Electrical charge of the antigen determines intraarticular antigen handling and chronicity of arthritis in mice.

Objective. To examine the ability of bacterial lipoproteins from the spirochete Borrelia burgdorferi to cause in vivo tissue injury (arthritis).Methods. Outer surface proteins (OSPs) from B burgdorferi were used in a rat model of antigen-induced allergic arthritis. Intraarticular challenge with recombinant OspA, OspB, and OspC in nonlipidated (peptide) and lipidated forms was performed in the left knee joint; the contralateral joint received buffer as control. Inflammation was monitored by technetium scintigraphy and histology.Results. Nonlipidated (peptide) OspA, OspB, and OspC did not induce arthritis; the only exception was polymerized OspA, which was tested in preimmunized rats. Lipidated OspA from 2 different strains and lipidated OspC induced severe arthritis, whereas lipidated OspB failed to induce injury. A synthetic analog of the OSP lipid modification, lipopeptide Pam 3 Cys-SerLys 4 -OH, either alone or coupled to bovine serum albumin, also failed to induce injury. Injury did not develop in control groups that were given the appropriate buffers or lipopolysaccharide. This showed that lipidated borrelial OSPs can be potent arthritogens but vary greatly with respect to their injury-inducing potential. The possession of a lipid modification is essential but is not sufficient to render an OSP arthritogenic.Conclusion. This is the first study to demonstrate that individual lipoproteins from B burgdorferi can induce experimental joint injury in vivo. These results may help elucidate the pathogenesis of Lyme arthritis and, above all, underline the importance of bacterial lipoproteins as major virulence factors.Lipoproteins are now being recognized as prime virulence factors of bacteria. For many decades this group of molecules played the role of poor relation to the lipopolysaccharides (LPS), but particularly the discovery that lipoproteins can act as ligands for the Toll-like receptor (TLR) complex has rekindled interest (1). In earlier studies, a number of naturally occurring bacterial lipoproteins and their synthetic lipopeptide analogs were shown to possess impressive biologic activities. The Braun protein, a prototype lipoprotein, can stimulate lymphocytes (2), and the corresponding synthetic lipopeptide is in fact now used as an adjuvant (3). Membrane lipoproteins and the corresponding lipopeptides from mycoplasma could induce mononuclear phagocytes to secrete cytokines; a particular lipopeptide from Mycoplasma fermentans, macrophage activating lipopeptide 2, was effective even at concentrations in the picogram range (4). The outer surface lipoproteins (OSPs) of Borrelia burgdorferi have been shown to exhibit similar stimulatory effects (5-8).Results of recent in vitro studies indicated that the lipid moiety plays a key role, and that the CD14/ TLR-2 receptors can be involved (9-11). Lipoproteins have been shown to be capable of inducing tissue injury in animals, mimicking certain common clinical manifestations of the corresponding infection in man. First, synthetic lipopeptide analogs of treponemal and...

Section: Discussionmentioning

confidence: 86%

Outer surface lipoproteins ofBorrelia burgdorferivary in their ability to induce experimental joint injury

Batsford

Dunn

Mihatsch³

2004

“…Thereafter, whole knee and/or ankle joints were removed and fixed for 4 days in 10% formalin. After decalcification in 5% formic acid, the specimens were processed for paraffin embedding (26). Tissue sections (7 m) were stained with hematoxylin and eosin or Safranin O. Histopathologic changes were scored using the following parameters.…”

Section: Methodsmentioning

confidence: 99%

Treatment with a neutralizing anti‐murine interleukin‐17 antibody after the onset of collagen‐induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion

Lubberts¹,

Koenders²,

Oppers‐Walgreen³

et al. 2004

659

457

Objective. Interleukin-17 (IL-17) is a proinflammatory cytokine that is expressed in the synovium of rheumatoid arthritis (RA) patients. This T cell cytokine is implicated in the initiation phase of arthritis. However, the role of IL-17 during the effector phase of arthritis has still not been identified; this was the objective of the present study.Methods. Mice with collagen-induced arthritis (CIA) were treated with polyclonal rabbit anti-murine IL-17 (anti-IL-17) antibody-positive serum or normal rabbit serum after the first signs of arthritis. In addition, during a later stage of CIA mice were selected and treated with anti-IL-17 antibody or control serum. Arthritis was monitored visually, and joint pathology was examined radiologically and histologically. Systemic IL-6 levels were measured by enzyme-linked immunosorbent assay, and local synovial IL-1 and receptor activator of NF-B ligand (RANKL) expression was analyzed using specific immunohistochemistry.Results

“…Mice were killed, and whole knee joints were removed and fixed in 10% formalin. After decalcification in 5% formic acid, the specimens were processed for paraffin embedding (21). Tissue sections (7 m) were stained with hematoxylin and eosin or with Safranin O.…”

Section: Methodsmentioning

confidence: 99%

Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

Devesa¹,

Ferrándiz²,

Terencio³

et al. 2005

Objective. Heme oxygenase 1 (HO-1) can be induced by inflammatory mediators as an adaptive response. The objective of the present study was to determine the consequences of HO-1 modulation in the murine collagen-induced arthritis (CIA) model.Methods. DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 22 to day 29 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, joints were examined for histopathologic changes. Cytokine levels in paws were measured by enzyme-linked immunosorbent assay. Levels of HO-1, cyclooxygenase 2 (COX-2), and prostaglandin E 2 (PGE 2 ) were determined. Effects of treatments on the early phase of disease and after prophylactic administration were also assessed.Results. CoPP strongly induced HO-1, resulting in the inhibition of cartilage erosion accompanied by extensive fibrosis in the joint. Levels of tumor necrosis factor ␣ (TNF␣), interleukin-2 (IL-2), and IL-10 were inhibited by CoPP, whereas levels of vascular endothelial growth factor were increased. Treatment with SnPP significantly reduced the severity of CIA, with inhibition of joint inflammation and cartilage destruction. The levels of PGE 2 , IL-1␤, and TNF␣ were also significantly reduced by SnPP treatment, which did not modify COX-2 protein expression. SnPP was more effective than CoPP in preventing the development of CIA (prophylactic administration).Conclusion. HO-1 is induced during CIA. Although overexpression of this protein causes some beneficial effects, strategies aimed at HO-1 overexpression cannot slow the progression of the chronic inflammatory disease, whereas treatment with SnPP, which inhibits HO-1, exerts prophylactic and therapeutic effects.