Immune Mediators of Murine Lyme Arthritis

Abstract

Lyme disease is the most common vector-borne disease in both the United States and Europe; however, its pathogenesis is incompletely understood. The studies described in this thesis aid in the elucidation of mechanisms regulating murine Lyme arthritis and may suggest mechanisms by which human Lyme disease is mediated. (1) We found that the chemokine KC is responsible for neutrophil recruitment and subsequent development of Lyme arthritis and carditis. This was the first study to describe an immunological regulatory mechanism mediating disease susceptibility to murine Lyme disease, as resistant mice (B6) produce less KC than susceptible (C3H/HeJ) mice and do not develop disease. (2) We found that metabolites produced via the COX-2 pathway are important for functional resolution and that resolution is likely mediated via the PGE2/EP2 axis. (3) We found that although dietary fish oil substitution leads to a global shift in eicosanoid production (from AA/LA-derived eicosanoids to EPA/DHA-derived eicosanoids) and promotes antiinflammatory prostaglandin production, disease severity is not altered. (4) We found that eicosanoid production throughout the course of autoantibody-drive K/BxN serum-transfer arthritis differs significantly from that seen during Lyme arthritis and that patterns of eicosanoid expression reflect the severity and kinetics of each type of arthritis. These studies aid in understanding the immunological mechanisms regulating the occurrence and severity of murine Lyme arthritis.