As both rosacea and autism affect my family, I was wondering if a link between the two conditions existed. Chronic inflammation is one of the hallmarks of both rosacea and autism and research has suggested that processes triggered by our innate immunity are to blame for such inflammation.
Innate immunity is how our body reacts to foreign microorganisms by activating specialized “killer” cells such as macrophages without the involvement of antibodies, which are part of our adaptive immune system.
Besides the inflammatory processes that play a role in the etiology of autism and rosacea, both conditions appear to have key trigger factors such as environmental factors, dietary factors and stress.
With the discovery in 2007 of a link between rosacea and antimicrobial peptides (specifically cathelicidins) that are aberrantly processed and overly abundant in rosacea skin, I wanted to find out if there were any studies done that looked at antimicrobial peptides such as cathelicidins and autism.
Cathelicidins belong to a group of antimicrobial peptides that are found in the skin and in certain white blood cells (neutrophils) and contribute to the body’s early host defense against infection.
Cathelicidins are produced as inactive precursor proteins and when cleaved into activated antimicrobial peptides, destroy bacteria by disrupting the integrity of their membranes (just as most antibiotics do).
Cathelicidins are not just activated by skin injuries and invading microorganisms. The cathelicidin response is also dependent on the steroid hormone vitamin D.
In addition to its effect on calcium homeostasis and bone formation, vitamin D is an important regulator of the innate immune response.
Studies have shown that the cathelicidin genes are controlled by a vitamin D response element (a molecular switch if you will): when activated vitamin D levels are low (such as in the winter), in theory there will be less production of cathelicidins.
How Does Vitamin D work?
We get some of our vitamin D through our food, but the majority of active vitamin D is produced in the skin: UVB radiation from the sun is required to produce pre-vitamin D3 (calciol) from 7-hydroxycholesterol. Pre-vitamin D3 needs to be modified by 2 additional enzymes (found in skin, liver and kidneys) to generate active vitamin D3 (calcitriol).
So how does vitamin D fit in with autism?
Some people believe that since vitamin D plays such an important role in innate immunity and early brain development, that vitamin D deficiency during gestation or early childhood may contribute to the development of autism.
The theory behind this is, that the increase in the number of autism cases over the last 20 years does not follow classic Mendelian inheritance. While autism has a strong genetic basis with many different genes playing a role, it is fair to say that the role these genes play in the etiology of autism could not have changed much over the last 20 years.
It may be possible that environmentally responsive genes play a much larger role in the development of conditions such as autism and that something in the environment, before or after birth, is influencing the outcome of our genotype.
The rise in autism incidence over the last 20 years corresponds with increasing medical advice to stay out of the sun and use high SPF sunscreens, which may have resulted in a severe vitamin D deficiency in many people (especially during the winter months).
In addition, a strikingly high male-to-female ratio in autism can be explained by the stimulating effect estrogen has on vitamin D levels in the brain: estrogen protects female brains from calcitriol deficiencies whereas testosterone does not. Note that in rosacea there seems to be a high female-to-male ratio.
If vitamin D deficiency plays any role in autism, then symptoms should improve during the summer. Also, autism prevalence would be higher in (more) Northern latitudes. Some studies (see Cannell 2008) found an association between prevalence of autism and latitude, including recent CDC data that looked at autism prevalence in 14 states.
How can sun avoidance in the summer lead to vitamin D deficiency?
When a fair skinned adult stays in the sun for 20 minutes (full body), approximately 20,000 units of vitamin D enters their circulation. You would have to drink 200 glasses of milk or take 50 multivitamins to receive a similar amount of vitamin D.
Patients suffering from Rickets, a condition in which vitamin D deficiency is caused by a genetically defective production of the enzyme that activates vitamin D, share some of the symptoms of autism such as hypotonia and developmental delay.
Children with Williams’s Syndrome, who have very high levels of vitamin D in early infancy, often show signs that are the complete opposite of autism such as overfriendliness, empathy and increased sociability.
A number of drugs can interfere with vitamin D metabolism. One of them is sodium valproate (a.k.a. Depakote), a drug that is frequently used to treat epilepsy, seizures and convulsions.
Numerous animal studies have shown that sodium valproate (or valproic acid) given during pregnancy can lead to abnormal brain development and symptoms of autism in offspring. It has been shown that sodium valproate interferes with vitamin D’s actions. Sodium valproate or valproic acid is often used to generate mice that show the classic symptoms of autism.
Vitamin D and rosacea
While the available data from studies suggests a possible risk factor for autism and vitamin D deficiency, it is unclear at the present time whether vitamin D has a positive or negative effect on the outcome of rosacea.
Based on the findings of Yamasaki and colleagues, vitamin D would increase cathelicidin production, which in rosacea would lead to a higher level of (disease causing) antimicrobial peptides.
However, some studies have looked at the seasonal effect of rosacea and reported that for the majority of rosacea patients, symptoms did improve during the summer months.
Also, other studies have found that vitamin D deficiency is associated with increased levels of the matrix metalloproteinases (MMP 2 and 9), which are related to the serine proteases involved in rosacea.
If higher levels of vitamin D could lower the levels of the serine proteases in the skin that are causing the inflammation-causing splicing of cathelicidin, then higher levels of circulating vitamin D could therefore be beneficial to the management of rosacea symptoms.
Zanetti, M. (2005) The role of cathelicidins in the innate host defenses of mammals. Curr. Issues Mol. Biol.7: 179-196.
Schauber, J. and Gallo, R.L. (2008) The vitamin D pathway: a new target for control of the skin’s immune response? Exp. Dermatol.17: 633-39.
Cannell, J.J. (2008) Autism and vitamin D. Med. Hypotheses70: 750-59.
Yamasaki, K. et al. (2007) Increased serine protease activity and cathelicidin promote skin inflammation in rosacea. Nat. Med.13: 975-80.