Advances in the genetics and immunology of psoriasis

Advances in Genetics

Psoriasis Gene Discovery

The number of genes associated with psoriasis has increased from 3 to 109 between 2008 and 2024. Genome-wide association studies (GWAS) have played a key role in the discovery of these genes across numerous populations. In 2024, researchers conducted the largest genetic study to date aimed at identifying susceptibility alleles that impact disease mechanisms and therapeutic targets. A meta-analysis of 18 GWAS with 36,466 cases and 458,078 controls revealed 109 psoriasis genetic loci, 45 of which were newly identified loci.¹

Genetic research has also impacted our understanding of the pathophysiology of psoriasis, revealing that psoriasis genes cluster into five main pathways:

1. TNF/NF-KB: TNIP1, TNFAIP3, TRAF3IP2, NFKBIA, REL
2. IL-17/IL-23: IL23R, IL12B, IL23A, IL18RA, IL17RA, TYK2, STAT3
3. AHR: AHR
4. Antigen Presentation: HLA-C, HLA-B, ERAP1
5. Innate Immunity: CARD14, IFIH1, RIGI, DHX58

Psoriasis Genes Elucidate Importance of New Cell Types

Psoriasis is typically associated with changes in the activity of T cells, dendritic cells, and keratinocytes. However, the discovery of these genes has highlighted the importance of fibroblasts, endothelial and lymphatic cells, eccrine cells, and melanocytes in the pathophysiology of psoriasis.

Psoriasis Subtypes

There are also distinct genes that are associated with the spectrum of pustular psoriasis, which includes subtypes such as generalized pustular psoriasis, palmoplantar pustulosis, and Acrodermatitis continua of Hallopeau. Studies have identified IL36RN, CARD14, AP1S3, MPO, SERPINA1/3, and BTN3A3 as the genes associated with pustular psoriasis and an increase in IL-1, IL-36, and IL-26. This understanding has impacted targeted psoriasis biologic therapeutics. Spesolimab, an anti-interleukin 36 receptor antagonist, has arisen as an effective treatment of generalized pustular psoriasis. Advancements in genetic research have also revealed trends in interleukin responses among the psoriasis subtypes along the autoimmune-autoinflammatory spectrum.

Applications of Genetics in Psoriasis

Genetics plays a large role not only in the pathophysiology, but also in the management of psoriasis. Applications span the study of genotype-phenotype, prediction of psoriatic arthritis, pharmacogenetics, and Mendelian randomization used to determine causality.

Genotype-Phenotype of Psoriasis

Psoriasis can be distinguished by early-onset, type I, and late-onset, type II. Many studies have evaluated the genetic associations of type I and type II disease. The IL-22 gene is associated with the earliest onset, with an age of psoriasis onset of 0-9 years, as well as with the clinical feature of inverse psoriasis. The ERAP1 and HLA-Cw6 genes are similarly associated with an earlier phenotype of age 10-20 years and with facial lesions. IL-1B is a gene associated with type II, and age of onset older than 40 years.^2–5

Prediction of Psoriatic Arthritis

Psoriatic arthritis is a common comorbid condition of psoriasis. Early detection and treatment are paramount in delaying and preventing irreversible joint damage. Application of machine learning methods and genetic research has characterized a genetic signature of around 200 genetic loci that can be used to provide robust risk assessment of psoriatic arthritis development within psoriasis patients, with an area under the receiver operating curve (AUROC) of about 80% indicating excellent accuracy.⁶

Pharmacogenetics and the Prediction of Response to Biologics

The identification of psoriasis genotypes has contributed to our understanding and prediction of individual responses to various biologics. For example, a meta-analysis of eight studies and 1,048 psoriasis patients revealed that the HLA-C*06:02 genotype showed a favourable response to ustekinumab (PASI75 of 92% in HLA-C*06:02-positive patients compared to 67% in HLA-C*06:02-negative patients).^7,8 A recent GWAS of ustekinumab response in psoriasis also found that HLA-C*06:02 plus the chr4 SNP predicted a two-fold PASI75 response (80% compared to 40% in patients who were HLA-C*06:02 and chr4 SNP-negative).⁹ Similarly, a study of 1,326 psoriasis patients found that the HLA-C*06:02-negative phenotype showed a favourable response by three-fold to anti-TNF therapy.^7,8 Additionally, the development of antidrug antibodies (ADA) is a common cause of loss of efficacy for biologic therapeutics. Recent genetic research on adalimumab ADA revealed that tryptophan at position 9 and lysine at position 71 of HLA-DR were protective against ADA, reducing the likelihood of adalimumab termination (HR 0.73 [0.57-0.94]).¹⁰

Similarly, genetic evaluation can be used to predict possible adverse effects of medications. A closer evaluation of single nucleotide polymorphisms (SNPs) may elucidate the phenomenon of paradoxical eczema in some psoriasis patients treated with biologics. A recent study of polygenic risk scores (PRS) found that atopic PRS (genetic burden) is associated with paradoxical eczema in biologic-treated patients with psoriasis. The authors generated three PRSs, PRS-AE using genome-wide significant loci for atopic eczema, PRS-AT for atopic diseases, and PRS-CO for both combined. They found that the PRS-CO with 170 SNPs was most significantly associated with paradoxical eczema (OR 1.83 [1.17-2.84]), followed by PRS-AT with 124 SNPs (OR 2.24 [1.20-4.17]) and PRS-AE with 71 SNPs (OR 1.89 [1.17-2.84]).¹¹

Genetic Tool: Mendelian Randomization

There are several well-studied environmental triggers of psoriasis, including obesity, biomechanical stress, diet, smoking, medications, and infections like streptococcus and HIV. Mendelian randomization has emerged as a genetic tool to identify causality in the relationship between factors like body mass index (BMI) and psoriasis, accounting for high vs low genetic variant burden.¹² A systematic review by Jin et al. reviewed 27 Mendelian randomization studies in psoriasis and identified five causal risk factors: obesity/BMI, smoking, Crohn’s disease, Type 2 diabetes, and depression, as well as three causal protective factors: vitamin D, fruit, and educational attainment.¹³

Advances in Immunology

Psoriasis Cascade and Therapies

The traditional psoriasis cascade begins with antigenic stimulation of dendritic cells, leading to the secretion of IL-23 that acts on IL-23R on T cells. T cells in turn release TNF, IL-17A, and IL-17F, which act on IL-17R on keratinocytes. This leads to the hyperproliferation of keratinocytes characteristic of psoriasis, as well as the release of additional TNF that positively feeds into the cascade. This understanding of the immunologic cascade has created the opportunity to develop effective biologic therapeutics that target IL-23, IL-17A, IL-17F, IL-17R, and TNF.

Single Cell and Spatial Advances

Two methods, single-cell sequencing and spatial transcriptomics, are used to sequence tissue samples and analyze and visualize cell types and heterogeneity. Single-cell sequencing begins with sample collection and cell isolation. Through library preparation, isolated RNA is extracted from which cDNA is derived for PCR and adaptor ligation. The sequencing process produces an expression profile for different cell types that can be analyzed. Spatial transcriptomics (ST) similarly starts with a tissue sample of diseased or healthy skin, and tissue sections are sequenced spatially either through barcodes or direct imaging on a slide. This allows for cell mapping and visualization of gene expression in the context of the skin architecture.

Prominent Cell Types in Psoriasis

These methods have highlighted the importance of several additional cell types. The first is fibroblasts, which demonstrate a role in amplifying inflammatory responses in psoriasis. SFRP2+ fibroblasts produce CCL13, CCL19, and CXCL12 to amplify myeloid, dendritic, T17, and keratinocyte cells.¹⁴ Fibroblast subsets in the reticular dermis (c3) and papillary dermis (c4) regulate keratinocytes and endothelial cells.¹⁵ The combination of WNT5A, IL-24, and fibroblasts has also shown early response to therapies, including IL-23 inhibitors, IL-17 inhibitors, and topical steroids.¹⁶

Endothelial cells are also crucial in the pathogenesis of psoriasis. IGFBP7hi endothelial cells in psoriasis degrade the glycocalyx barrier, allowing for T-cell infiltration and further psoriatic inflammation. In the imiquimod mouse model, an anti-IGFBP7 antibody restored glycocalyx thickness and reduced T-cell infiltrates, vascular proliferation, and disease severity.¹⁷

Keratinocytes also play an important role in amplifying psoriatic inflammation. Hypoxia-inducible factor 1a (HIF1a), downstream of IL-17 signalling, targets GLUT1 and drives psoriatic epithelial remodelling via glycolysis and lactate production. The imiquimod mouse model also demonstrated that genetic or pharmacologic knockdown of HIF1a ameliorates inflammation.¹⁸ Finally, single-cell and spatial transcriptomics have also elucidated the prominence of B-cells, sebaceous glands, and epidermal plasmacytoid dendritic cells in psoriasis.^19–21

Tissue scale-cartography has revealed the presence of B lymphocytes in lesional skin, which is absent in healthy skin.¹⁹ This has been confirmed by immunohistochemical staining of lesional skin with B cell antigen CD20, which confirmed B cell clusters.¹⁹ B cells may have a potential role in psoriasis pathology, as analysis of B cell cluster pathways within lesional skin has revealed functional signatures of cytokine production and antigen presentation. ¹⁹ It has been proposed that IL-10-producing regulatory B cell (B_regs) depletion may play a role in activating the IL-23/Th17 axis.^22,23 A study by Hayashi et al. has observed that patients with psoriasis have increased B_regs progenitors and a loss of mature IL-10-producing B_regs, compared to healthy individuals. This observation is reversible with biologic therapy.²⁴ This contributes to the understanding of positional immune dynamics in the epithelium and upper dermis during inflammation.¹⁹

Through the investigation of the spatial transcriptome of sebaceous glands, it is now known that sebaceous glands actively modulate inflammation and contribute to skin homeostasis with a cell type-specific lipid metabolism.²⁰ Psoriasis and atopic dermatitis sebaceous glands express genes for proteins that have a role in lipid metabolism and transport. These genes include ALOX15B, APOC1, FABP7, FADS1/2, FASN, PPARG, and RARRES1. For psoriasis specifically, SERPINF1, FKBP5, IFIT1/3, and DDX58 were identified as inflammation-related spatially variable genes. ²⁰ Researchers have also identified psoriasis-specific pathways within lipid metabolism, keratinization, neutrophil degranulation, and antimicrobial peptides that further support the role of sebaceous glands in modulating skin disease and inflammation.²⁰

Epidermal plasmacytoid dendritic cells (pDC) are most commonly found in the dermis during the acute phase of psoriasis. ²¹ However, a study utilizing single-cell sequencing and Cell Interaction by Multiplet utilizing an optimized, gentler, cell dissociation protocol has identified cells expressing markers of pDCs previously not found in single-cell RNA-Seq studies with full-depth biopsies and other dissociation protocols. ^14,25 This finding was validated using single-molecule in situ hybridization and immunofluorescence staining for the pDC-specific marker, CLEC4C/BDCA-2, which revealed coexpression of BDCA2 with IRF7 that suggests activated pDCs. Altogether, this may underscore the role of activated pDCs in sustained skin inflammation.²¹

A Refined Psoriasis Paradigm

The advancements in genetics and immunology have led to the discovery of additional, essential components of the psoriasis cascade. Beyond the traditional cascade, we summarize the role of these additional cell types. Plasmacytoid dendritic cells stimulate TNF and IFN-𝛼; TNF feeds into the dendritic cell stimulation of IL-23, and IFN-𝛼 stimulates IL-17A and IL-17F that act on keratinocytes. HIF-𝛼 leads to the expression of GLUT1 channels on keratinocytes, driving glycolysis and lactate production. Keratinocytes also stimulate IL36G, CCL20, TNF, and TGFB1, which stimulates fibroblasts to produce CCL13, CCL19, and CXCL12 further stimulating the cascade by acting on dendritic cells (Figure 1).

Figure 1. Refined Psoriasis Paradigm. The psoriatic inflammation produced by antigen-presenting cells, T cells, and keratinocytes is amplified by interactions with fibroblasts, vascular endothelial cells, and plasmacytoid dendritic cells.

Infectious and Environmental Triggers of Psoriasis

Research by Chen et al. identifies the role of Group A streptococcus (GAS) antigens in inducing CD1a-autoreactive T cells, promoting psoriatic inflammation. ²⁶ Individuals with psoriasis were found to have significantly higher frequencies of circulating GAS-reactive T cells. Subsets of expanded GAS-reactive T cell clones were also auto-reactive to self-lipid antigen lysophosphatidylcholine.²⁶ A study of environmental triggers by Ishimoto et al. revealed that wheat, yeast, tobacco, and bacteria, along with ADAMTSL5, are recognized by the V𝛼3S1/V𝛽13S1 T-cell receptor and are antigens that potentially trigger psoriasis.²⁷

Conclusion and Discussion

In summary, recent scientific advances have deepened our understanding of psoriasis immunology, genetics, and the role of antigens. Genetic research has revealed over 100 genes that contribute to psoriatic susceptibility. Additionally, genetic factors influence psoriasis phenotypes, development of PsA, and response to therapy. Finally, mendelian randomization elucidated the causal associations in psoriasis with factors such as obesity and smoking. Advancements in immunology have built upon the basic psoriasis model by elucidating the role of fibroblasts, endothelial cells, and other cell types. Research has also broadened our understanding of psoriasis triggers to include infectious and environmental antigens like Group A streptococcus/lipid antigens and ADAMTSL5/wheat, tobacco, and microbial antigens. With consistent growth and innovation within these fields, the scientific community continues to lead the way toward psoriasis remission and a cure.

Conflict of Interest

No conflict of interest.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This article has no funding source.

W.L. has received research grant funding from Amgen, Janssen, Leo, Novartis, Pfizer, Regeneron, and TRex Bio.

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Posted on 11 November 202425 November 2024