Interleukin-23 Is Required for Development of Arthritis in Mice Vaccinated and Challenged withBorreliaSpecies

Abstract

We recently hypothesized that T helper 17 (Th17) cells and their associated cytokines are involved in the development of arthritis following infection with Borrelia burgdorferi. Here, we show that interleukin-23 (IL-23), a survival factor for Th17 cells, is required for the induction of arthritis in mice vaccinated with B. burgdorferi strain 297 and challenged with "Borrelia bissettii." When Borrelia-vaccinated and -challenged mice were given antibodies to the p19 subunit of IL-23, they failed to develop the histopathological changes observed in untreated vaccinated and challenged mice. In addition, viable B. bissettii organisms stimulated the secretion of IL-17 from Borrelia-immune lymph node cells during in vitro culture. When anti-IL-23 p19 antibody was included in cultures of B. bissettii organisms and Borrelia-immune lymph node cells, the production of IL-17 was reduced to levels observed in cultures containing immune cells alone. Taken together, these results support the hypothesis that Th17 cell-associated cytokines are involved in the development of Borrelia-mediated arthritis. These findings provide insight into previously overlooked immune mechanisms responsible for the development of Lyme arthritis.The development of severe, destructive arthritis in animals vaccinated and challenged with Borrelia species (12, 29) is dependent upon the production of Borrelia-specific CD4 ϩ T lymphocytes (28) and their cytokines. Recently, we showed that the proinflammatory cytokine interleukin-17 (IL-17) plays a major role in the induction of arthritis following Borrelia vaccination and challenge. Borrelia-vaccinated and -challenged mice given antibodies to IL-17 or to the IL-17 receptor failed to develop the histopathological changes observed in isotype control antibody-treated mice (10,38). Taken together, these findings suggested that IL-17-producing CD4 ϩ T cells augment the development of arthritis during the adaptive immune response to Borrelia infection.Although naïve T cells respond to Borrelia infection, their differentiation into T helper 1 (Th1) and Th2 cells is promoted by IL-12 and IL-4, respectively. In the Borrelia vaccination and challenge model of arthritis, a different pathway of T-cell activation occurs because of the existence of memory T cells. It is known that a subset of activated, or memory, T cells distinct from Th1 and Th2 cells, Th17 cells, can produce IL-17 (42). Differentiation into Th17 cells relies on transforming growth factor ␤ and inflammatory cytokines such as 31,46), while the survival and propagation of Th17 cells are dependent on IL-23 (8). IL-23 is produced by activated dendritic cells and macrophages (7,25) and is known to stimulate the release of IL-17 from activated CD4 ϩ T cells (1). IL-23 is also required for the development of collagen-induced arthritis, and its absence correlates with a reduction in Th17 cells (14, 35) and mRNA encoding IL-17 (35). Therefore, we hypothesized that IL-23 plays a significant role in the IL-17-mediated development of arthritis in Borrelia-vacci...

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

“…It is a heterodimeric molecule composed of p40 and p19 subunits [3]. The proinflammatory activities of IL-23 are responsible for the onset not only of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis [4,5], but also infection-induced pathological consequences of infection with the pathogens causing Lyme disease and toxoplasma encephalitis, for example [6,7]. The known biological roles for IL-23 in inflammation include induction of Th17-induced secretion of IL-17 [8] and suppression of CD4 + CD25 + Treg [9].…”

Do Behçet's syndrome patients with acne and arthritis comprise a true subset? Comment on the article by Hatemi et al

“…Also, patients with BS-WA can fall within the spectrum of SpA, especially if they are positive for HLA-B27. The significance of folliculitis is still to be determined, since it is not necessarily associated with arthritis but is detectable in a relevant percentage of patients with BS-WA (87% in the group considered by Hatemi et al [5]). Larger cohorts of patients of different ethnic origins need to be examined in order to clearly define arthritis, assess SI joints and the enthesis with reproducible techniques such as MRI and US, and evaluate the association with HLA-B27.…”

“…In their recent article, Hatemi and colleagues took the latter position (5). Using ultrasound (US) to evaluate the enthesis in Behçet's syndrome, the authors demonstrated an increased presence of enthesitis, a typical feature of SpA, in a subgroup of patients from Turkey with Behçet's syndrome with acne and arthritis (BS-AA).…”

“…In summary, the studies by Codolo and colleagues (1) and those using the Borrelia vaccination and challenge model of Lyme arthritis (3)(4)(5)(6)(7)(8) can be used to further explore the complex immunologic pathways responsible for the development and resolution of Lyme arthritis.…”

Interleukin-10 (IL-10) Inhibits Borrelia burgdorferi-Induced IL-17 Production and Attenuates IL-17-Mediated Lyme Arthritis

“…However, studies with multiple animal models have shown that a Th1 response is not absolutely necessary for the development of arthritis after B. burgdorferi infection (9)(10)(11), while the inflammatory cytokine interleukin-17 (IL-17) contributes to disease (12)(13)(14)(15). Specifically, blocking IL-17 and various Th17-associated cytokines in vivo reduced the severity of arthritis observed in models of Borrelia-associated arthritis in the presence (15)(16)(17) or absence (12)(13)(14) of IFN-␥. Importantly, Infante-Duarte et al described the capacity of synovial cells of human Lyme arthritis patients to produce IL-17 when stimulated with B. burgdorferi microbes or lipoproteins (18).…”