Resolution of plaque-type psoriasis: what is left behind (and reinitiates the disease)

Abstract

Psoriasis is a chronic inflammatory skin disease that involves numerous types of immune cells and cytokines resulting in an inflammatory feedback loop and hyperproliferation of the epidermis. A more detailed understanding of the underlying pathophysiology has revolutionized anti-psoriatic treatment and led to the development of various new drugs targeting key inflammatory cytokines such as IL-17A and IL-23. Successfully treated psoriatic lesions often resolve completely, leaving nothing visible to the naked eye. However, such lesions tend to recur within months at the exact same body sites. What is left behind at the cellular and molecular levels that potentially reinitiates psoriasis? Here, we elucidate the cellular and molecular "scar" and its imprints left after clinical resolution of psoriasis treated with anti-TNFα, anti-IL-17, or anti-IL-23 antibodies or phototherapy. Hidden cytokine stores and remaining tissue-resident memory T cells (TRMs) might hold the clue for disease recurrence.

Immunological Memory in Imiquimod-Induced Murine Model of Psoriasiform Dermatitis

“…T cell receptor sequencing has shown that in resolved psoriasis, pathogenic T cell clones are maintained at similar levels to those found in acute lesions [ 22 ]. Moreover, pathogenic T cell clones that remain in resolved, clinically healed lesions that are actively producing proinflammatory cytokines have been suggested to be Trm cells and their renewed activation results in keratinocyte activation, chemokine release and recruitment of circulating leukocytes, closely correlating with clinical relapse after therapy [ 7 , 23 ]. Interestingly, pathogenic Trm cells have also been shown to be present in the non-lesional skin of psoriatic patients [ 17 ].…”

“…Additionally, it would be interesting to further dissect the interplay between CD49a + Trm cells and epidermal Langerhans cells in disease relapse as dysfunction of these cells has been attributed to the rapid initiation of inflammation in the same location, hence contributing to the memory of psoriatic eruptions [ 26 ]. Additionally, Langerhans cells are found in close proximity to T cells and have been shown to cross-talk with both T cells and keratinocytes, suggesting their potential role in renewed activation of T cells and disease recurrence [ 7 ]. A recent study has shown that Langerhans cells isolated from resolved psoriatic lesions have the ability to produce proinflammatory IL-23 post stimulation, further implying the potential role of these cells in restarting the activation of “sleeping” Trm cells, potentially the GzmB + CD49a + Trm cells described, leading to re-occurrence of psoriatic lesions ( Figure 5 ) [ 26 ].…”

“…Previous studies have rightfully investigated the role of IL-17 in the pathobiology of this disease. While CD103 + Trm cells have the capacity to express IL-17, a large proportion of epidermal CD103 + T cells in human psoriatic patients are known to express CD49a that have potentially a more cytotoxic function rather than cytokine release, including in psoriatic “molecular fingerprints” that remain after disease treatment [ 7 ]. Due to the lack of a good animal model for this chronic inflammatory skin disease, the importance of this subset has not been proven.…”

“…The hallmark of psoriasis is the relapsing nature of the disease and long-term persistence of lesions in the same anatomical regions (90% in the same location) and the appearance of new lesions in places where treated lesions have successfully resolved, often necessitating long-term therapies [ 5 ]. In the past decade, advancements in the development of psoriatic therapies and targeted biological drugs have significantly improved patient outcomes; however, disease relapse, alongside an understanding of the disease priming which results in lesion recurrence, is still lacking [ 6 , 7 ]. Site-specific immunological memory response in psoriasis has been linked to both CD8 + CD103 + tissue resident memory T cells (Trm) and dendritic cells in the epidermis [ 5 ].…”

“…Epidermal Trm cells have been shown to be retained in resolved psoriatic lesions of patients and mediate detrimental pro-inflammatory responses by producing interleukin (IL)-17a and IL-22 cytokines upon stimulation, both of which are critical in psoriasis pathogenesis [ 8 , 9 ]. A number of studies have suggested that Trm cell biology is critical in disease recurrence as their resistance to elimination by current conventional therapies provides a potential mechanism to resume the psoriatic inflammatory feedback loop at the site of residence [ 7 ].…”