Battling Psoriatic Arthritis

About 8 million people in the U.S. have psoriasis and around a third of that population also develop psoriatic arthritis (PsA) in 5-7 years after diagnosis of psoriasis. Psoriasis is an inflammatory skin condition characterized by scaly, red patches, caused by a disorder in the body’s immune system that causes it to attack the healthy body’s skin cells, while psoriasis arthritis is an inflammatory condition that targets both the skin and joints. This observation where cutaneous psoriasis usually leads to PsA indicates that psoriasis can promote the joint inflammation seen in PsA but the reason and mechanism as to how is yet to be uncovered. This study done by researchers of UCSF, such as Ryan Tobias of the Department of Dermatology, prioritize their study into A20, or TNFAIP3, a gene that’s associated with the prevention of psoriasis and PsA to contribute to learning more about the relation of A20 to psoriasis and how to apply the knowledge to prevent PsA.
The significance of A20 was tested with mice that were modified so that their A20 gene could be deleted specifically from their keratinocytes, a type of skin cell from on the epidermis which is the uppermost layer of skin. After deletion of A20 once the mice were adults, they developed similar symptoms of psoriasis and PsA, supporting the thesis that A20 in the skin’s outer layer can play a vital role in prevention of the diseases. However, there was further investigation that led to the discovery that T cells, a form of immune cell, are necessary for activation of pathways that would lead to the characteristics of the two skin conditions. 
To better understand the mechanism behind the symptoms of the conditions, they focused on three cytokines, messengers for the immune system, with all three having higher frequency after A20 deletion: IL-23, IL-17A, and TNF. Both IL-17A and TNF were supported to produce psoriatic inflammation by inducing inflammatory myeloid inflammation, with myeloid referring to a specific white blood cell that’s also part of the immune system. Experiments for IL-23 were also done and also supported that it contributes to symptoms. Investigation regarding T cells were also done to see if they were a required contributor to the disease, a specific T cell is needed, or not needed at all. Two kinds of T cells were used, γδ and αβ T cells, but results concluded that there is no difference in requirement between the two. As long as one of them was present, the symptoms of the disease would appear. However, mice that had no T cells in the experiments showed that cutaneous inflammation, like psoriasis, could still develop. 
Experiments on skin samples of mice were then done to identify potential pathways involved. It led to the conclusion that loss of A20 in keratinocytes activates MyD88 and antiviral pathways, with MyD88 being the gene that mediates for receptor pathways including IL-23 for example. Additionally, studies into interferon receptors, receptors to proteins that combat viral infections, such as IFNAR and IFNLR, were shown to play a role in an antiviral response but also that MyD88 pathway is independent of their presence. Thus, while just blocking IFNAR and IFNLR would be ideal, it won’t be a solution, targeting MyD88 might be the solution. Following that idea, investigation of A20 and MyD88’s role for keratinocytes supported that the presence of A20 stops the MyD88 pathway and that A20 works directly in keratinocytes to do so.