Sun exposure can induce, or reduce, the incidence of certain autoimmune diseases
May 5, 2003
By Stacie Zoe Berg
The Scientist, Volume 17, Issue 9, 32
It's an interesting conundrum: The effects of ultraviolet (UV) radiation from sun exposure can induce the onset of, or exacerbate, the symptoms of certain autoimmune diseases. Now flip the coin: UV also can prevent, or reduce, the symptoms of others. Current research focuses on lupus, multiple sclerosis (MS), type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, dermatomyositis, and atopic eczema.
What is going on? "These irradiations may alter the delicate regulatory network of the immune system to result in an immune dysregulation [overreaction or underreaction to certain substances], and because different diseases are modulated by different types of cells, these effects could be different in different diseases," says Frederick W. Miller, chief of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences.
UV radiation encompasses the electromagnetic spectrum from 200 to 400 nanometers in wavelength and is sub-divided into UV-A (320-400 nm), UV-B (290-320 nm), and UV-C. The atmosphere blocks UV-C. Both UV A and UV B contribute to the deleterious effects on the skin, but it appears that UV-B is more associated with autoimmune research.
The direct effects of increases in UV-B on health are manifest through those organs that are exposed to sunlight, including the skin. These effects occur because molecules absorb UV-B photons in these organs; the resulting energy transfer produces changes that may be either beneficial or adverse. A direct beneficial influence of exposure is the formation of vitamin D in the skin, a process important to the maintenance of bone tissue.1
STIMULATION AND EXACERBATION
Harvard researchers showed recently that UV radiation absorbed from working in the sun can induce the onset of lupus.2 "It has been known for decades that UV radiation can cause lupus to get worse," says Patricia A. Fraser, assistant professor of medicine, who led the investigation. Now, they report that accumulated UV exposure from sunlight, in a subset of genetically predisposed individuals, can increase by threefold the risk of developing lupus. Both sunlight and the GSTM1 null gene are to blame, says Fraser.
UV light exposure triggers production of reactive oxygen species as normal by-products. If the cell does not quickly eliminate the reactive oxygen species, however, the buildup can cause cellular and DNA damage. The GSTM1 gene normally codes for an enzyme, glutathione S-transferase, which rids the body of reactive oxygen species. Individuals who have the GSTM1 null genotype and are missing the enzyme may, therefore, be at an increased risk of DNA damage, Fraser says.
The body sometimes interprets damaged DNA as a foreign substance, and the subsequent autoimmunologic response can result in lupus, a chronic inflammatory disease that can affect various parts of the body, especially the skin, joints, blood, and kidneys.
UV light exposure modulates the onset and activity of dermatomyositis and polymyositis. Miller and colleagues looked at geoclimatic variables and found that global surface UV radiation intensity was the strongest factor contributing to the relative proportion of dermatomyositis compared with polymyositis. These autoimmune diseases, says Miller, are ideal for studying the effect of UV radiation because one form, dermatomyositis, presents with a photosensitive rash, and the other does not. Dermatomyositis and polymyositis are both systemic diseases of the connective tissues. A number of organ systems can be adversely affected, and they are characterized by muscle weakness, among other symptoms. Patients presenting with dermamyositis have characteristic rashes.
THE FLIP SIDE
Regional and climatic variations exist in the numbers of people with MS, type 1 diabetes, and rheumatoid arthritis. The prevalence of MS decreases from north to south in the northern hemisphere and from south to north in the southern hemisphere. In general, MS becomes more prevalent with increasing latitude, but differences in prevalence can be seen within populations. The prevalence of MS decreases as skin pigmentation increases.3
In comparing black and white populations, the prevalence of MS is lower in blacks, regardless of latitude. Moreover, regardless of skin color, individuals who live in tropical climates from early childhood until adolescence and then relocate to a more temperate region have a reduced risk of MS developing, indicating that they have undergone a protective environmental (UV radiation) effect.3
Skin pigmentation and sensitivity to UV light were the focus of a case-control study of susceptibility to type 1 diabetes.4 German researchers found that, compared with controls, patients with type 1 diabetes more often had blue or green (low pigment) eye color, fair skin, and more sensitivity to UV light.
Exactly how UV exposure suppresses the cellular immune response is unknown. Some cells that reside in the skin, including lymphocytes, macrophages, and Langerhans cells, are generated in the bone marrow. Langerhans cells and dermal macrophages present antigens to lymphocytes. In experiments in which the skin is exposed locally to small amounts of UV radiation, Langerhans cell loss occurs at the exposure site, suppressing the local cellular immune response. This cell loss is associated with local suppression of the cellular immune response.
Some, like Michel Dumas, believe that the low prevalence of MS near the equator results from immunosuppression induced by UV radiation on the epidermal Langerhans cells. Dumas, a professor at Institut d'Epidémiologie et de Neurologie Tropicale in Limoges, France, says that two protective factors are missing in patients with MS: one is a genetic factor that influences immune responsiveness; the other is an environmental factor, namely, exposure to UV radiation, particularly in childhood. In MS, the autoimmune process causes chronic inflammation of the central nervous system, resulting in demyelination. It appears that UV radiation promotes immune tolerance toward certain antigens, particularly myelin autoantigens.3
Five factors, Dumas says, could be responsible for UV mediated immunosuppression in MS: (1) decreased production of Langerhans cells; (2) reduction in the expression of adherence molecules and co-stimulating proteins (vital for activating T lymphocytes) on these cells; (3) increased production of Interleukin-10, dermal macrophages and increased recruitment of T-lymphocytes that can inhibit immune response; (4) reduction of interlukin-12, a cytokine responsible for lymphocyte activation; and (5) vitamin D3 synthesis, which interferes with Langerhans cell function.
THE ROLE OF VITAMIN D
Not all scientists agree with how latitude and UV radiation lead to immunosuppression. Stephen C. Reingold, vice president of research programs at the National Multiple Sclerosis Society, says that the link may result from vitamin D mediated immunosuppression rather than direct cellular changes.
In the United States, the MS prevalence rates in black Americans are half those for white Americans. This apparent anomaly could reflect numerous explanations including: that autoimmune disease prevalence is underreported in vitamin D deficient populations, and that vitamin D deficiency in early life may be more important. In the United Kingdom, for example, MS was uncommon among adult immigrants from India, Asia, and Africa; the children of these immigrants had a higher MS prevalence similar to the general English population.5 Evolution has selected darker skin pigmentation in lower latitudes and lighter skin color in higher latitudes to enhance vitamin D synthesis.6 But people who migrate require time to adapt to their new environments.
Margherita T. Cantorna, assistant professor of nutrition at Pennsylvania State University, and her team showed that in animal models for lupus, arthritis, inflammatory bowel disease, and MS, "... if you change vitamin D status [making it insufficient], the disease comes on more quickly. If you give back pharmacological amounts of vitamin D, you can prevent the diseases from happening in the animals."
Research has shown that vitamin D can prevent symptoms from worsening in patients with MS and in animal models with inflammatory bowel disease, says Cantorna. Vitamin D could be one of many factors contributing to the etiology of these diseases; but she warns against patients taking high amounts of vitamin D, noting that it can be toxic.
"Contrary to popular belief, you cannot get enough vitamin D to meet your biological needs by ingesting fortified foods," says professor Colleen E. Hayes, Department of Biochemistry, University of Wisconsin, Madison. "Urged by the fear of skin cancer, individuals are avoiding sun exposure and using sunscreens. Somewhere, there is a balance between too much sun and melanoma risk or too little sun and autoimmune disease."
Stacie Zoe Berg is a freelance writer in Washington, DC
1. J.D. Longstreth, "Environmental effects of ozone depletion: 1994 Assessment," in Effects Of Increased Solar Ultraviolet Radiation On Human Health, available online at http://sedac.ciesin.org/ozone/UNEP/chap2.html
2. P.A. Fraser et al., "Glutathione S-transferase M null homozygosity and risk of systemic lupus erythematosus associated with sun exposure: A possible gene-environment interaction for autoimmunity," J Rheumatol, 30:276-82, February 2003.
3. M. Dumas, M.O. Jauberteau-Marchan, "The protective role of Langerhans' cells and sunlight in multiple sclerosis," Med Hypoth, 55:517-20, 2000.
4. A.G. Ziegler et al., "Low-pigment skin type and predisposition for development of type I diabetes," Diabetes Care, 13:529-31, 1990.
5. L.A. Ponsonby et al., "Ultraviolet radiation and autoimmune disease: Insights from epidemiological research," Toxicology, 181:71-8, 2002.
6. R.M. Luca, A.L. Ponsonby, "Ultraviolet radiation and health: Friend
and foe," Med J Aust, 177:594-98, December 2002.
© 2003, The Scientist Inc.