Interleukin-4 (IL-4) and IL-13 signaling pathways do not regulate Borrelia burgdorferi-induced arthritis in mice: IgG1 is not required for host control of tissue spirochetes.

Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia burgdorferi (17, 25, 42). Illness in humans can be successfully treated with antibiotics; however, in the absence of treatment, arthritis, carditis, neurological complications, and skin abnormalities may develop (42). Arthritis is a late-stage symptom in approximately 60% of individuals who are not treated with antibiotics at the time of infection. The arthritis is associated with the presence of spirochetes in the joint tissue and is characterized by tendonitis, synovitis, and inflammatory cell infiltrate (41, 42). The mouse model of Lyme disease has provided an opportunity to study the development of arthritis upon infection with B. burgdorferi. In mice, arthritis is coincident with spirochetes in the joint tissues and is characterized by tendonitis, synovial hyperproliferation, and infiltration of neutrophils (7). There is a spectrum of disease with different mouse strains having differing susceptibilities to B. burgdorferi-induced pathology. Infected C3H mice develop severe arthritis with large numbers of bacteria infiltrating joint tissue (8, 12, 52). C57BL/6 mice predominantly develop mild arthritis and yet harbor large numbers of spirochetes that equal those in C3H mice (8, 10, 30). BALB/c mice show a spectrum of disease severity. At low inoculum doses, BALB/c mice develop mild arthritis which becomes more severe as the inoculum dose is increased (30). It appears that there may be more than one mechanism of resistance, since resistance in BALB/c mice correlates with low levels of spirochetes in the joints, while in C57BL/6 mice arthritis is mild even in the presence of large numbers of spirochetes (30). A mapping project has been carried out in this laboratory using the F2 intercross generation of C3H/HeNCr and C57BL/6NCr mice (51). Four chromosomal regions were linked to arthritis development by quantitative trait loci (QTL) analysis, confirming that arthritis development is a complex, multigenic trait with multiple mechanisms. Interestingly, ankle swelling and histopathological severity were linked to distinct chromosomal regions in this study. An additional suggestive quantitative trait locus for histopathology was identified in a region of chromosome 11 that contains a cluster of immune and inflammatory regulatory cytokines, including interleukin-3 (IL-3), IL-4, IL-5, and IL-13. This cluster of genes is associated with the regulation of Th cell responses, regulating T-cell and inflammatory responses to infection (22). Previous studies provide conflicting evidence regarding the involvement of IL-4 in Lyme arthritis. Antibody (Ab)-mediated depletion of IL-4 in BALB/c and C3H mice suggested a protective effect for IL-4 (29, 33), as did experiments in which treatment of C3H/HeN mice with recombinant IL-4 reduced arthritis severity (28). Others have shown that the kinetics of IL-4 production differs in severe and mildly arthritic mice (27). However, in BALB/c mice, interruption of the B7/CD28 costimulatory pathway using an Ab to CD86 prevented T-cell production of IL-4, yet it had no effect on arthritis development (48). Most recently, arthritis-resistant DBA mice that were genetically deficient in IL-4 did not show increased arthritis severity when infected with B. burgdorferi (14). These conflicting results suggest that the regulation, production, and action of IL-4 during B. burgdorferi infection may be more complex than could be examined in previous experiments. In response to conflicting results in the literature and the suggestive linkage from our mapping study, we have chosen to look at the effects of IL-4 production in Lyme disease by using mice that are genetically altered to prevent the expression of IL-4, the α chain of the IL-4 receptor, or both. These mice enabled us to examine the involvement of IL-4 in the development of Lyme arthritis, regardless of the cell type producing it, location of its production, site of action, or responsive cell type. In other pathogen systems, it has been found that IL-13 signaling through the IL-4Rα chain can compensate for the absence of IL-4, because the two cytokines have many of the same effects (20, 24, 39, 49). Therefore, the IL-4Rα knockout with disruption of both IL-4 and IL-13 signaling allowed us to determine whether IL-13 plays a role in the severity of Lyme arthritis and/or is able to compensate for a loss of IL-4 during infection.