi SV, Ward T, Schimmack G, Burchard J, et al T lymphocyte activation gene identification by coregulated expression on DNA microarrays. Genomics. 2004;83:989–99.[PubMed][Google Scholar]
  • 49. Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, et al Newly identified genetic risk variants for celiac disease related to the immune response. Nature genetics. 2008;40:395–402.[Google Scholar]
  • 50. Raychaudhuri S, Thomson BP, Remmers EF, Eyre S, Hinks A, Guiducci C, et al Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nature genetics. 2009;41:1313–8.[Google Scholar]
  • 51. Festen EA, Goyette P, Green T, Boucher G, Beauchamp C, Trynka G, et al A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease. PLoS genetics. 2011;7:e1001283.[Google Scholar]
  • 52. Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J, et al Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Annals of neurology. 2011;70:897–912.[Google Scholar]
  • 53. Chang M, Li Y, Yan C, Callis-Duffin KP, Matsunami N, Garcia VE, et al Variants in the 5q31 cytokine gene cluster are associated with psoriasis. Genes and immunity. 2008;9:176–81.[PubMed][Google Scholar]
  • 54. Muranski P, Restifo NPEssentials of Th17 cell commitment and plasticity. Blood. 2013;121:2402–14.[Google Scholar]
  • 55. Hirahara K, Vahedi G, Ghoreschi K, Yang XP, Nakayamada S, Kanno Y, et al Helper T-cell differentiation and plasticity: insights from epigenetics. Immunology. 2011;134:235–45.[Google Scholar]
  • 56. Li X, Ampleford EJ, Howard TD, Moore WC, Torgerson DG, Li H, et al Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases. The Journal of allergy and clinical immunology. 2012;130:861–8 e7.[Google Scholar]
  • 57. Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PFNF-kappaB: an essential transcription factor in psoriasis. Journal of dermatological science. 2013;69:89–94.[PubMed][Google Scholar]
  • 58. Hoesel B, Schmid JAThe complexity of NF-kappaB signaling in inflammation and cancer. Molecular cancer. 2013;12:86.[Google Scholar]
  • 59. Perkins NDIntegrating cell-signalling pathways with NF-kappaB and IKK function. Nature reviews Molecular cell biology. 2007;8:49–62.[PubMed][Google Scholar]
  • 60. Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V, et al Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept. The Journal of investigative dermatology. 2005;124:1275–83.[PubMed][Google Scholar]
  • 61. Stuart PE, Nair RP, Ellinghaus E, Ding J, Tejasvi T, Gudjonsson JE, et al Genome-wide association analysis identifies three psoriasis susceptibility loci. Nature genetics. 2010;42:1000–4.[Google Scholar]
  • 62. Lorenz VN, Schon MP, Seitz CSc-Rel downregulation affects cell cycle progression of human keratinocytes. The Journal of investigative dermatology. 2014;134:415–22.[PubMed][Google Scholar]
  • 63. Huffmeier U, Uebe S, Ekici AB, Bowes J, Giardina E, Korendowych E, et al Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nature genetics. 2010;42:996–9.[Google Scholar]
  • 64. Ellinghaus E, Ellinghaus D, Stuart PE, Nair RP, Debrus S, Raelson JV, et al Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nature genetics. 2010;42:991–5.[Google Scholar]
  • 65. Suzuki E, Mellins ED, Gershwin ME, Nestle FO, Adamopoulos IEThe IL-23/IL-17 axis in psoriatic arthritis. Autoimmunity reviews. 2014;13:496–502.[Google Scholar]
  • 66. Chang SH, Dong CSignaling of interleukin-17 family cytokines in immunity and inflammation. Cellular signalling. 2011;23:1069–75.[Google Scholar]
  • 67. Wu NL, Huang DY, Tsou HN, Lin YC, Lin WWSyk mediates IL-17-induced CCL20 expression by targeting Act1-dependent K63-linked ubiquitination of TRAF6. The Journal of investigative dermatology. 2015;135:490–8.[PubMed][Google Scholar]
  • 68. Blonska M, Lin XNF-kappaB signaling pathways regulated by CARMA family of scaffold proteins. Cell research. 2011;21:55–70.[Google Scholar]
  • 69. Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, et al PSORS2 is due to mutations in CARD14. American journal of human genetics. 2012;90:784–95.[Google Scholar]
  • 70. Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, et al Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. American journal of human genetics. 2012;90:796–808.[Google Scholar]
  • 71. Scudiero I, Zotti T, Ferravante A, Vessichelli M, Vito P, Stilo RAlternative splicing of CARMA2/CARD14 transcripts generates protein variants with differential effect on NF-kappaB activation and endoplasmic reticulum stress-induced cell death. Journal of cellular physiology. 2011;226:3121–31.[Google Scholar]
  • 72. Harden JL, Lewis SM, Pierson KC, Suarez-Farinas M, Lentini T, Ortenzio FS, et al CARD14 Expression in Dermal Endothelial Cells in Psoriasis. PloS one. 2014;9:e111255.[Google Scholar]
  • 73. Vabret N, Blander JMSensing microbial RNA in the cytosol. Frontiers in immunology. 2013;4:468.[Google Scholar]
  • 74. Reikine S, Nguyen JB, Modis YPattern Recognition and Signaling Mechanisms of RIG-I and MDA5. Frontiers in immunology. 2014;5:342.[Google Scholar]
  • 75. Schmid P, Itin P, Cox D, McMaster GK, Horisberger MAThe type I interferon system is locally activated in psoriatic lesions. Journal of interferon research. 1994;14:229–34.[PubMed][Google Scholar]
  • 76. Yao Y, Richman L, Morehouse C, de los Reyes M, Higgs BW, Boutrin A, et al Type I interferon: potential therapeutic target for psoriasis? PloS one. 2008;3:e2737.[Google Scholar]
  • 77. van der Fits L, van der Wel LI, Laman JD, Prens EP, Verschuren MCIn psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered. The Journal of investigative dermatology. 2004;122:51–60.[PubMed][Google Scholar]
  • 78. Kitamura H, Matsuzaki Y, Kimura K, Nakano H, Imaizumi T, Satoh K, et al Cytokine modulation of retinoic acid-inducible gene-I (RIG-I) expression in human epidermal keratinocytes. Journal of dermatological science. 2007;45:127–34.[PubMed][Google Scholar]
  • 79. Racz E, Prens EP, Kant M, Florencia E, Jaspers NG, Laman JD, et al Narrowband ultraviolet B inhibits innate cytosolic double-stranded RNA receptors in psoriatic skin and keratinocytes. The British journal of dermatology. 2011;164:838–47.[PubMed][Google Scholar]
  • 80. Prens EP, Kant M, van Dijk G, van der Wel LI, Mourits S, van der Fits LIFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis. The Journal of investigative dermatology. 2008;128:932–8.[PubMed][Google Scholar]
  • 81. Bijlmakers MJ, Kanneganti SK, Barker JN, Trembath RC, Capon FFunctional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis. Human molecular genetics. 2011;20:3129–37.[Google Scholar]
  • 82. Li Y, Liao W, Cargill M, Chang M, Matsunami N, Feng BJ, et al Carriers of rare missense variants in IFIH1 are protected from psoriasis. The Journal of investigative dermatology. 2010;130:2768–72.[Google Scholar]
  • 83. Xue F, Li X, Zhao X, Wang L, Liu M, Shi R, et al SRSF1 facilitates cytosolic DNA-induced production of type I interferons recognized by RIG-I. PloS one. 2015;10:e0115354.[Google Scholar]
  • 84. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, et al Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. The Journal of experimental medicine. 2009;206:1983–94.[Google Scholar]
  • 85. Zuo X, Sun L, Yin X, Gao J, Sheng Y, Xu J, et al Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis. Nature communications. 2015;6:6793.[Google Scholar]
  • 86. Ramirez VP, Gurevich I, Aneskievich BJEmerging roles for TNIP1 in regulating post-receptor signaling. Cytokine & growth factor reviews. 2012;23:109–18.[Google Scholar]
  • 87. Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R, et al ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. The Journal of biological chemistry. 2006;281:18482–8.[PubMed][Google Scholar]
  • 88. Zhang XJ, Huang W, Yang S, Sun LD, Zhang FY, Zhu QX, et al Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nature genetics. 2009;41:205–10.[PubMed][Google Scholar]
  • 89. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, et al Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature genetics. 2010;42:508–14.[Google Scholar]
  • 90. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, et al Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nature genetics. 2009;41:1234–7.[PubMed][Google Scholar]
  • 91. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, et al Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nature genetics. 2008;40:1059–61.[Google Scholar]
  • 92. Heyninck K, De Valck D, Vanden Berghe W, Van Criekinge W, Contreras R, Fiers W, et al The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN. The Journal of cell biology. 1999;145:1471–82.[Google Scholar]
  • 93. Flores AM, Gurevich I, Zhang C, Ramirez VP, Devens TR, Aneskievich BJTNIP1 is a corepressor of agonist-bound PPARs. Archives of biochemistry and biophysics. 2011;516:58–66.[Google Scholar]
  • 94. Roberson ED, Liu Y, Ryan C, Joyce CE, Duan S, Cao L, et al A subset of methylated CpG sites differentiate psoriatic from normal skin. The Journal of investigative dermatology. 2012;132:583–92.[Google Scholar]
  • 95. Hayden MS, Ghosh SShared principles in NF-kappaB signaling. Cell. 2008;132:344–62.[PubMed][Google Scholar]
  • 96. Liu L, Zhou Z, Huang S, Guo Y, Fan Y, Zhang J, et al Zc3h12c inhibits vascular inflammation by repressing NF-kappaB activation and pro-inflammatory gene expression in endothelial cells. The Biochemical journal. 2013;451:55–60.[Google Scholar]
  • 97. Liang J, Wang J, Azfer A, Song W, Tromp G, Kolattukudy PE, et al A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages. The Journal of biological chemistry. 2008;283:6337–46.[PubMed][Google Scholar]
  • 98. Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. The New England journal of medicine. 2011;365:620–8.[PubMed][Google Scholar]
  • 99. Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. American journal of human genetics. 2011;89:432–7.[Google Scholar]
  • 100. Yoshimura A, Suzuki M, Sakaguchi R, Hanada T, Yasukawa HSOCS, Inflammation, and Autoimmunity. Frontiers in immunology. 2012;3:20.[Google Scholar]
  • 101. Ilangumaran S, Rottapel RRegulation of cytokine receptor signaling by SOCS1. Immunological reviews. 2003;192:196–211.[PubMed][Google Scholar]
  • 102. Yoshimura ARegulation of cytokine signaling by the SOCS and Spred family proteins. The Keio journal of medicine. 2009;58:73–83.[PubMed][Google Scholar]
  • 103. Quaranta M, Knapp B, Garzorz N, Mattii M, Pullabhatla V, Pennino D, et al Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema. Science translational medicine. 2014;6:244ra90.[PubMed][Google Scholar]
  • 104. Coimbra S, Santos-Silva AA specific molecular signature for psoriasis and eczema. Annals of translational medicine. 2015;3:76.[Google Scholar]
  • 105. Uotila P, Valve E, Martikainen P, Nevalainen M, Nurmi M, Harkonen PIncreased expression of cyclooxygenase-2 and nitric oxide synthase-2 in human prostate cancer. Urological research. 2001;29:23–8.[PubMed][Google Scholar]
  • 106. Klotz T, Bloch W, Volberg C, Engelmann U, Addicks KSelective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer. 1998;82:1897–903.[PubMed][Google Scholar]
  • 107. Glynn SA, Boersma BJ, Dorsey TH, Yi M, Yfantis HG, Ridnour LA, et al Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients. The Journal of clinical investigation. 2010;120:3843–54.[Google Scholar]
  • 108. Heinecke JL, Ridnour LA, Cheng RY, Switzer CH, Lizardo MM, Khanna C, et al Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression. Proceedings of the National Academy of Sciences of the United States of America. 2014;111:6323–8.[Google Scholar]
  • 109. Obermajer N, Wong JL, Edwards RP, Chen K, Scott M, Khader S, et al Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. The Journal of experimental medicine. 2013;210:1433–445.[Google Scholar]
  • 110. Donnelly RP, Kotenko SVInterferon-lambda: a new addition to an old family. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2010;30:555–64.[Google Scholar]
  • 111. Doyle SE, Schreckhise H, Khuu-Duong K, Henderson K, Rosler R, Storey H, et al Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology. 2006;44:896–906.[PubMed][Google Scholar]
  • 112. Sommereyns C, Paul S, Staeheli P, Michiels TIFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS pathogens. 2008;4:e1000017.[Google Scholar]
  • 113. Lovendorf MB, Mitsui H, Zibert JR, Ropke MA, Hafner M, Dyring-Andersen B, et al Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis. Experimental dermatology. 2015;24:187–93.[PubMed][Google Scholar]
  • 114. Pivarcsi A, Stahle M, Sonkoly EGenetic polymorphisms altering microRNA activity in psoriasis--a key to solve the puzzle of missing heritability? Experimental dermatology. 2014;23:620–4.[PubMed][Google Scholar]
  • 115. Zhang W, Yi X, Guo S, Shi Q, Wei C, Li X, et al A single-nucleotide polymorphism of miR-146a and psoriasis: an association and functional study. Journal of cellular and molecular medicine. 2014;18:2225–34.[Google Scholar]
  • 116. Nanney LB, Stoscheck CM, Magid M, King LE., Jr Altered [125I]epidermal growth factor binding and receptor distribution in psoriasis. The Journal of investigative dermatology. 1986;86:260–5.[PubMed]
  • 117. Bowes J, Budu-Aggrey A, Huffmeier U, Uebe S, Steel K, Hebert HL, et al Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nature communications. 2015;6:6046.[Google Scholar]
  • 118. Prieto-Perez R, Cabaleiro T, Dauden E, Abad-Santos FGene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases. The pharmacogenomics journal. 2013;13:297–305.[PubMed][Google Scholar]
  • 119. Tejasvi T, Stuart PE, Chandran V, Voorhees JJ, Gladman DD, Rahman P, et al TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis. The Journal of investigative dermatology. 2012;132:593–600.[Google Scholar]
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