Molecular mechanisms in psoriasis: historical perspective and current pathogenesis

Keywords::

• biologics
• cytokines
• immunotherapy
• psoriasis
• Th17

Psoriasis is a disease with universal occurrence affecting 1–3% of all individuals. The earliest description consistent with psoriasis was given in the Corpus hippocraticum which dates somewhere between the 4th and 5th century BC. While the cause of psoriasis remains unknown, it appears to result from a combination of genetic and environmental factors. It is frequently inherited but does not follow a classical autosomal mendelian profile. Several candidate genes have been identified and recently, 15 new psoriasis susceptibility loci have been found [1].

Historically, the disease has been confused with other skin diseases, particularly leprosy. This confusion was addressed a little over 200 years ago with a clinical description of psoriasis provided by Robert William in 1808. The clinical description of psoriasis was further clarified by the Viennese dermatologist Ferdinand Von Hebra in 1841.

Over the next 100 years, there were further advances in clinical categorization of the disease with identification of distinct clinical subtypes including the common psoriasis vulgaris, guttatepsoriasis, pustular psoriasis, inverse psoriasis and erythrodermic forms. Treatment was sometimes effective but was empirical and lacked a pathogenic basis. Initial mechanistic-based therapies targeted the hyperplasic epidermis to arrest keratinocyte growth using antiproliferative agents such as arsenic, hydroxyurea and methotrexate.

In 1968, a leading psoriasis investigator Eugene M Farber at Stanford University, CA, USA, published a comprehensive review of psoriasis with his colleague Richard P McClintock [2]. Absent from that review was any significant discussion of the role of immune dsyregulation in psoriasis. Yet this is hardly surprising for it was not until 1975 that Köhler and Milstein cloned the first monoclonal antibody [3] and it was not until 1984 that Tak Mak at the University of Toronto, Canada and, separately, Mark Davis at Stanford, USA, identified and characterized the T-cell receptor [4,5]. The first interleukins were identified in 1980 [6] and keratinocyte production of interleukins and cytokines were first identified in 1982 [7,8].

Since that time there have been remarkable advances in the molecular pathogenesis of psoriasis and resulting targeted therapies. As with most discoveries in medicine, serendipity played a significant role. Early evidence that psoriasis is a T-cell mediated disease came from a trial in which individuals with rheumatoid arthritis (who also had psoriasis and psoriatic arthritis) were treated with cyclosporine. Cyclosporine is a calcineurin antagonist that inhibits T-cell activation. The treatment of these patients led to marked improvement in psoriasis [9]. Treatment with tacrolimus (FK506), another calcineurin inhibitor, showed similar improvement in psoriasis. These studies implicated T-cells in the immunopathogenisis of psoriasis. However, because these agents also inhibited keratinocyte proliferation [10], the success of treatment could not be attributed solely to effects on T-cells.

The first definitive evidence of T-cell involvement in the pathogenesis of psoriasis was demonstrated by treatment with a diphtheria toxin fused to the IL-2 receptor. This fusion protein DAB₃₈₉IL-2 bound to the IL-2 receptor on activated T-cells and the complex was then internalized. Once inside the cell, the diphtheria toxin induced the apoptosis of T-cells. Since the fusion protein bound only to cells expressing functional IL-2 receptors, it was highly selective for activated T-cells. DAB₃₈₉IL-2 treatment improved the psoriatic lesions and also depleted lesional T-cells, highlighting the fact that activated T-cells are central to psoriasis [11].

The above studies were followed by further targeted therapies based on molecular mechanisms. Alefacept is a human leukocyte function-associated antigen-3 (LFA-3)/ Immunoglobulin G1 (IgG1) Fc fusion protein that binds to CD2 on memory T-cells. It selectively blocks the interaction between CD2 on T-cells and LFA-3 on antigen-presenting cells thus impairing T-cell activation. In addition, Alefacept induces antibody-dependent cellular cytotoxicity in T-cells and leads to apoptosis of memory CD45RO-positive T-cells in the skin. Alefacept was capable of inducing remissions of psoriasis albeit with a relatively small percentage of patients [12].

Following the introduction of Alefacept in 2003, Efalizumab was introduced. Efalizumab was a humanized, chimeric monoclonal anti-CD11a antibody that bound to the α subunit of lymphocyte function associated antigen-1 (LFA-1). This antibody blocked the interaction between LFA-1 and its counter ligand intracellular adhesion molecule (ICAM-1) on antigen-presenting cells, with resultant blockage of T-cell activation. Efalizumab also blocked the adhesion of T-cells to endothethial cells and was capable of inducing remission in psoriasis [13]. However, a rare but serious side effect was noted, namely progressive multifocal leukoencephalopathy (PML). Four cases of PML were reported in plaque psoriasis patients, an incidence of approximately one in 500 treated patients. Due to the increased life-threatening risk of PML, the EMA and the US FDA suspended Efalizumab from the market starting with a phased voluntary withdrawal from the US market in April 2009.

While these therapies provided a novel mechanism of action and expanded the understanding of the molecular pathogenesis of psoriasis, they have limited efficacy and, in the case of Efaluzumab, major toxicity. TNF targeting, however, provided the next ‘magic bullet’.

TNF is a primary cytokine prevalent in most, if not all, inflammatory disease and is present in skin in high amounts in psoriasis patients. The central role of TNF in the pathogenesis of psoriasis was clearly established with the introduction of drugs that inhibited TNF. The initial discovery of the use of TNF inhibitors in psoriasis was also serendipitous. Infliximab is a chimeric monoclonal antibody that neutralizes soluble and membrane bound forms of TNF-α [14]. This was used in patients with inflammatory bowel disease who also had psoriasis demonstrating a dramatic improvement in psoriatic lesions [15]. While infliximab led the way, it was the TNF receptor antagonist etanercept that first received approval for psoriasis, followed by infliximab and then adalumimab. TNF inhibitors downregulate a number of cytokines including IL-1, IL-6 and IL-8 and indirectly downregulate γ-interferon.

It has been almost 30 years since Mosmann et al. classified T-cell subsets as either Th1 or Th2 based on their production of protypical cytokines [16]. IFN-γ was the protype for Th1 cytokines and IL-4 the prototype for Th2 cytokines. Psoriasis was regarded as a Th1-mediated disease. In addition to Th1 and Th2, there exists a recently new population of T-cells termed Th17 as well as a population of regulatory T-cells termed Treg. Th17 cells, as the name implies, produce the cytokine Th17. IL-17 cells promote inflammation indirectly by inducing chemokines such as IL8. IL-17 also stimulates TNF production and acts synergistically with TNF. The importance of IL-17 has recently been demonstrated with the use of anti-IL-17 antibodies and anti-IL-17 receptor antibodies in the treatment of chronic plaque psoriasis [17,18].

IL-17 also functions as a key molecule in the maturation and development of IL-23. Th17 cells express the receptor for IL-23. IL-23 is a heterodimeric cytokine comprising a p19 subunit (encoded by IL-23-A) and a p40 subunit encoded by IL-12-B. The expression of both subunits was found to be significantly unregulated in lesional psoriatic skin [19]. Monoclonal antibodies that neutralize the shared p40 subunit of IL-12 and Il-23, has provided a new effective therapy for psoriasis [20]. Current understanding of pathogenesis of psoriasis is summarized below and recently reviewed by Johnson-Huang et al. [21], Perera et al. [22] and Cai et al. [23].

In a genetically predisposed individual, environmental stimuli, such as trauma, infection or certain drugs induces keratinocytes to secrete proinflammatory cytokines including IL-1, IL-18 and TNF. This initial release of cytokines causes further autocrine release of keratinocyte cytokines as well as activating myeloid dendritic cells. These activated dendritic cells release mediators such as IL-12 and IL-23 leading to differentiation of Th1 and Th17 cells [24]. These cells in turn release Th1 and Th17 cytokines including IFN-γ production by Th1 cells and IL-17, IL-12, Il-23. These cytokines further activate keratinocytes and induce keratinocyte proliferation. IL-23 also induces production of IL-22 which further contributes to keratinocyte proliferation. Th1 and Th17 cytokines lead to production of antimicrobial peptides and chemokines. These in turn cause further immune-cell recruitment and inflammation.

IL-12/23 antagonists have already been shown to be very effective in treatment of psoriasis and have clearly established a role of IL-23 in the pathogenesis. IL-17 inhibitors are completing Phase II studies and will likely play an important therapeutic role in the near future. The future is bright for targeted and potentially more efficacious treatments and for further delineation of the molecular pathogenesis of psoriasis.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.