Psoriasis is a complex, chronic, multifactorial, inflammatory disease that involves hyperproliferation of the keratinocytes in the epidermis. The disease manifestation is thought to be the result of an interplay between a genetic predisposition and a range of environmental factors (triggers)including injury, infection, allergy, extremes of temperature, alcohol use, chemicals or stress, resulting in an inflammatory response. Furthermore different clinical patterns of psoriasis are described, each thought to have a specific etiological mechanism:
- Psoriasis vulgaris, is the most common and is seen in approximately 90% of patients. Presenting typically with red, scaly, symmetrically distributed plaques on extensor surfaces- as is seen in a severe form in our case study patient.
- Guttate psoriasis, is characterized by the eruption of small papules on the upper trunk and proximal extremities, often but not exclusively triggered by Group A streptococcal throat infections.
- Inverse psoriasis, is characterised by lesionsin a flexural distribution with involvement of axillae, groin and perineum.
- Erythrodermic psoriasis represents a generalized form of disease that affectsmore than 90% of body surface area.
- Pustular psoriaris, is characterised by predominatly pustular lesions.
For the ease of demonstrating the development of psoriasis our discussion and graphics have remained general with Psoriasis vulgaris as our chosen clinical pattern and infection as the inflammatory trigger. However we will indicate when a specific etiological factor has been identified.
The activated Langerhans’ cells then migrate to skin lymph nodes and present antigens to CD4+ T cells. The phenotype of activated CD4+ T cells is dependent on the type of cytokines produced by the antigen presenting cells. Although Th1 and Th22 CD4+ T cells also participate in the inflammatory response, Th17 cells have been shown to play a central role in the development of psoriasis due to the secretion of IL-17A and IL-17F. The differentiation of naïve CD4+ T cells into Th17 CD4+ T cells results from cytokine stimulation by TGF-b and IL-6. Additional enhancement of Th17 CD4+ T cell development occurs by additional stimulation by IL-23. Activated Th17 CD4+ T cells clonally expand and migrate out of the lymphoid tissues and extravasate into the dermis where IL-17A and IL-17F is produced. IL-17A and IL-17F activates keratinocytes which in turn secrete cytokines, attracting and recruiting more immune cells and in so doing setting up a self-perpetuating inflammatory process in the skin. These mechanisms of differentiation, extravasation, activation, secretionand recruitment will be discussed here in further detail.
Following activation of Langerhans’ cells in the T cell zones of the skin lymph nodes, the group of cytokines secreted by the Langerhans’ cell will determine the phenotype of the activated T cell. In this case, TGF-beta, IL-6 and IL-23 will causenaïve CD4+ T cells to differentiate into Th17 CD4+ helper T cells. These activated T cells then undergo clonal expansion with the resulting effector cells migrating out of the lymph node to the dermis of the skin.
Homing of Th17 effector CD4+ helper T cells to the skin and extravasation is a multi-step process that begins with initial binding of CLA andCCR4 receptors expressed on T cells to E-selectin and CCL17 chemokine ligands on skin post-capillary venule endothelial cells, respectively. Additional stabilisation then occurs by binding of T cell integrins LFA-1 and VLA-4 to endothelial cell adhesion molecules ICAM-1 and VCAM-1, respectively. The T cell then extravasates into the dermis by diapedesis. Completing the migration of Th17 effector cells from skin lymph nodes to the dermis, where activation of keratinocytes will now take place.
The Th17 CD4+ helper T cells, which have migrated into the dermis, are so called because they secrete the pro-inflammatory cytokine IL-17. Pro-inflammatory cytokines stimulate other cells to respond to an infection. There are variant isoforms of IL-17, currently six have been identified and designated IL-17A through to F. Th17 polarised T cells have been found to secrete the isoforms IL-17A and IL-17F and bind the heterodimeric IL-17 receptor composed of IL-17RA and IL-17RC chains. This IL-17 receptor has been found to be expressed on epithelial cells such as keratinocytes,that become activated upon stimulation of the IL-17 receptor.
Once keratinocytes are activated by IL-17 they go on to produce and secrete various antimicrobial peptides and immunomodulatory cytokines. Antimicrobial peptides such as beta-defensins and cathelicidins have been identified as playing a role in thecontrol of micro-organisms. In particular cathelicidin LL-37 is speculated to have a disease modifiying function in psoriasis. The various immunomodulatory cytokines produced and secreted by keratinocytes and their role in the disease process will be discussed here in further detail.
Keratinocytes produce the IL-17C isoform of IL-17 that binds the alternative IL-17 receptor composed of the IL-17RA andIL-17RE chain. IL-17C does not bind to the same receptor as IL-17A and IL-17F. The IL-17C receptor is also expressed bykeratinocytes, and bindingactivates the cell. Similarly, keratinocytes produce IL-36 that also activates keratinocytes bybinding to the IL-36 receptor. IL-36Ra is an IL-36 receptor antagonist molecule that competes with IL-36 for binding to theIL-36 receptor (and modulates/reduces excessive keratinocyte responses to IL-36). Genetic mutations in the IL-36Ra gene that encode non-functional IL-36a proteins have been shown to cause pustular psoriasis due to increased stimulation of the IL-36 receptors
Secretion of CCL20 chemokines by keratinocytes
Activated keratinocytes produce CCL20, a chemokine that binds to the CCR6 chemokine receptor expressed by immune cellssuch as myeloid dendritic cells, Th17 CD4+ helper T cells and gamma-delta CD4+ T cells. Recruitment of these CCR6+immune cells into the dermis is facilitated by CCL20 chemokine gradients.
ctivated keratinocytes produce chemokines that recruit neutrophils to the dermis. CXCL1, -2 and -3 bind to the CXCR2receptor expressed by neutrophils, while CXCL8 can bind to both CXCR1 and -2 receptors. In psoriasis, large numbers ofneutrophils are recruited to inflamed skin due to these chemokines.
Clinically this inflammatory infiltrate of neutrophils seen in the superficial dermis, is a histologic feature in keeping with the diagnosis of psoriasis.
Vascular endothelial cell growth factor (VEGF) is produced by activated keratinocytes and binds to the VEGFR2 receptor onskin capillary endothelial cells promoting angiogenesis. In psoriasis increased blood supply is evident below the epithelial celllayer of inflamed skin. The vessels are also dilated which gives psoriatic lesions a red colour.
Clinically this is in keeping with the positive Auspitz sign which is seen as capillary bleeding occurring after overlying scale removed typically seen in cases of psoriasis.
Cytokine secretion by recruited immune cells
An amplification of activation signals targeting keratinocytes occurs via cytokines produced by recruited immune cells. Th17CD4+ helper T cells, gamma-delta CD4+ T cells and neutrophils all produce IL-17A and IL-17F that can activate additionalkeratinocytes by binding to the IL-17R (RA and RC chain variant). Myeloid dendritic cells produce IL-1, IL-6 and TNF-a thatare proinflammatory cytokines and enhance immune activation of the skin.
The hallmark histological observation of psoriatic skin (see Figure 2 below) is a thickening of the epidermal cell layer, with defects in the normaldevelopment and maturation of keratinocytes and the formation of plaques. Accumulation of immune cells in the skin, particularly neutrophils occurs along with an increased blood supply.
Once this stage has been reached,irrespective of the trigger, the condition becomes self-perpetuating due to the constant cytokine stimulation (particularly IL-17) of keratinocytes and ongoing influx of inflammatory cells into the skin.
Please note: specific treatment options are available as targeted treatment of psoriasis. The mechanisms of how these various therapeutic agents act to reduce disease symptoms will be available in a future case study presentation.