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Pathophysiology


Pathophysiology and targeting IL-17 in treatment


Knowledge of the complex regulatory and functional mechanisms of the interleukin-17 pathway has led to the development of highly specific, targeted strategies associated with favourable long-term efficacy and safety profiles in the treatment of psoriasis


Antonio Costanzo MD Dermatology Unit, NESMOS Department, Sapienza University of Rome, Italy


Psoriasis is a common immune- mediated skin disease that affects 1–3% of the population worldwide, with an equal gender distribution.1


The common


form of the disease, termed ‘chronic plaque psoriasis’, affects more than 80% of patients and is characterised by erythematous scaly plaques typically arising on elbows, knees, scalp and buttocks. The extension of these plaques can vary from minimal to the involvement of the entire skin surface (erythrodermic psoriasis).2


Histological


examination of psoriatic plaques reveals keratinocyte hyperproliferation with parakeratosis and elongation or rete ridges, increased angiogenesis and dermal infiltration of inflammatory cells including T cells, neutrophils, macrophages and dendritic cells. Although the primary clinical manifestations are usually in the skin, it is increasingly appreciated that psoriasis could be a systemic condition.3–5 Evidence has also accumulated to support that psoriasis is not only a polygenic but also a multifactoral disease. Various environmental triggers including trauma, stress, infection and drugs might operate on a complex genetic background leading to an activation of immune response with inflammation and keratinocyte proliferation establishing a vicious circle with an auto-amplification loop. Because of this complicated pathogenesis, there are different variants of psoriasis.


of inflammatory pathways. In this context, it is also important to note that cutaneous biota is significantly altered in psoriatic patients, both on lesional and non-lesional skin; this may be due to both skin barrier defects and altered antimicrobial peptide synthesis in psoriatic patients and may be extremely important for triggering the innate immune response.11


The skin-damaging inflammatory reaction in psoriasis is the result of an active interplay between immune and non-immune cells. Data support the contribution of innate and adaptive immunity in the pathogenesis of psoriasis.


A genetic background


Results of several population analyses clearly suggest a genetic background for psoriasis.6 However, linkage analysis studies suggest a complex inheritance modality. At least 12 susceptibility loci were identified, called Psoriasis Susceptibility (PSORS).7


The locus with strongest


association is PSORS1 that is located on chromosome 6, in proximity of major histocompatibility complex genes (MHC).8


PSORS 1 is estimated to contribute up to 50% of heritability.9


Innate immunity in psoriasis The genetic background of psoriatic patients may lead to a stronger activation of the innate immune system that is considered to be the key initial step of plaque formation. In a recent analysis, genes belonging to innate immunity were found to also be upregulated in non-lesional psoriatic skin,10


suggesting that skin that appears normal may have a subclinical increase


T cells as mediators of skin damage in psoriasis


T cells are crucial in the adaptive immune response. Naïve T cells to be differentiated into different effector subsets (Th) necessitate the lineage- specifying transcription factor. This process requires interaction with dendritic cells and is dependent on antigenic stimulation, cytokines, chemokines and growth factor signalling. Various stimuli are able to differentiate different T cells with peculiar functions and patterns of cytokines (Figure 1). Effector cells are classified as:


● Th1 cells, promoted by interleukin 12 (IL-12), producing high levels of interferon (IFN)-γ and which are involved in autoimmune disease and cell-mediated immunity against intracellular pathogens


● Th2 cells, promoted by IL-4, which mostly produce IL-4, IL-5 and IL-13 and are involved in allergy and in immunity against extracellular


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