PracticalDermatology

One of my favorite lines from the movie Philadelphia is when Denzel Washington says, “Now, explain it to me like I’m a four-year-old.” In the film, Washington plays the lawyer who begrudgingly takes on a client’s civil lawsuit against his former employer under the Americans with Disabilities Act for firing him when they found out he had AIDS. (That client was famously played by Tom Hanks, but I digress…)

The reason I mention my favorite line from this movie is that my article aims to explain the complex pathogenesis of psoriasis in an easy-to-understand manner.

The more we learn about the pathogenesis of psoriasis, the more interactions we observe between keratinocytes and the immune system. We consistently detect new molecules, new cells, and new feedback loops. Many of these discoveries have helped advanced therapies from the bench to the bedside. As a result, we now have treatments that can clear 40 percent of patients with moderate to severe psoriasis within 12 weeks, and at least 80 percent of them can be maintained for years. (See Table 1. Also, click here to read my article from the April edition to learn more.)

The Epidermis

We know that epidermis in psoriasis grows seven times faster than normal epidermis. Histologically in psoriasis, we see a thickened epidermis, a loss of the granular layer, parakeratosis (i.e nucleated cells within the stratum corneum), pustules of Kugoj, munro microabsesses (a collection of neutrophils in the stratum corneum), and a very irregular stratum corneum. In addition, Langerhans cells and melanocytes are present in both normal and psoriatic epidermis.

Normal versus Psoriatic Dermis

Normal dermis and psoriatic dermis are composed of a collagen and fibrin matrix. Normal dermis has blood vessels, and some lymphocytes (most of which are non-differentiated naive T-cells). Within the dermis, there are some macrophages and some dendritic cells that have Toll-like receptors on their surface that can be bound by molecules like autologous DNA or RNA via koebnerization. This process activates the dendritic cells to synthesize and release various cytokines, namely IL-12 and IL-23. These cytokines activate lymphocytes and neutrophils.

In the psoriatic dermis, by contrast, there are a plethora of lymphocytes, mostly helper T-cells (CD-4) cells including Th1, IL-17, and IL-22. There are also many dendritic cells, dilated blood vessels, macrophages, and some neutrophils.

So What’s Really Going On Here?

The red, raised plaques of psoriasis are caused by proliferation of leukocytes, an avascular response, and an enhanced keratinocyte proliferation, which decreases normal keratinocyte maturation. Keratin 16 is a marker that shows keratinocytes are not differentiating normally above the basal layer on psoriatic epidermis.

When psoriatic plaques are treated adequately, however, Keratin 16 disappears. One current hypothesis is that dermal dendritic cells may be primed by such anti-microbial peptides as b-defensin and cathelicidin, which are expressed on the surface of psoriatic keratinocytes and subsequently released into the dermis. Upon binding to dermal dendritic cells, keratinocytes are primed to activate when exposed to autologous DNA and/or RNA.

Activated dendritic cells produce IL-12 and IL-23. These interleukins are composed of two proteins that contain a p40 subunit. IL-12, however, contains a p35 subunit whereas IL-23 contains a p19 subunit.

IL-12 activates the innate immune system by increasing the colonization of neutrophils, which are full of IL-17. Neutrophils travel to the epidermis, which are noted as collections of neutrophils (i.e pustules of Kugoj and Munro microabsesses). Neutrophils in the epidermis are one of the first histologic signs of psoriasis.

IL-17 induces the keratinocytes to produce and express anti-microbial peptides such as b-defensin and a host of cathelicidins on its surface. There is rarely impetiginization in psoriatic skin, due to the increased expression of anti- microbial peptides.

Anti-microbial peptides and Il-17 stimulate the keratinocytes to produce other molecules including IL-19 and IL-36, which directly induce keratinocyte proliferation and an aberrant epidermis. So in essence, psoriasis is a result of an activation of the innate and adaptive immune system.

Innate and Adaptive Immune Responses in Psoriasis

Let’s put it another way: The innate immune system delivers the first punch, and the adaptive immune system throws the second. Activated dermal dendritic cells produce IL-12 which, in turn, directs neutrophils and activates naive T-cells to become Th1 cells. These cells produce TNF-alpha.

TNF has many functions. This cytokine sends naive T-cells to local lymph nodes where they activate naive T-cells and induce the proliferation of Th1 and Th17 cells. TNF-alpha induces the synthesis of intercellular adhesion molecules (ICAMs), which facilitates diapedesis, whereby activated T-cells in the lymph vessels and blood vessels can traverse the lumen into the dermis. This protein can also induce the synthesis of epidermal growth factor and vascular endothelial growth factor, which enhances keratinocyte proliferation and blood vessel growth and dilation, respectively. TNF is also a co-factor in activating helper T-cells.

Activated dendritic cells also produce IL-23, which induces the activation and proliferation of T helper cells, which produce both IL-17 and IL-22. Both IL-17 and IL-22 directly or indirectly induce the proliferation of keratinocytes. IL- 17, in conjunction with TNF, induces the transcription of many keratinocyte genes that result in the release of even more IL-17, TNF, cathelicidin, IL-37 (an autoantigen that is chemotactic for Th17), and dendritic cells, plus IL-19, 36 and 22 which induce keratinocyte proliferation.

Remission Possible?

In essence, the activation of the innate and adaptive immune system results in a self-perpetuating T-cell mediated disease marked by aberrant keratinocyte growth. There is no check in the pathogenic pathway, which is why psoriasis is chronic.

Many of the available biologic drugs already approved to treat psoriasis—and many in the pipeline—seek to block the cytokines involved in the pathogenesis of psoriasis at various steps along the the psoriatic inflammatory cascade. In the future, we may be able to put psoriasis into remission as a result of the research that is shining a light on its pathogenesis.

For Further Reading:

1. Alexander H, Nestle FO. Pathogenesis and Immunotherapy in Psoriasis. Current Opin Rheum. 2017-Jan-29 (1) 71-78

2. Luger TA1, Loser K.  Novel insights into the pathogenesis of psoriasis. Clin Immunol. 2017 Jul 21. pii: S1521-6616(17)30526-0. doi: 10.1016/j.clim.2017.07.014

3. Hwang ST, et al. Recent Highlights in Psoriasis Research. J Invest Dermatol. 2017 Mar; 137(3):550-556 doi: 10.1016/j.jid.2016.11.007

4. Van den Berg WB, McInnes IB. Th 17 cells and Il-17 a-focus on immunopathogenesis and immunotherapeutics. Semin Arthritis Rheum. 2013; 43:158-170 https://www.ncbi.nlm.nih.gov/pubmed/24157091

5. Nestle FO,  et al. Psoriasis. N Engl J Med. 2009; 361:496-509. http://www.nejm.org/doi/full/10.1056/NEJMra0804595#t=article

6. Nestle FO, et al. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009; 9: 679-691. https://www.ncbi.nlm.nih.gov/pubmed/19763149

7. Capon F, Barker JN. The quest for psoriasis susceptibility genes in the postgenome-wide association studies era: charting the road ahead. Br J Dermatol. 2012; 166: 1173-1175. https://www.ncbi.nlm.nih.gov/labs/articles/22626038/

8. Di Meglio P, Nestle FO. The role of IL-23 in the immunopathogenesis of psoriasis. Biol Rep. 2010; 2: 40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950033/