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Center for Musculoskeletal Research, Division of Allergy, Immunology and Rheumatology, University of Rochester School of Medicine & Dentistry, Rochester, New York, USA
Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USADepartment of Dermatology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
Correspondence: Wilson Liao, UCSF Department of Dermatology, University of California San Francisco, 2340 Sutter Street, Box 0808, San Francisco, California 94143, USA.
Psoriasis is a chronic inflammatory condition characterized by systemic immune dysregulation. Over the past several years, advances in genetics, microbiology, immunology, and mouse models have revealed the complex interplay between the heritable and microenvironmental factors that drive the development of psoriatic inflammation. In the first of this two-part review series, the authors will discuss the newest insights into the pathogenesis of psoriatic disease and highlight how the evolution of these scientific fields has paved the way for a more personalized approach to psoriatic disease treatment.
). In its skin manifestation, psoriasis (PsO) most commonly presents with plaques as PsO vulgaris (PsV) but also includes rarer subtypes such as guttate, pustular, erythrodermic, and inverse PsO. Approximately 30% of patients with PsO have psoriatic arthritis (PsA) (
), which can manifest as synovitis, enthesitis, dactylitis, and spondylitis. Owing to the overlap between the skin manifestation of PsO, PsA, and other comorbidities associated with the systemic inflammation from this immune-mediated disease state, some researchers, providers, and patients as well as the National Institutes of Health consider these conditions to be part of a spectrum of psoriatic disease. It has only been in the last few decades that researchers have truly begun to unravel the pathogenesis of PsO and PsA. Since then, this research has evolved rapidly.
Although the mechanism of PsO is now understood to involve IL-23/IL-17 signaling, there is increasing recognition that PsO is driven by a complex interplay between numerous other intrinsic and extrinsic factors. Recent innovations in next-generation sequencing and single-cell profiling coupled with increases in computing power have enabled a multiomics approach to understand the genetic landscape of PsO, tissue-specific immune microenvironments, and host‒microbiome interactions. These data provide a more nuanced understanding of PsO and PsA, revealing novel pathways and mechanisms that contribute to the development of PsA, particular psoriatic disease subtypes, and characteristic patterns of inflammation.
In the first of this two-part review series, the authors highlight the latest developments in genetics, environmental triggers, and immunology of PsO and PsA, novel insights from mouse models, and how these new developments have enabled more personalized treatment for psoriatic disease.
The genetics of PsO and PsA
Genetic architecture of PsO
Genetic susceptibility to PsV is polygenic, according to the sum of multiple genetic risk factors. To date, GWASs have identified over 63 genetic risk loci, which account for 28% of PsV heritability (
). GWASs have revealed valuable insights into disease pathogenesis (Table 1). Of particular importance are genes associated with antigen presentation, such as major histocompatibility complex (MHC) I: HLA-C∗06:02, HLA-C∗12:03, HLA-B∗57:01, HLA-B∗38:01, and HLA-A∗02:01. Coding mutations in ERAP1 and ERAP2, involved in peptide processing, have also been linked to PsV. Genetic risk loci have been identified in the NF-κB pathway, which mediates keratinocyte (KC) proliferation and differentiation, production of proinflammatory cytokines in T helper (Th)17 cells, clonal expansion of T cells, and Wnt signaling in osteoblasts (
). These include genetic variants in TRAF3IP2, CARD14, TNFSF15, TNIP1, IKBKE, CHUK, REL, and NFKBIA and noncoding mutations in TNFAIP3. Other genetic risk loci, such as IFIH1, DDX58, KLF4, ZC3H12C, CARD14, and CARM1, are involved in IFN-I signaling and the innate immune response, whereas variants in IL23R, IL12B, IL23A, and TYK2 play a role in adaptive (IL-23/IL-17) immunity. PsV genes also include those involved in host defense and in the maintenance of the skin epithelial barrier, such as β-defensin gene DEFB and LCE3B/LCE3C.
Table 1Major Identified Genetic Risk Loci for Psoriasis and Their Associated Pathways
Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2 A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.
Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2 A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis [published correction appears in Nat Commun 2015;6:7741].
). Surprisingly, only a few genetic variants so far have been identified as being discrepant between PsA and PsV, one of the main ones being HLA-C∗06:02, which is a risk factor for PsV but protective for PsA, with other discrepant variants observed near IL23R, TNFAIP3, LCE3A, and TNFRSF9 (
). This may indicate a more prominent role for environmental factors in the development of PsA. Notably, mice expressing three distinct targeted mutations of the ZF7 ubiquitin-binding motif of the TNFAIP3 gene were found to develop distal arthritis through IL-17‒mediated NF-κB activation (
Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression.
). Interestingly, different HLA alleles have been found to be preferentially associated with PsA features such as synovitis, sacroiliitis, dactylitis, and enthesitis (
). Coding mutations in IL36RN, CARD14, AP1S3, SERPINA3, and MPO that affect IL-1 and IL-36 signaling have been associated with the clinical spectrum of pustular PsO (Supplementary Table S1). Psoriasis genetic variants overlap with Crohn’s disease (
Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms [published correction appears in Am J Hum Genet 2015;97:933].
Sequencing data from a large Chinese cohort has revealed a potentially important, unexpected role for small genomic insertions and deletions in PsO susceptibility (
). Future studies employing Mendelian randomization are likely to help define the directionality between PsO and its comorbidities. Finally, several studies have highlighted the potentially powerful role of psoriatic genetics in precision medicine. A meta-analysis showed that HLA-C∗06:02 is associated with favorable response to ustekinumab in patients with PsV (
). Using a machine learning approach involving ~200 genetic loci, researchers have developed a model to predict PsA with an area under the receiver operator curve of 0.82 (
). Although smoking is associated with a higher risk of PsA in the general population, among patients with PsO, there is either a decreased incidence of PsA or no significant relationship (
Medications such as β-blockers, lithium, antimalarials, imiquimod (IMQ), nonsteroidal anti-inflammatory drugs, IFN-α, and terbinafine have been linked to induction and exacerbation of PsO (
). Animal studies have shown that mice with diet-induced obesity have more severe psoriasiform dermatitis, suggesting that the chronic inflammatory state caused by adipokines in excessive fat tissue could be a pathogenic link between obesity and PsO (
). A meta-analysis showed that weight loss through dietary intervention in individuals who are obese improves pre-existing PsO and prevents de novo PsO (
However, more recent studies suggest that mechanisms other than obesity may mediate the impact of diet on PsO. For example, an increase of saturated fatty acids (SFAs) in healthy, lean mice alone was sufficient to induce an exacerbation of psoriasiform inflammation, and reduction of nutritional SFAs diminished the psoriatic phenotype in mice without obesity (
). Another study showed that exposure to a high-sugar and moderate-fat western diet (WD), even in the absence of obesity, was enough to induce skin inflammation in mice in as little as 4 weeks through the recruitment of IL-17A‒producing γδ-type T cells (
). Interestingly, WD-induced skin inflammation was blocked by systemic antibiotic treatment, suggesting a critical role of gut dysbiosis in diet-induced inflammation. Further studies are warranted to determine whether specific diets, in the absence of weight reduction, would bring meaningful clinical improvement in PsO and PsA.
Biomechanical stress is another major microenvironmental factor in psoriatic inflammation (
). This is supported by a recent study showing that erosive disease in mice is confined to mechanosensitive regions and driven by mesenchymal cells that recruit monocytes by CXCL1 and CCL2 before differentiation into mature osteoclasts (
). The pathogenic importance of exogenous mechanical loading suggests that rather than inherent genetic predisposition, dynamic interplay between the immune system and microenvironmental factors plays a major role in the development of PsA.
Various infections have been known to trigger or worsen PsO. HIV has been linked to a higher prevalence of PsO (
), possibly through similarities between streptococcal antigens and KC proteins, may induce cross reactivity in streptococcal specific T cells leading to the activation of PsO (
Psoriasis vulgaris--a sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis.
). Periodontitis has also been associated with PsO, with patients with PsO demonstrating more gingival inflammation, alveolar bone loss, and missing teeth (
Emerging research now suggests that the interactions between the skin and gut microbiome and the host immune system may play a key pathogenic role in the development of PsO and PsA (Supplementary Table S1). Bacteria play crucial roles in host IL-17–mediated mucosal barrier immunity, Th17 cell development, and RORγt+ regulatory T cells (Tregs) immune homeostasis (
). PsV skin is enriched in proinflammatory Streptococcus and Staphylococcus, although not all studies observed this enrichment. Both Streptococcus aureus and Staphylococcus aureus elicit a strong Th17-type response in skin T effector cells, resulting in the induction of IL-17A, IL-17F, and IL-22 cytokines in murine models (
The role of gut microbiome in psoriasis: oral administration of Staphylococcus aureus and Streptococcus danieliae exacerbates skin inflammation of imiquimod-induced psoriasis-like dermatitis.
). Interestingly, murine models of PsA and PsV do not develop inflammatory disease when treated with antibiotics or raised in a germ-free environment (
Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats.
Similarly, the gut microbiome in PsV has demonstrated a decrease in Bacteroides and Faecalibacterium prausnitzii, a gut commensal that produces the immunomodulatory SCFA, butyrate (
). The only study of the gut microbiome in PsA showed decreases in Akkermansia, Ruminococcus, and Pseudobutyrivibrio, which were associated with decreased levels of immunomodulatory medium-chain fatty acids (
Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease.
In addition to its role in disease pathogenesis, the microbiome may also be a modulator of therapeutic response. Gut bacteria are not only involved in drug metabolism but also indirectly influence drug efficacy through effects on host gene expression and interactions between drugs and bacterial metabolites (
). For example, patients with PsV and PsA who responded to secukinumab had a higher abundance of intestinal Citrobacter, Staphylococcus, and Hafnia/Obesumbacterium (
Not surprisingly, the microbiome is now a prime target for novel therapeutics. Already, clinical trials are investigating the efficacy of probiotic supplements for the treatment of PsO. One double-blinded, placebo-controlled clinical trial did not find any significant clinical improvement in PsV with a probiotic containing Lactobacillus (
). Intriguingly, a recent case report described a patient who developed sustained remission of her PsA after undergoing fecal microbiota transplantation (FMT) for a Clostridium difficile infection (
Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis: protocol for a 6-month, double-blind, randomised, placebo-controlled trial.
Data from GWAS and other preclinical studies suggest that although certain immunopathogenic mechanisms may be shared, there are likely also tissue-specific microenvironmental factors that contribute to the phenotypic heterogeneity of PsO and PsA. The IL-23/IL-17 axis is common to the pathogenesis of both cutaneous PsO, PsA, and enthesitis (
). Binding of IL-23 to the heterodimeric IL-23R/IL-12Rβ1 receptor activates Tyk2- and Jak2-dependent signal transducer and activator of transcription 3 signaling, which promotes the expansion of Th17 and Tc17 cells that secrete IL-17A, IL-17F, and TNF (
). Components of innate immunity also facilitate the inflammatory cascade in cutaneous PsO and PsA in which plasmacytoid and conventional DCs are activated in the skin (
), respectively, and produce inflammatory cytokines, including IL-23, to facilitate the priming and proliferation of Th17 and Tc17 cells. Antimicrobial peptides, most notably cathelicidin (LL37), bind to self-DNA and stimulate plasmacytoid DCs through toll-like receptor (TLR) 9 or serve as autoantigen presented to T cells by HLA-C∗06:02. IL-17A can also be produced by group 3 innate lymphoid cells (ILCs) that are abundant in PsV and PsA (
In addition to heightened proinflammatory signaling, PsO involves the suppression of anti-inflammatory pathways. Both PsO and PsA demonstrate decreased numbers of CD73+ Tregs (
IL-38 has an anti-inflammatory action in psoriasis and its expression correlates with disease severity and therapeutic response to anti-IL-17A treatment.
Differences in tissue-specific cues result in the activation of unique pathogenic pathways in the skin and synovium. In the skin, IL-17 and IL-22 stimulate KC hyperplasia as well as CXCL8-dependent neutrophil recruitment and microabscess formation (
). In the joints, local inflammatory cytokines and GFs promote osteoclast‒osteoblast decoupling and RANKL-mediated destructive bone remodeling in PsA (
) in the osteoblasts of patients with PsA. A recent study utilizing an in vitro cell culture system to mimic the local inflammatory microenvironment of bone-forming sites validated the link between Wnt signaling and inflammation, establishing that constitutive low-intensity stimulation with TNF induces persistent expression of Wnt proteins, causing increased bone formation through NF-κB signaling (
). Furthermore, binding of osteoclast-derived RANK to osteoblastic RANKL leads to the activation of RUNX2, which mediates bone remodeling and bone formation in Rankl-mutant mice (
Locally presented antigens are another element of the immune microenvironment that may play a key role in psoriatic inflammation. In PsV, a large proportion of cutaneous CD8+ T cells is oligoclonal, with the oligoclonality usually confined to lesional skin. To date, putative autoantigens in PsO include LL-37, ADAMTSL5 (
Autoantigens ADAMTSL5 and LL37 are significantly upregulated in active psoriasis and localized with keratinocytes, dendritic cells and other leukocytes.
Preclinical mouse models are a valuable tool for investigating the pathogenic role of pathways, genes, or transcripts identified in genetic analyses and other studies. These approaches model one or more components of human PsO, but none to date replicate the disease in its full complexity. Mouse models of PsO can be broadly classified as spontaneous, xenotransplants, induced/acute, and genetically engineered (reviewed in
). However, the use of these models was limited because they lacked T-cell infiltration.
Other early approaches used grafts of uninvolved skin from patients with PsO onto immunodeficient mice (athymic nude, AGR), which triggered a conversion into a psoriatic plaque (
) are the most translatable approach for studying treatment efficacy and the role of skin-resident versus that of circulating immune cells. However, developing them is challenging, as they require full-thickness patient skin, and some of them require autologous activated T cells (
). However, nonlesional skin from patients with PsV treated with IMQ has different transcriptomic signatures from those of lesional skin, suggesting that IMQ models recapitulate only limited aspects of PsO (
Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1{alpha}, and TNF-{alpha} recapitulates some features of psoriasis.
). These models reproduce some features of PsO and provide insight into the pathogenic role of individual cytokines and their synergistic effects. However, the need for repeated injections limits their utility for long-term study. The development of novel DNA minicircles allowing for sustained transgenic expression of IL-23 (
) reproduces chronic psoriasiform skin inflammation, enthesitis, arthritis, and vascular inflammation in mice, providing an innovative model for studying psoriatic comorbidities.
Recently, advances in genetic engineering have led to the development of transgenic and knockout animal models, which have provided novel insights into PsO. For example, the CD18 hypomorphic model (CD18hypo PL/J background; CD18[Itgb2tm1Bay]) helped to define the role of skin-infiltrating T cells (
Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia.
). These models will be helpful in identifying the cellular mechanisms underlying CVD comorbidities.
The newest murine model of PsO overexpresses a serine protease called kallikrein 6 (KLK6). Klk6 mice (Klk6+) develop severe psoriasiform dermatitis and arthritis that are Klk6- and PAR1- (F2R) dependent (
). These models demonstrate how epidermal factors can cause arthritis.
Precision medicine
Although major advances in the treatment of PsO have been made over the last few decades, many patients are treatment refractory, especially those with PsA (
), and achieving long-term remission remains a significant challenge. Precision medicine can be used to address these gaps in care by tailoring treatment on the basis of individual patient characteristics.
Clinical features, serologic factors, and omics datasets can help us classify patients into subpopulations on the basis of their likelihood to respond to a specific therapy or their probability of developing systemic comorbidities (
). Factors such as therapeutic levels and neutralizing antidrug antibody levels can also help to guide clinicians when assessing the initial response and sustained efficacy of a drug (
). However, in the near future, clinicians will be able to utilize more sophisticated approaches that integrate clinical phenotypic data with predictive or diagnostic classifiers constructed from omic datasets, such as for the transcriptome (
LC-MS metabolomics of psoriasis patients reveals disease severity-dependent increases in circulating amino acids that are ameliorated by anti-TNFalpha treatment.
Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer [e-pub ahead of print].
). Already, some promising biomarkers and predictive models are starting to emerge (Supplementary Table S2).
Further advancements in omic datasets will give rise to more precise clinically relevant PsO models in the future. Complementing these technologies are the advances driven by big data analysis and machine learning, which has been applied to improve the diagnostic accuracy of tissue pathology (
). The last critical element is to improve the high throughput capture of multimodal clinical data from the electronic medical record, a major requirement in the development of precision medicine (
The latest developments in psoriatic research suggest that a multitude of interconnected factors is responsible for the heterogeneous presentation of psoriatic disease (Figure 1). Numerous genetic variants and the interactions occurring in the microenvironment between immune cells, KCs, osteoclasts, and the microbiome determine the development of psoriatic disease, disease severity, therapeutic response, and the development of comorbidities such as inflammatory arthritis and cardiometabolic conditions. These advances have not only revealed novel therapeutic targets but also provide data to optimize treatment for the individual patient. The next frontier lies in harnessing this information in the clinical setting to deliver more timely, effective, and personalized care.
Figure 1The multifactorial pathogenesis of psoriatic disease. The development of psoriasis and psoriatic arthritis is influenced by a combination of genetic risk loci (red), many of which are involved in the regulation of IL-23 receptor signaling and the NF-kB pathway, imbalances in Treg/T17 immunity (blue), as well as changes in the gut and cutaneous microbiome (yellow). Heather McDonald, BioSerendipity, LLC (Elkridge, MD) assisted with the illustration. KLK6, kallikrein 6; MCFA, medium-chain fatty acid; SCFA, short-chain fatty acid; STAT, signal transducer and activator of transcription; Th, T helper; Treg, regulatory T cell.
Illustration assistance provided by Heather McDonald, BioSerendipity, LLC, Elkridge, MD.
JEG has received grant support from AbbVie, Almirall, Bristol-Myers Squibb/Celgene Novartis, Eli Lilly, and Kyowa-Kirin and served as an advisor to Almirall, Novartis, Eli Lilly, and AnaptysBio. JUS has consulted for AbbVie, Janssen, Novartis, Sanofi, Eli Lilly, UCB, Amgen, and Pfizer and received research grant support from Pfizer and Amgen. WL has received research grant support from AbbVie, Amgen, Janssen Pharmaceuticals, Novartis, Pfizer, Regeneron, and TRex Bio. SB is an employee of the National Psoriasis Foundation. The remaining authors state no conflict of interest.
Acknowledgments
The authors would like to thank Jerry Bagel, Jackie Domire, Joel Gelfand, George Gondo, Alice Gottlieb, Samantha Koons, and Gil Yosipovitch for the review of the manuscript. DY is supported by a grant from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. JEG is supported by P30-AR075043 and R01-AR060802. OP is supported by T32 AR007197. JUS is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institute of Health (NIH) (R01AR074500), the Snyder Family Foundation, the Riley Family Foundation, and the National Psoriasis Foundation. NLW is supported by the following awards from the NIH: R01-AR073196, P50-AR070590, and R01-AR069071. CR is supported by a grant from the NIH (R01 AR0609000). WL is supported by grants from the NIH U01-AI119125 and the National Psoriasis Foundation.
This study reported a significant increase in the Streptococcus-to-Propionibacterium ratio between PsV skin and healthy controls but did not report the significance of the difference in Streptococcus abundance on its own.
Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease.
Abbreviations: NS, not significant; PsA, psoriatic arthritis; PsV, psoriasis vulgaris.
1 Nonsignificantly different between PsV or PsA and healthy controls.
2 This study reported a significant increase in the Streptococcus-to-Propionibacterium ratio between PsV skin and healthy controls but did not report the significance of the difference in Streptococcus abundance on its own.
Supplementary Table S2Biomarkers of Psoriatic Disease that Were Found to be Associated with the Development of PsA, Disease Severity, and Therapeutic Response in Larger Patient Cohorts and Consortium Studies
Biomarker
Association
References
Genetic markers
A set of 200 genetic markers were able to predict the development of PsAwith an area under the curve of 0.82% and 100% specificity
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