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  • Review Article
  • Published:

Getting under the skin: the immunogenetics of psoriasis

Nature Reviews Immunology volume 5, pages 699–711 (2005)Cite this article

A Corrigendum to this article was published on 01 October 2005

Key Points

  • Psoriasis is an inflammatory disease of the skin that is mediated by T cells, dendritic cells (DCs), and a broad range of cytokines and chemokines. However, much of the clinical disease phenotype is caused by hyperplasia of epidermal keratinocytes, altered differentiation of these cells in a 'regenerative' pathway and increased growth of dermal blood vessels (causing thick, red, scaly plaques on the skin surface).

  • Psoriasis has been proposed to be a T-cell-mediated autoimmune disease, because clonal populations of T cells have been identified in skin lesions and the overall characteristics of these T cells indicate that they are T helper 1 cells and type 1 cytotoxic T-cell effectors. However, as reactivity to a self-antigen has not been shown, others have suggested that immune activation in the skin is triggered through innate immune pathways stimulated by Toll-like receptors, heat-shock-protein receptors or glycolipid-antigen receptors.

  • The molecules that are involved in pathogenic inflammation in the skin have been defined by large-scale gene-expression studies, and many interactive pathways of inflammation have been suggested to occur. Two ideas that stem from this work are that, first, lymphoid tissue (self-perpetuating infiltrates of T cells and DCs) is organized in the skin by local expression of chemokines and that, second, a 'type 1' pathway of inflammatory gene products (involving interleukin-23, interferon-γ and signal transducer and activator of transcription 1) is central to pathogenic inflammation in psoriasis.

  • There is a strong interrelationship between regenerative growth of the epidermis (as programmed for wound healing) and activation of cellular immunity through innate and adaptive immune pathways. Genes that confer susceptibility to psoriasis could alter keratinocyte differentiation responses, cellular immune responses or common molecular pathways that control the balance of epithelial-cell hyperplasia and immune activation in the skin.

  • Approximately half of all patients with psoriasis have a susceptibility variant from the MHC class I region. However, some patients can develop psoriasis without any contribution from the MHC locus. In most cases, several genetic variants are required for disease to develop. Genetic studies of families have localized 20 such loci.

  • So far, only a handful of psoriasis-susceptibility genes have been identified in a single population. Their role in disease pathogenesis and the effect of environmental triggers on these genes is not clear.

  • One susceptibility variant for psoriasis that maps to human chromosome 17q25 has been shown to result in the loss of an enhancer binding site for the RUNX (runt-related transcription factor) family of transcription factors. Changes in RUNX-binding sites have also been seen at different loci in individuals with either systemic lupus erythematosus or rheumatoid arthritis, indicating that some changes in psoriasis are within pathways that are altered in other autoimmune diseases.

  • Several variants for psoriasis and other autoimmune or inflammatory diseases reduce the threshold for T-cell activation or affect immunological synapse formation or dissolution.

Abstract

Psoriasis is a chronic inflammatory disorder of the skin that is mediated by T cells, dendritic cells and inflammatory cytokines. We now understand many of the cellular alterations that underlie this disease, and genomic approaches have recently been used to assess the alterations of gene expression in psoriatic skin lesions. Genetic susceptibility factors that contribute to predisposition to psoriasis are now also being identified. It is hoped that we will soon be able to correlate the cellular pathogenesis that occurs in psoriasis with these genetic factors. In this Review article, we describe what is known about genes that confer increased susceptibility to psoriasis, and we integrate this with what is known about the molecular and cellular mechanisms that occur in other inflammatory and autoimmune disorders.

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Figure 1: Characteristic histological features of psoriatic plaques.
Figure 2: Differentiation of keratinocytes in psoriatic plaques compared with normal skin (or uninvolved skin of patients with psoriasis).
Figure 3: Sequential steps in the development of a psoriatic plaque.
Figure 4: Map of the MHC locus.
Figure 5: Molecules in T cells that are associated with autoimmunity and psoriasis.

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Acknowledgements

The authors acknowledge the invaluable contributions of the clinicians and patients who have contributed to this study. We thank M. Akin for tireless help in preparing this manuscript and A. Shaw for comments on figure 5. The studies carried out in our laboratories were supported, in part, by grants to A.M.B. and J.G.K. from the National Institutes of Health (United States) and to A.M.B. from the National Psoriasis Foundation (United States).

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Authors and Affiliations

  1. Department of Genetics, Washington University School of Medicine, Saint Louis, 63110, Missouri, USA

    Anne M. Bowcock

  2. Laboratory for Investigative Dermatology, The Rockefeller University, New York, 10021, New York, USA

    James G. Krueger

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  1. Anne M. Bowcock
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Correspondence to Anne M. Bowcock or James G. Krueger.

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DATABASES

Entrez Gene

PSORS1

PSORS2

PSORS4

PSORS5

OMIM

psoriasis

Glossary

PLAQUE

A raised, flat-topped lesion of the skin that is greater than or equal to 1 cm in diameter. This type of lesion typifies psoriasis vulgaris. Smaller lesions (known as papules) characterize guttate psoriasis. Pustular or erythrodermic forms of psoriasis might not show well-formed plaques but, instead, have pustules or extensive inflammation of the skin.

CYCLOSPORIN

A commonly used immunosuppressive drug that blocks calcineurin A and thereby inhibits Tcell activation. It is used to prevent the rejection of transplanted organs and to treat some inflammatory diseases.

SEVERE COMBINED IMMUNODEFICIENT MOUSE

(SCID mouse). An inbred mouse that has a naturally occurring mutation that impairs the development of B and T cells.

AGR129 MOUSE

A mouse that is deficient in type-I- and type-II-interferon receptors and recombination-activating gene 2. These mice lack functional B and T cells and have impaired interferon-mediated innate immune functions. They have been used in transplantation experiments to improve graft acceptance.

RETE

Regions of the interfollicular epidermis that project down into the dermis. These regions are also known as rete pegs. In normal skin, the projections are shallow, giving a wavy pattern to the epidermal–dermal junction. In psoriasis, rete are highly elongated and form finger-like downward projections into the dermis.

DESMOSOME CONNECTION

An adhesive junction that connects epithelial cells in stratified squamous tissues. These junctions are composed of multiple protein subunits and are the points where keratin filaments are inserted into the plasma membrane.

DC LYSOSOMAL-ASSOCIATED MEMBRANE PROTEIN

(DC-LAMP). A membrane protein that is associated with lysosomes in dendritic cells (DCs) and is a marker of activated and/or mature DCs.

PSORIATIC ARTHRITIS

A form of inflammatory arthritis that occurs in patients with psoriasis.

PLASMACYTOID DC

A dendritic cell (DC) that lacks myeloid markers such as CD11c and CD33 but expresses high levels of HLA-DR and CD123. These cells produce high levels of interferon-α after activation: for example, when stimulated through Toll-like receptors.

CONCORDANCE

The occurrence of the same trait in both members of a pair of twins.

LINKAGE DISEQUILIBRIUM

The non-random association of alleles from two independent loci, owing to their close physical proximity and a lack of recombination between them.

DERMAL PAPILLA

The dermis is divided into a superficial region, known as the papillary dermis, and a deeper region, known as the reticular dermis. Portions of the papillary dermis that fill the space between the rete of the epidermis are known as dermal papillae. In normal skin, dermal papillae form shallow waves of upward projections. By contrast, in individuals with psoriasis, the papillae are long, finger-like upward projections.

DESQUAMATION

The normal process through which terminally differentiated squamous keratinocytes (which are present in the cornified layer) are shed into the environment.

ODDS RATIO

The ratio of the odds of an event occurring in each of two different groups. For example, the odds of individuals with psoriasis having a given allele compared with normal control individuals having the same allele.

EPIDERMAL DIFFERENTIATION COMPLEX

(EDC). A group of ∼70 genes that is located on chromosome 1q21. These genes are expressed in terminal stages of keratinocyte differentiation. Some of the gene products generate differentiation-defining structures in granular and cornified keratinocytes.

SHARED EPITOPE

A region in two or more unrelated molecules that has antigenic similarity.

SINGLE-NUCLEOTIDE POLYMORPHISM

(SNP). A SNP indicates a particular site in the genome where more than one base can exist. In general, alleles of any polymorphism are present at a frequency of 1% or greater in the human genome.

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Bowcock, A., Krueger, J. Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol 5, 699–711 (2005). https://doi.org/10.1038/nri1689

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