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A closer look: Cytokines, vitamin D, and autism

Posted on: September 3, 2012   by  Dr William Grant

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A paper published online ahead of print by Goines and Ashwood1 reviewed findings on cytokine concentration in those with autism spectrum disorders. Cytokines are proteins released by cells in the body that carry signals to other cells such as in the immune response to infection, often leading to inflammation. In those with autism, the normal concentrations of several cytokines are disrupted or “dysregulated” either in fetal development or in childhood or later. The review by Goines and Ashwood found the cytokines reported at higher concentrations for those with autism are interleukin-1B (IL-1B), IL-4, IL-6, interferon-gamma (IFN-γ) while transforming growth factor-beta (TGF-β) is sometimes increased, sometimes decreased.

The roles of these cytokines are as follows1:

  • IL-1B increases inflammation and stimulates production of IL-6.
  • IL-6 is another inflammatory cytokine that appears later and persists longer. IL-6 can cross the placenta and can induce changes in gene expression. In adults, IL-6 can adversely affect a number of brain functions.
  • IL-4 has a number of functions including promoting tissue repair and participate in allergy- and asthma-related immune responses. IL-4 may play a more important role in the development of autism early in life rather than in maintaining autism later in life.
  • IFN-γ is generated in immune responses and may play a role in development of autism early in life.
  • TGF-β is a cytokine that tries to maintain a balance among other cytokines. Proteins in this family are critical for proper neurodevelopment.

Goines and Ashwood examined whether environmental pollutants such as heavy metals (lead and mercury) and pesticides might be involved in the dysregulation of these cytokines. While these pollutants may affect cytokine concentrations, the authors did not claim that they were necessarily involved in the development of autism. However, they mentioned that serious infections during pregnancy had been found to increase the risk of autism.2 Vitamin D reduces the risk of many types of infections.3, 4 Serum 25(OH)D concentrations decrease as pregnancy progresses5 unless sufficient vitamin D supplements are taken.6

Not mentioned in the paper by Goines and Ashwood is the role of vitamin D in regulating cytokine concentrations. A quick search at pubmed.gov found that vitamin D reduces concentrations of IL-1B,7 IL-4 and IL-6,8, 9 IFN-γ7, 8, 9 and TGF-β.10, 11

Further search at pubmed finds that John Cannell mentioned this role of vitamin D in his hypothesis that vitamin D reduced the risk of autism.12 A recent study in Saudi Arabia found that children with autism had low serum 25-hydroxyvitamin D [25(OH)D] concentrations.13

My synthesis of the above findings is that the role of vitamin D in reducing risk of autism is most pronounced during fetal development. A seasonal variation in birth rates for autism with highest rates in spring has been reported for years.14 The brain received most of its fetal development during the third trimester of pregnancy, and late winter/early spring is the period with lowest serum 25(OH)D concentrations. One way to evaluate my hypothesis would be to compare maternal serum 25(OH)D concentrations during the third trimester of pregnancy of those later diagnosed with autism with maternal 25(OH)D concentrations for those who did not develop autism.

In the meantime, pregnant and nursing women should be strongly advised to take 4000 IU/d vitamin D3 and reach a serum 25(OH)D concentration above 40 ng/ml (100 nmol/l). This was shown to be required for optimal production of the hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D, and had no adverse effects.6

References

  1. Goines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment. Neurotoxicol Teratol. 2012 Aug 17. [Epub ahead of print]
  2. Atladóttir HO, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, Parner ET. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord. 2010;40(12):1423-30.
  3. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129-40.
  4. Hewison M. Antibacterial effects of vitamin D. Nat Rev Endocrinol. 2011 Jun;7(6):337-45.
  5. Charatcharoenwitthaya N, Nanthakomon T, Somprasit C, Chanthasenanont A, Chailurkit LO, Pattaraarchachai J, Ongphiphadhanakul B. Maternal vitamin D status, its associated factors and the course of pregnancy in Thai women. Clin Endocrinol (Oxf). 2012 Jun 16. doi: 10.1111/j.1365-2265.2012.04470.x. [Epub ahead of print]
  6. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26(10):2341-57.
  7. Froicu M, Cantorna MT. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol. 2007;8:5.
  8. Guillot X, Semerano L, Saidenberg-Kermanac’h N, Falgarone G, Boissier MC. Vitamin D and inflammation. Joint Bone Spine. 2010;77(6):552-7.
  9. Khoo AL, Chai LY, Koenen HJ, Sweep FC, Joosten I, Netea MG, van der Ven AJ. Regulation of cytokine responses by seasonality of vitamin D status in healthy individuals. Clin Exp Immunol. 2011;164(1):72-9.
  10. Halder SK, Goodwin JS, Al-Hendy A. 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells. J Clin Endocrinol Metab. 2011;96(4):E754-62.
  11. Isik S, Ozuguz U, Tutuncu YA, Erden G, Berker D, Acar K, Aydin Y, Akbaba G, Helvaci N, Guler S Serum transforming growth factor-beta levels in patients with vitamin D deficiency. Eur J Intern Med. 2012;23(1):93-7.
  12. Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9.
  13. Mostafa GA, Al-Ayadhi LY. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: Relation to autoimmunity. J Neuroinflammation. 2012;9(1):201.
  14. Grant WB, Soles CM. Epidemiologic evidence supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism. Dermatoendocrinol. 2009 Jul;1(4):223-8. Erratum in: Dermatoendocrinol. 2009;1(6):314.
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