Better Understanding the Immunopathogenesis of Psoriasis

The immunopathogenesis of psoriasis involves complex interactions between the innate and the adaptive immune system, with emphasis on participation of keratinocytes, neutrophils, dermal dendritic cells and T lymphocytes.The knowledge of the immunopathogenesis of the disease is essential for understanding the mechanism of action of several systemic medications used in the treatment of the disease, especially the biologics.In this article the main and current knowledge of the immunopathogenesis of psoriasis is summarised.

The IIS cells are activated via receptors that recognize molecular patterns that are repeated in several pathogens (Pathogen Recognition Receptors -PRR); through molecules produced in cellular stress situations (such as the heat shock proteins -HSP and the antimicrobial peptides -AMP) or via other cytokines produced by activated cells [2,3].In psoriasis there is enhanced expression of "Toll Like Receptors" (TLR) on the keratinocytes and on the DC (TLR is a type of PRR) [2,3].It occurs also excessive production of HSP and AMP by keratinocytes [1][2][3].Moreover, there is increased expression of several genes that participate in innate immune (and adaptive) responses [2,[4][5][6].Activated keratinocytes, DC and macrophages produce various proinflammatory cytokines such as interleukin (IL) 1, IL-6, tumoral alpha necrosis factor (TNF-α) and interferon (INF) [1][2][3][4].
In the early development of lesions, it appears to be essential the activation of the plasmacytoid dendritic cells (pDC), producing INF-α [2][3][4].INF-α and other proinflammatory cytokines (produced mainly by activated macrophages and keratinocytes) promote an excessive activation of the myeloid dermal dendritic cells (mDC), whose number is much increased in psoriatic plaques (Figure 1) [1][2][3][4][5].[1][2][3][4][5].Some authors believe that this Ag can be a protein from the skin microbiota [7].Others suggest that it is the LL-37 (AMP that may form a complex with self-RNA or self-DNA, leading to the activation of DC through TLR) [2][3][4].A recent study highlights the participation of a melanocyte protein as the possible Ag of the disease [8].
Keratinocytes are the principal target for IL-17 (also known as IL-17A) in psoriasis.IL-17A stimulates keratinocyte expression of multiple chemokines for neutrophils: CXCL1, CXCL2, CXCL3, CXCL5 e CXCL8 (IL-8).[1][2][3][4][5][6].In psoriasis skin lesions, neutrophils are potential sources of IL-17, they concentrate in the epidermis and appear to play an important role in maintaining the inflammatory process [2,4,6,10].Secukinumab (inhibitor of IL-17A) quickly causes the disappearance of neutrophils of the skin [10].The inhibition of IL-17 by this biologic would reduce the production of chemokines by keratinocytes and therefore the arrival of neutrophils in the epidermis [10].The disappearance of neutrophils correlated with the decrease in proliferation of keratinocytes, demonstrating a strong interaction between these IIS cells in the the immunopathogenesis of psoriasis [10].
It is important to point out that IL-23 stimulates the mDC to produce TNF-α and that TNF-α stimulates the mDC to produce IL-23 [3][4][5].Incidentally, the main therapeutic mechanism of action of anti-TNF in psoriasis seems to be just the decreased activation of mDC [5,6].
Finally, psoriasis pathogenesis includes both innate and adaptive immune cells that interact with tissue cells producing large amounts of cytokines that, in turn, create reverberating inflammatory and proliferative circuits.Moreover, recent data point out the possibility that regulatory T lymphocytes of psoriasis patients could differentiate in vivo into Th17 cells, under proinflammatory conditions [11].

Conclusion
In conclusion, the knowledge of the main cells and cytokines involved in the immunopathogenesis of psoriasis is essential for dermatologists to understand better the disease as well as the mechanism of action of the biologics, drugs that revolutionized the treatment of psoriasis in the last two decades.