Immune modulation by phototherapy: why immune suppression?

Phototherapy, the use of light to treat disease, has been in use for centuries. To treat vitiligo, ancient physicians in Egypt, China and India applied boiled extracts from the roots, leaves and seeds of psoralen-containing plants (Ammi majus and Psoralea corylifolia) onto the affected skin and sent their patients into bright sunlight. In 1903, as every bright young dermatology fellow knows (or should know), Niels Finsen was awarded the Nobel Prize in Medicine in ‘recognition of his contribution to the treatment of diseases with concentrated light radiation’. Finsen used sunlight, and/or artificial UV radiation to treat the cutaneous manifestations of tuberculosis infection. In the award presentation speech, KAH Mörner, Rector of the Royal Caroline Institute, (Stockholm, Sweden) pointed out, “…the results are particularly satisfactory and are far superior to those obtained previously in the battle against this disease” [101]. Later, advances with antibiotics replaced phototherapy as the treatment of choice for tuberculosis, but modern phototherapy therapy evolved into using psoralen and UVA (PUVA), narrow (311–313 nm) and broadband UVB (290–315 nm), and UVA I (340–400 nm) to treat a variety of skin diseases.

Using phototherapy, however, presents a dilemma. Although it is very effective for treating a wide variety of skin disorders, it has two major adverse side effects: phototherapy induces immune suppression; chronic PUVA and UVB therapy induces non-melanoma skin cancer. Moreover, phototherapy-induced immunosuppression is a major risk factor for skin cancer induction. Considering that skin cancer is the most prevalent cancer diagnosed in the USA, and the costs of treating nonmelanoma skin cancer come close to US$1 billion every year, the concerns that both the patient and the clinician face when starting a course of phototherapy are not trivial.

If we are ever going to divorce the harmful side effects of phototherapy from its beneficial effects, we must have a better understanding of the mechanisms involved. In this issue of Expert Review of Dermatology, Yang and Baron present an excellent and a timely update on the immunology of phototherapy [1]. Besides reviewing the types of therapeutic regimens that are commonly used in phototherapy, and the skin disorders that are commonly treated, they present a concise review of the mechanisms involved. In addition, the authors present their 5-year view of how recent advances in biologics used to affect immunologic processes may be married with phototherapy in the future to generate treatment protocols that yield longer disease remissions, with fewer side effects.

An example of how a better understanding of the mechanisms underlying phototherapy-induced immune modulation may yield new insights into the development of novel therapeutic agents comes from a recent paper published by Wolf and colleagues [2]. These authors demonstrated that, using selective platelet-activating factor (PAF) receptor antagonists, the binding of PAF to its receptor is a critical event in PUVA-induced immune suppression and is involved in other PUVA-induced effects such as apoptosis, cytokine production, upregulation of p53 protein expression in the skin and inflammation. This suggests that topical application of PAF may mimic the effects of PUVA. The advantage of using such an approach is that topical application of PAF would not cause mutations in the DNA, therefore the harmful side effect of skin cancer induction can be avoided. Another serious problem with PUVA-treatment is the life-threatening phototoxic burning of the skin that can occur with accidental PUVA overdose. Wolf and colleagues found that administering a PAF receptor antagonist to a PUVA-treated mouse blocked PUVA-induced skin inflammation and reduced the inflammatory infiltrate into the skin. This is not to say that PAF should replace PUVA. These studies were conducted on a mouse model and the end point was immune suppression, rather than the inhibition of psoriasis, but the data in this paper illustrate how a better understanding of the mechanisms involved may lead to new approaches for treating the disease, or perhaps may lead to a better way to deal with a toxic side effect.

As pointed out by Yang and Baron, ‘Much has been studied on the effects of UV-induced immunosuppression, which has lead to greater understanding of the UV radiation-mediated effect on the skin immune system and it’s therapeutic relevance’ [1]. This raises an interesting and unresolved question concerning phototherapy and immune suppression: why does the UV radiation in sunlight, which is necessary for life as we know it, induce immune suppression? After all, we are exposed, almost daily, to doses of UVB that suppress delayed and contact hypersensitivity, suppress epidermal Langerhans cells function and can suppress tumor rejection in vivo[3]. It appears counter intuitive that our immune system would evolve to respond to sunlight exposure by depressing the immune response. Over the years, a number of models have been proposed to explain sunlight-induced immune suppression. One of the first, originally proposed by George Kline of the Karolinska Institute, Sweden [4], was based on the findings presented in a paper that was one of the foundations of photoimmunology. In 1974 Margaret Kripke published data demonstrating that the tumors induced by UV radiation were highly antigenic. Unlike most tumors induced by other physical or chemical carcinogens, tumors induced by UV radiation were recognized as foreign and were destroyed by the immune systems of normal mice. UV-induced skin cancers would only grow progressively in mice whose immune systems were compromised [5]. Professor Klein suggested that, during UV exposure, new antigens were constantly being created in the skin, owing to UV’s mutating and carcinogenic properties, and UV-induced immune suppression was evolution’s way of preventing an un-wanted autoimmune reaction that would result in rejecting one’s own skin (autoimmune model).

A second proposed mechanism dealt with the relationship between UV-induced DNA damage and UV-induced cytokine production. In the early 1990s, Kripke and colleagues demonstrated that UV-induced DNA damage led to immune suppression, in part by the upregulation of cytokine production by UV-irradiated keratinocytes [6]. Kripke suggested that many of the cytokines produced after UV exposure, such as granulocyte-macrophage colony-stimulating factor, nerve growth factor, melanocyte-stimulating hormone, IL-1, IL-4 and IL-6, are involved in hematopoiesis and lymphoid development. He also suggested that and epidermal cytokine production may represent an ‘SOS’ response in the skin to restore hematopoietic balance following environmental damage. Owing to coordinate regulation of cytokine production, immune regulatory cytokines, such as IL-10, are also released, which results in immune suppression. Kripke suggested that, ‘UV-irradiation may produce a small gap in immune surveillance in exchange for rapid mobilization of hematopoietic cells in response to DNA-damaging reagents’ (hematopoiesis model) [4].

My laboratory’s work with PAF suggests another interpretation for the evolution of UV-induced immune suppression. After exposure to DNA-damaging mutagens and carcinogens, such as UV radiation, a cell must progress through a series of checkpoints, which then determine whether that cell repairs its DNA and lives, or does not and progresses down the apoptotic pathway. UV-induced DNA damage promotes arrest at the G₂/M checkpoint, in part by activating MAP kinase p38. MAP kinase p38 plays a prominent role in activating phospholipaseA₂, which is the first enzymatic step in the biosynthesis of PAF. PAF then upregulates the production of a wide variety of immunomodulatory factors, including IL-10 and prostaglandin E₂, two molecules known to play an important role in UV-induced immune suppression. I propose that a side effect of the DNA damage caused by UV irradiation is the activation of PAF, which results in a transient immune suppression. The most important job that a cell faces is maintenance of genomic integrity, and evolution allows a transient immune suppression in return for DNA repair (genomic integrity model).

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.