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Janis Weis

Professor of Pathology

B.A. University of Kansas

Ph.D. University of Minnesota Medical School

Research

References

janis.weis@path.utah.edu

Janis Weis Lab Page

Research

My laboratory investigates the mechanism of inflammatory arthritis development, using the murine model of Lyme disease.  Our goals are to identify the events associated with arthritis development in this model of acute, infection-associated disease, with the understanding that these events may set the stage for chronic autoimmune arthritis in MHC susceptible individuals.  Mice of the C3H strain develop severe arthritis when infected with Borrelia burgdorferi, whereas C57BL/6 mice develop mild arthritis.  We generated intercross populations between C3H and C57BL/6 mice and identified six Quantitative Trait Loci (QTL) that regulate arthritis severity.  Reciprocal, interval-specific, congenic lines of mice have been developed that transfer each of the QTL singly to the opposite strain.  In five of the congenic lines there was transfer of arthritis severity including phenotypes of edema, tendon sheath thickness and hyperproliferation, PMN infiltration, and reactive/reparative responses.  We are currently narrowing the interval associated with each QTL by generating recombinants within the interval.  The ultimate goal of this research is to identify the allelic genes responsible for differences in Lyme arthritis severity.

Our second approach to understanding the mechanism of Lyme arthritis development is to study the responses to the bacterial products that contribute to the inflammatory responses associated with inflammatory pathologies.  We demonstrated that the Borrelia outer surface lipoproteins activate mammalian cells through toll-like receptor 2, and hypothesized that this signaling pathway would be necessary for arthritis development.  Surprisingly, infection of mice deficient in TLR2 and in the signaling molecule MyD88 resulted in more severe arthritis than the wild type animal, indicating involvement of additional signaling pathways and cell types in arthritis.  Further investigation of infection in TLR2-/- mice suggests they may provide a model for T cell mediated disease, which we are currently pursuing.  The contribution of other, novel signaling pathways to arthritis development was assessed by global gene expression analysis of joint tissue from mice developing severe and mild arthritis.  Microarray analysis revealed entirely distinct patterns of early gene activation in infected mice that develop severe and mild arthritis.  The expression profile in mice destined to develop severe arthritis was dominated by induction of interferon inducible genes.  In contrast, mouse strains resistant to arthritis development displayed an early anti-inflammatory pathway that may prevent the development of arthritis several weeks later.  We are currently investigating the cells and pathways involved in these newly discovered pro- and anti-inflammatory profiles.  Identification of genes that regulate arthritis severity will impact our genetic studies, and could result in identification of novel therapeutic targets.

Distinct gene expression profiles revealed in mice developing severe (C3H) and mild (C57BL/6) arthritis following infection with Borrelia burgdorferi.

References