Janis Weis
Professor of Pathology
B.A. University of Kansas
Ph.D. University of Minnesota Medical School
Janis Weis' Lab Page
Janis Weis' PubMed Literature Search
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, using infection with Borrelia burgdorferi as a natural trigger for disease development. Importantly, the pathways involved in acute disease may also set the stage for chronic arthritis in susceptible individuals. We have focused on genetically regulated differences in arthritis severity between infected C3H mice, which develop severe arthritis, and C57BL/6 mice, which develop mild disease. Using intercross populations between C3H and C57BL/6 mice we have identified six Quantitative Trait Loci (QTL) that regulate arthritis severity. Reciprocal, interval-specific, congenic lines of mice have been developed and have identified penetrant phenotypes associated with transfer of three QTL. Two QTL resulted in reciprocal transfer of arthritis phenotype: edema, tendon sheath thickness and hyperproliferation, PMN infiltration, and reactive/reparative responses. The physical regions associated with these QTL have been narrowed by the development of recombinant interval specific congenic mice. These have revealed several loci within the original QTL identified on Chr 5 and 11, and have significantly reduced the physical size associated with each loci. Current experiments are focused on characterization of candidate genes within these QTL and assessment of their roles in regulating the severity of Lyme arthritis. 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. Microarray analysis revealed entirely distinct patterns of early gene activation in joint tissue of infected mice depending on the severity of subsequent arthritis. The expression profile in mice destined to develop severe arthritis was dominated by induction of interferon inducible genes, an unexpected finding. 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 have recently shown that Type I IFN plays an important and novel role in Lyme arthritis development. 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
1. Ma, Y, Miller JC, Crandall H, Larsen E, Dunn DM, Weiss RB (2009) Meenakumari Subramanian, Weis JH, Zachary J, Teuscher C, Weis, JJ. Interval-specific congenic lines reveal QTL with penetrant Lyme arthritis phenotypes on chromosomes 5, 11, and 12. Infection and Immunity, In Press
2. Miller JC, Ma Y, H, Wang X, Weis JJ (2008) Gene expression profiling provides insights into the pathways involved in inflammatory arthritis development: Murine model of Lyme disease. Experimental and Molecular Pathology 85:20-27
3. Miller, JC, Ma Y, Bian J, Sheehan KCF, Zachary JF, Weis JH, Schreiber RD, Weis JJ (2008) Critical role for Type I IFN in arthritis development following Borrelia burgdorferi infection of mice. J. Immunol. 181:8492-8503
4. Wang X, Ma Y, Yoder A, Crandall H, Zachary JF, Fujinami RS, Weis JH, Weis JJ (2008) T cell infiltration is associated with increased Lyme arthritis in TLR2-/- mice. FEMS Immunol Med Micro. 52:124-133
5. Crandall H, Dunn DD, Ma Y, Wooten RM, Zachary JF, Weis JH, Weiss RB, Weis JJ (2006) Gene Expression Profiling Reveals Unique Pathways Associated with Differential Severity of Lyme Arthritis. J. Immunol. 177:7930-42
6. Bolz, DD, Sundsbak RS, Ma Y, Akira S, Weis JH, Schwan TG, Weis JJ (2006) Dual Role of MyD88 in Rapid Clearance of Relapsing Fever Borrelia. Infect. Immun. 74:6750-6760
7. Crandall H, Ma Y, Dunn DM, Sundsbak RS, Holmdahl R, Olofsson P, Zachary JF, Weis JH, Weiss RB, Teuscher C, Weis JJ (2005) Bb2Bb3 regulation of murine Lyme arthritis is distinct from Ncf1 and independent of the phagocyte NADPH oxidase. American Journal of Pathology 167:775-785
8. Wang X, Ma Y, Weis JH, Zachary JF, Kirschning CJ, Weis JJ (2005) Relative contributions of innate and acquired host responses to bacterial control and arthritis development in Lyme disease. Infect. Immun. 73:657-660
9. Bolz DD, Weis JJ (2004) Molecular Mimicry to Borrelia burgdorferi : Pathway to Autoimmunity? Autoimmunity 37:387-392
10. Yoder A, Wang X, Ma Y, Philipp MT, Heilbrun M, Weis JH, Kirschning CJ, Wooten RM, Weis JJ (2003) Pam 3 Cys-dependent OspA-vaccination of TLR2-deficient mice results in effective protection from B. burgdorferi challenge. Infect. Immun. 71:3894-3900
11. Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH, Zachary JF, Kirschning CJ, Weis JJ (2002) Toll-like receptor 2 is required for innate but not acquired host defense to Borrelia burgdorferi . J. Immunol. 168:349-355
12. Roper RJ, Weis JJ, McCracken BA, Green CB, Ma Y, Weber KS, Fairbairn D, Butterfield RJ, Potter MR, Zachary JF, Doerge RW, Teuscher C (2001) Genetic control of susceptibility to experimental Lyme arthritis is polygenic and exhibits consistent linkage to multiple loci on chromosome 5 in four independent mouse crosses. Genes and Immunity 2:388-397
13. Hirschfeld M, Kirschning CJ, Schwandner R, Wesche H, Weis JH, Wooten RM, Weis JJ (1999) Inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. J. Immunol. ( Cutting Edge ) 163:2382-2386
