Parasite infections in multiple sclerosis modulate immune responses through a retinoic acid-dependent pathway

J Immunol. 2013 Oct 1;191(7):3827-37. doi: 10.4049/jimmunol.1301110. Epub 2013 Aug 23.


We recently demonstrated better outcomes in helminth-infected multiple sclerosis (MS) patients, compared with uninfected ones. The present study evaluates the role of TLR2 and retinoic acid (RA) in parasite-driven protection in MS patients. RA serum levels were significantly higher in helminth-infected MS patients than in uninfected MS subjects or healthy controls. Genes involved in RA biosynthesis and metabolism, such as Adh1 and Raldh2, as well as RA receptors and IL-10, were induced in dendritic cells (DCs) via TLR2-dependent ERK signaling. This programmed DCs to induce FOXP3(+) T regulatory cells and suppressed production of proinflammatory cytokines (IL-6, IL-12, IL-23, and TNF-α) via induction of suppressor of cytokine signaling 3 (SOCS3), an effect mediated by soluble egg Ag (SEA) obtained from Schistosoma mansoni, and by RA. SEA-activated DCs also inhibited IL-17 and IFN-γ production through autoreactive T cells. These inhibitory effects were abrogated when SOCS3 gene expression was silenced, indicating that SEA-mediated signaling inhibited production of these cytokines by T cells, through a SOCS3-dependent pathway. Overall, helminth-related immunomodulation observed in MS patients was mediated by TLR2- and RA-dependent pathways, through two different mechanisms, as follows: 1) induction of IL-10 and FOXP3(+) T regulatory cells, and 2) suppression of proinflammatory cytokine production mediated by SOCS3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Dehydrogenase / genetics
  • Alcohol Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase 1 Family
  • Antigens, Helminth / immunology
  • Cytokines / biosynthesis
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Female
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Male
  • Models, Biological
  • Multiple Sclerosis / complications
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / metabolism*
  • Parasitic Diseases / complications
  • Parasitic Diseases / immunology*
  • Parasitic Diseases / metabolism*
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Retinal Dehydrogenase / genetics
  • Retinal Dehydrogenase / metabolism
  • Signal Transduction*
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Tretinoin / blood
  • Tretinoin / metabolism*


  • Antigens, Helminth
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Inflammation Mediators
  • Receptors, Retinoic Acid
  • SOCS3 protein, human
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Tretinoin
  • Alcohol Dehydrogenase
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A2 protein, human
  • Retinal Dehydrogenase