Investigation of the pathogenesis of murine Lyme arthritis

Lyme disease is caused by the spirochete Borrelia burgdorferi and if left untreated, often causes arthritis. The spirochetes possess outer surface lipoproteins (Osps) that are capable of stimulating inflammatory cytokine production from B cells, macrophages, and endothelial cells, and the production of nitric oxide (NO). The role of NO during infection of mice with B. burgdorferi was investigated. Both the severely arthritic (C3H) and mildly arthritic (BALB/c) mice produced high levels of NO approximately 7 days after infection, but C3H animals rapidly downregulated NO production to background levels, whereas BALB/c animals sustained NO production throughout the course of infection. Complete inhibition of NO production by the compound N[G]-monomethyl-L-arginine (LMMA) during infection had no significant effect on either arthritis development or spirochete numbers in tissues. These results indicate that NO is ineffective at controlling spirochete numbers in tissues, and, therefore, B. burgdorferi probably does not require an intracellular localization for survival in the mammalian host. The reproducible downregulation of NO in C3H animals may be induced by anti-inflammatory cytokines which could modulate other aspects of the immune response to B. burgdorferi. In vitro studies showed that OspA could stimulate IL-10 production by naive murine splenocytes and that physiological concentrations of IL-10 could significantly downregulate the responses of OspA-treated macrophages. The inappropriate or uncontrolled production of IL-10 during infection could result in dysregulation of host defenses, thus leading to the development of pathology. The Osps also stimulate adhesion molecule expression on cells. The role of two adhesion molecules, E-selectin and P-selectin, in the development of Lyme arthritis, was investigated by infecting mice lacking both molecules with B. burgdorferi and assessing arthritis development and spirochete number. Mice lacking E- and P-selectin showed resistance to arthritis development and spirochete numbers virtually identical to their wild-type littermates, indicating that these adhesion molecules are not required for resistance to Lyme arthritis. Additionally, a correlation between influx of neutrophils into joints and arthritis severity was noted, indicating that neutrophil infiltration into joints may be required for the development of arthritis. These studies may aid in the determination of pathogenic mechanisms in Lyme arthritis.