Over recent years, significant progress has been made in characterisation of the underlying pathogenic mechanisms in psoriasis, a common cutaneous disease that is associated with major systemic co-morbidity and reduced life expectancy. Basic science discoveries have informed the design of novel therapeutic approaches, many of which are now under evaluation in late-stage clinical trials.
Here we describe the complex interplay between immune cell types and cytokine networks that acts within self-perpetuating feedback loops to drive cutaneous inflammation in psoriasis. Genetic studies have been pivotal in the construction of the disease model and more recently have uncovered a distinct aetiology for rare, pustular variants of psoriasis. The therapeutic armamentarium for psoriasis has expanded over the past two decades with the development of several highly selective therapies that are both efficacious and have a favourable safety profile.
Novel insights into psoriasis immunopathogenesis have informed the design of these treatments, and in turn, mechanistic studies within clinical trials are helping to further characterise the role of different cellular players and cytokine axes in the pathogenic disease model.
Psoriasis is a phenotypically heterogeneous, immune-mediated skin condition that often follows a relapsing and remitting course.
It is characterised by well-demarcated, scaling, erythematous plaques that frequently manifest at sites of trauma extensor aspects of elbows, knees , however can appear anywhere on the body. Other clinical variants include pustular psoriasis, guttate psoriasis and erythroderma. Emerging evidence indicates that the distinct phenotypes have different immunogenetic profiles, which will likely influence treatment choices [ 5 ].
Discoveries from genetics and immunology research have converged to shape the current pathogenic model for psoriasis. The pathogenesis of psoriasis involves dynamic interactions between multiple cell types and numerous cytokines in response to triggers, culminating in the disruption of skin immune homeostasis in genetically predisposed individuals.
The histological features of a psoriatic plaque provide an insight into the immunological complexities of the disease.
There is thickening of the epidermis acanthosis due to an increase in keratinocyte turnover [ 7 ]. The retention of keratinocyte nuclei in the stratum corneum parakeratosis due to abnormal differentiation further highlights the importance of these skin cells in the development of psoriasis. Psoriatic lesions are also densely infiltrated by T cells and dendritic cells DC. Plaques are highly vascular and new vessel formation is mediated by angiogenic factors such as vascular endothelial growth factor VEGF.
The initiation phase of a psoriatic lesion involves a close interplay between external factors and genetic alterations that predispose to the phenotype [ 3 ].
Triggers include physical injury which causes Koebner phenomenon , infections particularly streptococcal and medications e. Although the exact mechanisms for the induction of psoriasis are not yet fully elucidated for many of these environmental factors, some insults such as physical trauma cause the release of the antimicrobial peptide LL37 cathelicidin by keratinocytes, which then mediates the breakdown of tolerance to self-nucleic acids Fig.
There is also evidence that LL37 may directly activate auto-reactive circulating T cells, and this phenomenon was more prevalent in psoriasis patients with greater disease activity [ 10 ]. Schema for the initiation of a psoriatic skin lesion. These antigen presenting cells release pro-inflammatory cytokines that drive T cell-mediated inflammation and keratinocyte activation and proliferation.
This promotes the recruitment and activation of further inflammatory cells such as neutrophils and macrophages, contributing to the formation of an inflamed cutaneous plaque. AMPs antimicrobial peptides. Once activated, T cells enter the circulation and move towards inflamed skin through interactions with adhesion molecules including P-selectin and E-selectin on the endothelial cells of blood vessels.
The effector molecules secreted by T cells then activate keratinocytes, resulting in the release of cytokines and chemokines that continue to recruit and activate inflammatory cells. Schema of the contribution of T cell subsets to the pathogenesis of psoriasis.
Activated myeloid dendritic cells mDC release cytokines that promote the differentiation of populations of resident T cells into Th22, T17 and Th1 cells. Cytokines secreted by these effector T cells stimulate keratinocytes, which promote the recruitment of other inflammatory cells such as neutrophils by release of chemokines.
Activation of autocrine and paracrine feedback loops culminates in the development and maintenance of cutaneous inflammation. The following sections summarise the roles of specific cells and cytokines in initiating and maintaining the dysregulated immune response that leads to psoriasis. An update on the therapeutic agents currently available and in clinical trial stage is also included. DCs are professional antigen presenting cells that activate T cells and are an important source of pro-inflammatory cytokines and chemokines in psoriasis.
Genetic studies indicate a fundamental role for antigen presentation in the disease process since the PSORS1 interval on chromosome 6p The protein product of ERAP1 trims peptides to enable effective loading onto MHC class I molecules, thus reinforcing the role for antigen presentation and subsequent abnormal T cell activation in the disease model.
They localise to the dermis and express distinct cell surface markers. The latter have been found in greater numbers in the dermis of lesional psoriatic skin compared with non-lesional or normal skin [ 22 — 24 ] and decrease in number following effective psoriasis treatment [ 24 , 25 ].
Plasmacytoid DCs are a rich source of type I IFN, an early signature cytokine in psoriasis, and have been found at increased levels in lesional skin compared with normal skin [ 26 — 28 ].
The importance of this cell type in the disease model has been supported by xenotransplantation models of psoriasis, in which non-lesional skin from patients with psoriasis are grafted onto athymic nude mice deficient in T cells or those with severe combined immunodeficiency without T and B cells [ 29 ].
In these experimental systems, inhibition of type I IFN release or signalling by plasmacytoid DC blocked pathogenic T cell activation, which prevented the development of psoriasis [ 15 , 16 ]. Langerhans cells are skin-resident immune cells that associate closely with keratinocytes in the epidermis via E-cadherin.
Although Langerhans cells are able to present antigens to T cells in local skin-draining lymph nodes, their role in disease pathogenesis and the nature of the putative psoriasis antigen remains unclear. Previous studies have shown that Langerhans cell migration in non-lesional skin is impaired in early-onset before age 40; type I psoriasis [ 30 , 31 ] and restored with anti-psoriatic biologic treatments [ 32 ].
This suggests that loss of cell mobility may cause a dysregulated cutaneous immune response.
Keratinocytes are believed to be crucial in both the early stages of disease pathogenesis and later amplification of chronic inflammatory circuits. As the major constituent of the epidermis, keratinocytes have structural and immunological functions. Genetic studies indicate a role for skin barrier dysfunction in psoriasis since deletion of LCE3B and LCE3C genes, encoding stratum corneum proteins involved in terminal differentiation of the epidermis, was found to be associated with psoriasis [ 33 ].
It is hypothesised that incomplete repair after minor skin injury, due to LCE gene deletion, contributes to the development of chronic inflammation [ 34 ]. Injury to the skin, resulting in cell death, causes the release of antimicrobial peptides AMPs by keratinocytes. AMPs have been shown to be upregulated in psoriasis and its expression is reduced after successful treatment with systemic agents [ 37 ].
This mediates the recruitment of macrophages and neutrophils. Keratinocytes contain inflammasomes, which are multi-protein complexes that consist of caspase-1, the adaptor protein ASC and a sensor protein either a nod-like receptor e.
AIM2 , that detect sterile stressors and pathogens [ 38 ]. Activated caspase-1 cleaves pro-IL-1 and pro-IL into the mature, active forms of the cytokines. This sets up positive feedback loops as activated Th1 and Th17 cells release IL and IL Th17 only , which drives keratinocyte proliferation and activation, hence contributing to the formation of a cutaneous plaque.
T cells also upregulate S proteins in keratinocytes, which in turn mediates further leucocyte chemotaxis. Several genes expressed within keratinocytes that promote innate responses to viral nucleic acids and are upregulated in psoriatic skin lesions have been found by GWAS to confer disease susceptibility.
Update on psoriasis immunopathogenesis and targeted immunotherapy
Hence, dysregulated antiviral immunity may contribute to the development of psoriasis by promoting the over-production of pro-inflammatory cytokines by keratinocytes. Keratinocytes also produce VEGF during inflammatory states, which induces angiogenesis by promoting the migration, survival and proliferation of endothelial cells, resulting in the formation of an erythematous, vascular plaque.
In support, VEGF overexpression in mouse skin results in a psoriasiform phenotype [ 44 ]. Neutrophils are important in the early stages of psoriasis as they are involved in the recruitment and activation of T cells and the proliferation and differentiation of keratinocytes [ 45 ]. NETs have been shown to mediate autoimmune disease-associated organ damage [ 46 ] and have been identified in psoriatic lesions [ 47 ].
It has several downstream effects, including the induction of keratinocyte proliferation and cleavage of cytokines into their active forms [ 48 ]. The importance of neutrophil-keratinocyte crosstalk in early psoriasis pathogenesis was highlighted by a recent report [ 49 ], in which the anti-ILA antibody secukinumab caused a rapid reduction in cutaneous neutrophils alongside histological improvement in keratinocyte abnormalities and downregulation of keratinocyte-derived neutrophil chemoattractants e.
The role of macrophages in psoriasis is not yet fully characterised; however, they are speculated to contribute to the disease as there is a threefold increase in cell numbers in lesional skin, with evidence of normalisation after successful treatment [ 24 ].
Mouse models with skin phenotypes that resemble human psoriasis support involvement from skin macrophages in disease development and maintenance [ 50 , 51 ]. The importance of abnormal T cell activation in the pathogenesis of psoriasis has been highlighted by several genetic studies that demonstrate a strong disease association with the HLA-Cw6 allele, as described above.
Further, a missense mutation RQ in IL23R was shown to impair ILinduced Th17 activation and effector function and confer protection against psoriasis [ 54 ]. Hence, aberrant IL signalling and Th17 activity contribute to chronic inflammation in psoriasis.
The immunopathogenesis of psoriasis.
A key role for T cells is also indicated by their prevalence in lesional skin biopsies [ 55 ]. This is supported by the effectiveness of several T cell-directed therapies in causing disease resolution. The observed beneficial effects of other agents such as abatacept CTLAIg , which blocks T cell co-stimulation, and alefacept, an LFAIg fusion protein that inhibits effector memory T cell activation, further re-enforced the important pathogenic activity of this cell type in psoriasis [ 57 — 59 ].
Clinical improvements with these agents were associated with a decrease in the number of T cells and DCs infiltrating skin lesions. Xenotransplantation mouse models provided additional evidence, since asymptomatic skin grafts developed typical features of psoriasis after injection of activated immunocytes [ 60 ].
ILspecific monoclonal antibodies prevented such lesions from developing, highlighting the pathogenic importance of Th17 cells [ 61 ]. Subsequent exposure to IL and IL promotes the activation and proliferation of mature, inflammatory Th17 cells [ 65 ].
It induces the expression of C-reactive protein part of the acute phase response , several cytokines such as IL-6 which mediates T cell proliferation and keratinocyte hyperproliferation , and chemokines including CCL20 recruits myeloid DCs and T17 cells and IL-8 for recruitment of neutrophils. It also facilitates IL production by DCs and enhances the effects of other cytokines relevant to psoriasis pathogenesis such as IL Therefore, more targeted immunotherapies are now being investigated.
It is also secreted by DCs and natural killer NK cells.
Further, in a clinical trial of an ILspecific monoclonal antibody, there was no effect on IFNG expression in patients with psoriasis despite a complete clinical and histologic response, in contrast to the significant reduction in IL17 messenger RNA levels observed [ 83 ]. CXCL10, CXCL11 and adhesion molecule release from keratinocytes, thus facilitating the recruitment of lymphocytes to inflammatory plaques. Several observations have indicated an important role for these cytokines in psoriasis development, particularly in the early stages.
Treatment with type I IFN for conditions such as hepatitis and multiple sclerosis has been shown to exacerbate existing psoriasis vulgaris and induce new lesions [ 87 , 88 ].
As discussed above, plasmacytoid DCs, which infiltrate psoriatic skin lesions, are a major source of type I IFN [ 28 ] and this promotes myeloid DC phenotypic maturation and activation, thus facilitating T cell priming.
Immunopathogenesis of psoriasis pdf printer
Thus, it may drive downstream inflammatory circuits, leading to keratinocyte hyperproliferation. In addition to the indirect modulation of T cell responses via regulation of DCs, type I IFN may have direct pro-survival and pro-proliferative effects on T cells [ 94 ].
Finally, type I IFNs are rapidly induced in many different cell types in response to viral infections. Since genetic studies have indicated the importance of innate antiviral immune responses in psoriasis pathogenesis, this also underlines type I IFN as a critical disease cytokine. Specifically, several genes regulating type I IFN production e. Engagement of the receptor triggers a signalling cascade that involves activation of STAT3.
In support, psoriasis lesions have elevated levels of IL expression [ 95 ] and this is reversed after successful treatment with medications such as etanercept [ 96 ] and alefacept [ 97 ]. It is overexpressed in psoriasis both skin and blood [ 74 , ] and its involvement in the immunopathogenesis of psoriasis has been increasingly recognised [ ].
Given that IL may promote the development of cardiovascular diseases [ ], and the established link between psoriasis and such co-morbid conditions, targeting of IL therapeutically may have benefits beyond the sole attenuation of skin inflammation.
However, the biological effects of ILA in various tissues are complex. Indeed, it may also help to stabilise atherosclerotic plaques [ ], which emphasises the need to enrol patients receiving IL inhibitors in long-term safety registries. Lesional psoriatic T cells produce large amounts of ILA when activated ex vivo; however, T cells from healthy skin do not produce ILA with the same stimuli [ ]. Analysis of the psoriasis transcriptome also reveals enrichment for ILA genes [ ].