Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens
- PMID: 21307853
- PMCID: PMC3076739
- DOI: 10.1038/nature09849
Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens
Abstract
Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.
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Comment in
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Immunology: Context is key in the gut.Nature. 2011 Mar 10;471(7337):169-70. doi: 10.1038/471169a. Nature. 2011. PMID: 21390118 No abstract available.
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Mucosal immunology: Acid attack.Nat Rev Immunol. 2011 Mar;11(3):156. doi: 10.1038/nri2948. Nat Rev Immunol. 2011. PMID: 21452586 No abstract available.
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Celiac disease: Retinoic acid and IL-15 jointly implicated in reversal of oral tolerance.Nat Rev Gastroenterol Hepatol. 2011 Apr;8(4):181. doi: 10.1038/nrgastro.2011.29. Nat Rev Gastroenterol Hepatol. 2011. PMID: 21595057 No abstract available.
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IL-15 modulates the effect of retinoic acid, promoting inflammation rather than oral tolerance to dietary antigens.Expert Rev Gastroenterol Hepatol. 2011 Jun;5(3):315-7. doi: 10.1586/egh.11.36. Expert Rev Gastroenterol Hepatol. 2011. PMID: 21651349
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