Autoimmune neurologic diseases

Oral

The Hygiene Hypothesis in Ms: Inducing tlr2 Tolerance Treats the Myelin Repair Component as Well as the Inflammatory Component of Ms

Friday, June 16
6:15 PM - 7:30 PM

Multiple sclerosis (MS) is a CNS autoimmune disease characterized by both an inflammatory/demyelinating component and a defective myelin repair (re-myelinating) component. Re-myelination defects, which may underlie progressive forms of MS, remain poorly understood. Recent studies implicate toll-like receptor 2 (TLR2) signaling as contributing to both the inflammatory component and defective re-myelination of MS. We previously reported evidence that the "Hygiene Hypothesis," as represented by a systemic deficiency in microbiome-derived "tolerizing" TLR2 ligands, may be involved in MS. In proof-of-concept studies, we reported that inducing TLR2 tolerance with low doses of microbiome-derived TLR2 ligands significantly attenuates adoptively transferred EAE. Here we ask if TLR2 tolerance also enhances the re-myelinating component of MS.


Utilizing the cuprizone-induced murine model of demyelination, we report that inducing TLR2 tolerance significantly improves myelin thickness during both the demyelination and re-myelination phases of myelin damage. Systemic TLR2 tolerance was induced by administering low dose TLR2 ligands for either 4 weeks during cuprizone administration (demyelinating phase) or 16 days after halting cuprizone administration (re-myelinating phase). Evaluation of myelin integrity via Black-Gold staining and electron microscopy (g-ratios) revealed significantly enhanced myelin recovery in mice tolerized either during (p=0.0012) or after cuprizone treatment (p=0.0006).


These results indicate that TLR2 tolerance enhances myelin repair via mechanisms independent of modulating systemic immune function. Given that defective re-myelination may represent an important component of the pathophysiology in progressive MS, our results suggest that inducing TLR2 tolerance may represent a two-pronged approach for treating both the inflammatory and myelin repair components of MS.

Nicholas J. Wasko

MD/PhD student
University of Connecticut Health Center

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    Mai Fujiwara

    University of Connecticut Health Center

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      Emily J. Anstadt

      MD/PhD Student
      University of Connecticut Health Center

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        Frank C. Nichols

        Professor, Division of Periodontology
        University of Connecticut Health Center

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          Robert B. Clark

          Professor of Immunology
          University of Connecticut Health Center

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