The immunogenetics of Psoriasis: A comprehensive review

doi:10.1016/j.jaut.2015.07.008

Journal of Autoimmunity

Volume 64, November 2015, Pages 66-73

https://doi.org/10.1016/j.jaut.2015.07.008 Get rights and content

Highlights

•
Psoriasis is a chronic inflammatory, skin disease with genetic features similar to other complex inflammatory diseases.
•
Many genetic associations are within immune genes, highlighting the importance of immune dysregulation in psoriasis.
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The role of the Th17/IL-23 axis in psoriasis is well established, and many genetic risk factors are found in this pathway.
•
Genetic-associations in both innate immunity and immunoregulatory genes points to a complex etiology of psoriasis.
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Understanding psoriasis-associated mutations may lead to improved treatment, novel therapeutics, and personalized medicine.

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.

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 co-morbidities, 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, and 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], [6], [7], [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.

Section snippets

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

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.

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

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

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

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 associations 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

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

Funding sources

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

Financial disclosures

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

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Review articleThe immunogenetics of Psoriasis: A comprehensive review

Highlights

Abstract

Introduction

Section snippets

Antigen presentation

The IL12/23 axis

T-cell polarization

Innate immunity

Negative regulators

Immune genes with less-well established links to psoriasis pathogenesis

Conclusions

Funding sources

Financial disclosures

J. Investigative Dermatology

J. Investigative Dermatology

J. Investigative Dermatology

J. Investigative Dermatology

Am. J. Hum. Genet.

Trends Immunol.

Trends Immunol.

J. Investigative Dermatology

Immunity

J. Investigative Dermatology

Am. J. Hum. Genet.

J. Biol. Chem.

Am. J. Hum. Genet.

J. allergy Clin. Immunol.

Immunology

Immunity

J. Dermatological Sci.

Genomics

Blood

J. Dermatological Sci.

J. Investigative Dermatology

J. Investigative Dermatology

Autoimmun. Rev.

Cell. Signal.

J. Investigative Dermatology

Am. J. Hum. Genet.

Am. J. Hum. Genet.

J. Investigative Dermatology

J. Dermatological Sci.

J. Investigative Dermatology

J. Investigative Dermatology

Cytokine & Growth Factor Rev.

J. Biol. Chem.

Archives Biochem. biophysics

J. Investigative Dermatology

Cell

J. Biol. Chem.

Am. J. Hum. Genet.

Immunology of psoriasis

Annu. Rev. Immunol.

Psoriasis

Annu. Rev. pathology

Cyclosporine regimens in plaque psoriasis: an overview with special emphasis on dose, duration, and old and new treatment approaches

The Scientific World J.

Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes

N. Engl. J. Med.

Cyclosporin A for psoriasis

N. Engl. J. Med.

Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis

Nat. Med.

Pathogenesis and therapy of psoriasis

Nature

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Proc. Natl. Acad. Sci. U. S. A.

Psoriasis vulgaris: a genetic approach

J. Investigative Dermatology

The genetics of psoriasis and autoimmunity

Annu. Rev. genomics Hum. Genet.

HLA diversity in the 1000 genomes dataset

PloS One

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

Nat. Genet.

Review article
The immunogenetics of Psoriasis: A comprehensive review