We have shown that severe destructive arthritis can be consistently elicited when vaccinated IFN-γ0
mice are challenged with an infectious isolate of B. burgdorferi
. These results confirm and extend the findings of Christopherson et al. (12
). Because these mice lack the gene that encodes IFN-γ and its receptor, the role of IFN-γ in the development of B. burgdorferi
vaccination- and challenge-associated arthritis is less controversial than the role of IFN-γ in the induction of arthritis in other Lyme animal models (3
). In support of our findings (12
), Brown and Reiner (6
) also showed that IFN-γ is not required for increased susceptibility of mice to arthritis following infection with B. burgdorferi
. Therefore, other cytokines, chemokines, and degradative enzymes are involved in the induction and maintenance of severe destructive arthritis.
We focused on IL-17. Considerable evidence has accumulated that IL-17 plays a central role in the induction of arthritis. IL-17 is found at high levels in the synovial fluid of patients with rheumatoid arthritis (10
). IL-17 is also secreted by CD4-activated memory T cells (1
), which can adoptively transfer susceptibility to Lyme arthritis (23
). Moreover, IL-17 shows synergy with other cytokines (1
) for induction of bone resorption (20
) and stimulation of osteoclast differentiation (20
). These properties of IL-17 make it a primary promoter of cartilage and bone damage in the development of arthritis.
We showed that treatment with anti-IL-17 antibody of vaccinated IFN-γ0 mice challenged with B. burgdorferi delayed the onset of swelling of the hind paws, but more importantly, it consistently inhibited the development of arthritis. Histopathologic examination confirmed that treatment with anti-IL-17 antibody prevented the extensive destructive arthropathy detected in non-IL-17-treated, vaccinated and challenged IFN-γ0 mice. Treatment of vaccinated and challenged IFN-γ0 mice with anti-IL-17 receptor antibody also delayed the onset of swelling of the hind paws and prevented cartilage and bone destruction. Similar ameliorative results were obtained when vaccinated and challenged IFN-γ0 mice were treated sequentially with anti-IL-17 antibody and then anti-IL-17 receptor antibody. By contrast, rIL-17 treatment of vaccinated and challenged IFN-γ0 mice did not alter the course of hind paw swelling or the development and progression of arthritis. No histopathologic differences were detected between vaccinated and challenged IFN-γ0 mice treated with rIL-17 and those not treated with rIL-17.
The immune response underlying the development of severe destructive arthritis involves IL-17. Vaccinated and challenged IFN-γ0 mice treated with antibodies to IL-17 or its receptor and those without treatment developed different levels of edema (swollen hind paws). More importantly, histologic examination clearly separated the two groups. Animals treated with anti-IL-17 antibody or with anti-IL-17 receptor antibody developed only minimal inflammatory changes. No destruction of cartilage, of the small bones of the feet, or of the ankle joints, long bones, or knee joints was found. Moreover, blockage of IL-17 completely alleviated damage to articular cartilage within joint spaces and prevented periarticular inflammation. By contrast, non-IL-17 antibody-treated vaccinated mice challenged with B. burgdorferi showed thickened synovial membranes in the joints and severe destruction of bone. Clearly, therapy with anti-IL-17 antibody or with anti-IL-17 receptor antibody benefits vaccinated IFN-γ0 mice challenged with B. burgdorferi.
What is the mechanism by which IL-17 induces arthritis? IL-17 may drive the arthritis by stimulating the production of IL-1 and tumor necrosis factor alpha (TNF-α) (1
), key mediators in the pathogenesis of other experimental models of arthritis (7
). We showed, however, that blockage of TNF-α by treatment with anti-TNF-α antibody augmented the severity of the destructive arthritis in vaccinated IFN-γ0
mice challenged with B. burgdorferi
). This suggests that other immune regulators may be responsible for the severe destructive arthritis in B. burgdorferi
-vaccinated and -challenged IFN-γ0
mice. Several reports have shown that IL-1 plays a critical role in synovial inflammation and joint destruction (15
). However, blocking IL-1 with neutralizing antibodies had no effect on IL-17-induced inflammation and joint damage (26
). IL-17 may contribute to synovial inflammation and joint destruction independently of IL-1 (26
). Therefore, IL-17 may be a novel upstream target for treatment of severe destructive arthritis.
We found the results obtained with rIL-17 surprising. We expected rIL-17 to enhance the severity of the destructive arthritis detected in vaccinated IFN-γ0
mice challenged with B. burgdorferi
. Infante-Duarte et al. (17
) also suggested that chronic expression of IL-17 induced by lipoproteins of B. burgdorferi
could be an important mediator of infection-induced immunopathology. Local overexpression of IL-17 can also promote destructive arthritis (8
) and enhance pathology observed with psoriasis, rheumatoid arthritis, and other connective tissue diseases (2
). By contrast, we found the courses of hind paw swelling and destructive arthritis in vaccinated IFN-γ0
mice challenged with B. burgdorferi
to be similar for mice treated with rIL-17 and those without treatment. An explanation is that excess IL-17 does not promote destructive arthritis unless the spirochete burden is elevated to interact with activated memory T cells. It is known that the number of B. burgdorferi
organisms rapidly decreases after infection of the host (13
). The decrease in the number of spirochetes also correlates with the resolution of severe destructive arthritis (35
). Only high infectious challenges can again induce the destructive response (25
This study demonstrates that IL-17 contributes to joint and bone destruction along with inflammation of subsynovial, subchondrial, and connective tissues. This may be due to a compensatory mechanism that is dominant in IFN-γ0
mice. Whether IL-17 is involved in induction and pathogenesis of the other arthritides associated with B. burgdorferi
) and vaccination (28
) needs to be determined. It seems likely that the B. burgdorferi
-associated arthritides, regardless of method of induction or elicitation (7
), share some pathways of pathogenesis. Since IL-17 is an upstream promoter of proinflammatory cytokines, chemokines, and other immune regulators, therapeutic intervention may be a realistic approach to prevent the Lyme arthritides. We are presently evaluating the role of IL-17 in models of infection-induced and -reactivated arthritis.
In conclusion, we showed that treatment with anti-IL-17 antibody or anti-IL-17 receptor antibody can prevent the development of severe destructive arthritis. Additional studies are needed to define whether anti-IL-17 therapy can cure not only severe destructive arthritis but also intermittent and chronic arthritis associated with natural infection of humans with B. burgdorferi.