Exploring the skin’s immune response system and how it reacts to exposure to UV radiation
The immune response is a complex interactive network of cellular and molecular systems that provides the first line of host defence[1] by numerous antioxidant strategies devised to protect biomolecules from the effects of Reactive Oxygen Intermediates (ROI).
Thus when most people think about the human body being invaded by a foreign organism they think about the body’s immune system, whereby an antigen recognises a component of the invading cell and launches a counter offensive of white cells and antibodies.
An antigen is in fact any material capable of provoking the lymphoid tissues to respond by generating an immune reaction specifically directed at the inducing agent but at no other unrelated substances. This adaptive scenario takes generally several days or weeks to develop and represents half of the story.[2] The other half is the innate immune response, which keeps random microbes from becoming infectious. As the body’s first line of defence, it comprises the intact cell layers of skin and mucous membrane, which form a physical barrier. The skin’s low pH level and bacterial fatty acids enhance the protection provided by this physical barrier. The innate response recognizes and eradicates pathogens and harmful environmental foreign molecules.
The most important humoral natural resistance factors are complement, lysozyme, interferons, collectins and a number of cyto-kines. Moreover an innate immune response can be triggered by binding pathogen associated molecular patterns or signalling molecules to pattern recognition receptors such as toll-like receptors located on the surface of Langerhans and other dendritic cells, mannose receptors or complement receptors on the surface of host cells.[3]
The binding of signalling molecules to pattern recognition receptors results in rapid marshalling of neutrophils, monocytes, macrophages, complement factors, cytokines, antimicrobial peptides and acute phase proteins in a complex and highly regulated response against infection. Thus microorganisms that succeeded in penetrating the first line of defence are ingested, killed and degraded by phagocytic cells (leukocytes, monocytes, macrophages), which are attracted to a microbial infection through chemotaxis.[4]
A special role in cellular natural resistance is reserved for the NK (natural killer) cells, which display considerable cytotoxic activity against virus infected cells. This NK activity is stimulated by interferons and, at a very early stage in the infection, serves to reinforce the non-specific defence mechanism. Moreover, during an innate response, excessive production of certain inflammatory mediators and pro-inflammatory cytokines can lead to a cascade that, if left unchecked, causes tissue damage or sepsis, a potentially lethal condition.[5]
For example, an uncontrolled inflammatory response can be triggered by bacterial components released during infection or by the bacteria themselves. It is therefore necessary to selectively up-regulate the infection clearing aspects of the innate immune response while limiting harmful inflammation. Recent research has demonstrated that human peptide LL-37 seems to be capable of up-regulating the expression of chemokines in macrophages without stimulating the pro-inflammatory cytokine TNF-alfa. However, both T-lymphocytes and macrophages play an important role in cellular defence.
Skin immunity suppression
The skin is known to possess its own sophisticated immune system but this is partially inhibited by UVA radiation.
UV radiation cripples immunity by diminishing the number of Langerhans cells and the skin’s ability to present antigens to T cells.[6] It is also inhibited by the release of cytokines, such as IL-10 (Interleukine-10). On the other hand UV rays can also convert normal skin chromophores into agents that are immunosuppressive, ie the conversion of trans-urocanic to cis-urocanic acid.[6+7] Therefore exposure of the skin to UV radiation is a multi-step process and a complex variety of mediators are produced both locally and, in some cases, systematically.
These include both pro- and anti-inflammatory cytokines, as well as histamine and prostanoids (Prostaglandyne E2). Most recently a range of neuropeptides and neurohormones have also been discovered in the skin, capable of controlling immunity and inflammation. As a result, they change the function and phenotype of the antigen presenting cells that occur within 24 hours after acute UV irradiation.
Sun exposure & skin cancer
UV absorption by cellular DNA results in various types of damage of which the formation of cyclo-butane pyrimidine dimers (CPDs) is most common. CPDs have been located in keratinocytes and Langerhans cells following UVB exposure, and also in dendritic cells in limphonodes draining the irradiated sites.
Removal of the dimers is slow with an estimated half-life of 33 hours in human skin.[7] Acute UV damage to keratinocytes usually leads to the activation of the tumor-suppressing gene p53, which is responsible for the induction of DNA repair and apoptosis. This is what happens in normal conditions of UV exposure. But when the UV exposure is chronic, errors associated with DNA repair and/or replication can result in mutations in the p53 gene. And p53 mutation in keratinocytes plays a key role in the process of carcinogenesis in skin.[8] In addition, mutations in another tumor-suppressing gene, the patched (PTCH) gene, seem to be implicated in the formation of skin carcinomas.
However long-term, sunlight exposure is a recognised risk factor for the development of skin cancers and DNA damage is known to initiate down-regulation of the immune system.[9]
Thus chronic changes due to ultraviolet radiation (UVR) consist of photoageing (solar elastosis) and the induction of premalignant changes (solar keratoses) and malignant skin tumors. Additional harmful effects are produced by the interaction of UVR with a variety of environmental and medicinal chemicals. Moreover it is also estimated that the frequent use of solaria (three times a week from from the age of 20 to 50) could double the likelihood of skin cancer development. And the increasing use of sun beds and sun canopies for home use gives another considerable cause for concern because no controls can be exercised there.[10]
Thus exposure to UVR occurs from both natural and artificial sources and increasing awareness of the damaging effects has led to a significant demand for improved photoprotection from topically applied sunscreen agents. Therefore applying sunscreens is just one element of a strategy aimed at controlling sun exposure. Others include seeking shade around the middle of the day and wearing clothing and wide-brimmed hats.[11-14]
Moreover recent data from human studies provide evidence that carotenoids, both oxygenated (lutein) and non-oxygenated (beta carotene and lycopene), when supplied over a period of several weeks together with vitamin E and vitamin C, protect both the skin against the UV-induced erythema and skin ageing and the eyes’ against cataracts and eye related maculae degeneration (AMD).[14-19]
In conclusion the probability of contracting certain skin cancers is related to the intensity and frequency of sunburn during our lifetime, implicating immune response modifications and the formation of skin carcinomas. Excess exposure to the sun’s rays can also be linked not only to the onset of neoplasias but to premature skin ageing. Consequently, there are many obvious reasons why exposure to UVR without protective sunscreens and antioxidant carot-enoids should be avoided. The regular use of these protective products, topically and orally, will therefore slow down these phenomena, providing effective protection against ageing and skin cancers. Furthermore, the contemporary use of immune response modifiers should play an innovative integral part in the future of photoprotective treatments.