Immunology of psoriasis

Abstract

The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases.

Figures

Figure 1

Components of healthy and inflamed skin. (a) The epidermis is formed by slowly differentiating keratinocytes. In granular layer keratinocytes, antimicrobial peptides (AMPs) may be stored, including S100A7, S100A8, S100A9, β-defensins, cathelicidin (CAMP/LL-37), and lipocalin 2 (LCN2). The nucleus is lost as granular keratinocytes transition to corneocytes, and a cross-linked protein membrane structure termed the cornified envelope is formed, between which many layers of neutral lipids are deposited. This produces an effective water-impermeable barrier. The epidermis contains Langerhans cells (LCs) that are immature antigen-presenting cells, and the dermis contains resident myeloid dendritic cells (DCs). Although there are nonrecirculating cutaneous lymphocyte antigen (CLA)+ resident memory T cells (Trm cells) in the skin, keratinocytes constitutively synthesize CCL27 (CTACK), which is the major chemokine that attracts CCR10+ CLA+ skin-homing T cells into noninflamed skin for immune surveillance. These components maintain steady-state cutaneous immunity or, effectively, a state of tolerance. (b) The epidermis can also participate in innate or adaptive immune responses to triggers such as injury, infection, or cytokine stimulation. Keratinocytes may ① proliferate in response to cytokines such as IL-22 to accelerate loss of surface keratinocytes and eliminate pathogens, ② increase synthesis of innate effector molecules such as AMPs, and ③ direct migration of new T cell subsets and other immune effector cells into the skin through production of chemokines. (Additional abbreviations used in figure: IFN-α, interferon-α; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin; T17, IL-17-producing CD4+ and CD8+ T cells; Th, T helper cells.)

Figure 2

Immune cellular components of normal-appearing and inflamed psoriatic skin. Representative immunohistochemistry of (a) normal-appearing, nonlesional skin of psoriasis patients and (b) lesional psoriasis skin is shown, as is (c) a diagram of immune cellular components and their surface receptors during inflammation. Keratin 16 stains basal epidermis in nonlesional skin but stains full thickness epidermis in psoriasis. Langerin/CD207+ Langerhans cells (LCs) are found scattered in the lower epidermis in nonlesional skin and are found higher up in the thicker epidermis of psoriasis lesions. LCs are also identified by CD1a and HLA-DR. CD11c+ BDCA-1+ resident myeloid dendritic cells (DCs) are found in the upper dermis in nonlesional skin. During psoriatic inflammation, numbers of CD11c+ inflammatory DCs that are CD1c/BDCA-1− increase in the epidermis and dermis. These cells also express HLA-DR, TNF, iNOS, IL-12/23p40, TRAIL, and TLR1/2. Resident DCs are stable in number between nonlesional and lesional skin and are both CD11c+ and BDCA-1+. However, resident myeloid dermal DCs become more mature in psoriasis, as evidenced by expression of DC-LAMP/CD208. CD163+ macrophages are scattered throughout the dermis in nonlesional skin and increased approximately twofold in lesional skin. These CD163 + cells are also FXIIIA+, although CD163 is preferred as a marker. All images are 10 × magnification. (Additional abbreviations used in figure: BDCA, blood dendritic cell antigen; DC-LAMP, DC-lysosome-associated membrane protein; iNOS, inducible nitric oxide synthase; TLR, Toll-like receptor; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor–related apoptosis-inducing ligand.)

Figure 3

Clinical and histological features of psoriasis. (a) Clinical appearance of chronic psoriasis vulgaris, showing well-defined erythematous scaly plaques of psoriasis on elbows and knees. (b) Back showing more extensive psoriasis lesions. (c) Histology of nonlesional and lesional skin biopsy at the same magnification, with hematoxylin and eosin stain (H&E) where cellular nuclei stain blue. The epidermis is seen as a dark layer due to keratinocyte nuclei and forms an undulating border with the pink dermis below. Nuclei of resident structural and immune cells are seen in the dermis. Lesional psoriasis skin shows a greatly thickened epidermis (acanthosis) with elongations into the dermis (rete ridges). Retention of nuclei (parakeratosis) can be seen in the thickened stratum corneum. There is a dramatic increase in the number of cells in the dermis, composed predominantly of DCs and T cells. (d) Increased numbers of CD3+ T cells are seen in lesional psoriasis skin, often forming lymphoid-like clusters with DCs. All images 10 × magnification.

Figure 4

Pathways for initiation and maintenance of psoriasis. (a) Early disease: Imiquimod (IMQ), a TLR7 agonist, can activate plasmacytoid dendritic cells (pDCs) to produce interferons (IFN). LL37, a peptide derived from cathelicidin, may have an important role in the initiation of psoriasis lesions via this pathway. LL37 released from keratinocytes (KCs) can bind to nucleic acids to activate pDCs to release IFN-α/β. LL37/RNA complexes can also activate resident myeloid DCs to produce IL-12 and IL-23, key psoriatic cytokines. (b) Chronic disease: The major pathogenic pathway in psoriasis occurs when (I) mature dermal DCs and inflammatory myeloid DCs produce cytokines such as IL-23 and IL-12. (II) These cytokines activate T17 (Th17 and Tc17), Th1, and Th22 cells to contribute to the cytokine milieu and further act on keratinocytes. (III) As outlined in Figure 1, keratinocytes can produce chemokines and antimicrobial peptides (AMPs) to (IV) augment cutaneous immune responses.

Figure 5

SNPs and gene expression in psoriasis lesions. Manhattan-type plot depicting (in gray shades) the magnitude of dysregulation of the HGU133 Plus 2.0 genes on the MAD3 psoriasis transcriptome by their base pair (bp) position on the genome (110). Blue lines on the x-axis represent a twofold change in the log2 scale. In a recent meta-GWAS, 36 SNPs were identified as psoriasis susceptibility loci (21 known loci, 15 new loci) (102). Genes that are located +/− 500 kb around each SNP are highlighted in colors (by chromosome). Dots in darker shades are for those genes differentially regulated in the MAD3 transcriptome, with the corresponding gene name listed on right, colored by chromosome.

Figure 6

Serum proteomics and lesional transcriptomics in psoriasis patients. Recently, our group compared serum proteins of psoriasis patients and healthy volunteers, with the accompanying skin psoriasis transcriptome [DEGs for lesional (LS) versus nonlesional (NL) skin] (119). This figure depicts a subset of these serum proteins (right side of y-axis) and their encoding genes (mRNA; left side of y-axis). Yellow lines represent a twofold change (FCH) in the log2 scale (x-axis). Green dots represent the protein dysregulation between psoriasis patients (PS) and healthy volunteers, with a more sensitive assay for IL-17. Red dots represent the log2FCH (LS versus NL) detected by microarray in skin for genes encoding each protein. Dark blue dots represent differential expression by RT-PCR in the same cohort of patients, and light blue dots represent differential expression by RT-PCR in a separate patient cohort (90). An asterisk indicates results where protein determination was below the limit of detection for at least one group, so fold change may be biased. Results are grouped as (I) upregulated serum protein and skin mRNA; (II) increased serum protein without expression in skin, which could indicate production of mediators in tissues outside of the skin; (III) decreased serum protein, which could indicated consumption of the serum proteins; (IV) abundant gene expression with little protein; and (V) decreased tissue gene expression with minimal or low serum protein.

Figure 7

Enrichment of cytokine-related inflammatory pathways (gene sets) in human psoriasis transcriptomes and in five mouse models of psoriasis. Normalized enrichment scores (NES) and false discovery rate (FDR) are shown for gene sets regulated in keratinocytes (KC), monocytes, immature dendritic cells (iDCs), fibroblasts, and reconstituted human epidermis (RHE) by several psoriatic inflammatory cytokines. An asterisk indicates cytokine pathways described in Reference 129. (a,b) Expression of these cytokine pathways in human psoriasis vulgaris is shown for lesional (LS) versus nonlesional (NL) skin in the MAD3 transcriptome (a) (110) and for lesional versus normal (N) skin (b) (130). (c–h) Cytokine enrichment in the five mouse models (123) is illustrated as follows: K14-amphiregulin (AREG) ear skin (c) and tail skin (d), K5-Stat3C (Stat-3) (e), K5-Tie2 (Tie-2) (f), K5-TGF-β1 (TGF-β) (g), and Imiquimod (h). (See Note Added in Proof.)