Objective. The arthritogenic potential of the cationic outer surface proteins (Osp) from Borrelia burgdorferi was tested in rats.Methods. Water-soluble Osps were prepared by butanol extraction and were administered by intraarticular injection. Tissue injury was assessed by scintigraphy and histology.Results. A mild arthritis was seen in naive rats. Preimmunized animals had more severe, longer lasting bouts of inflammation.Conclusion. The Osps of Borreliu burgdorfen are potent arthritogens in rats. These immunodominant antigens may play a role in the development of Lyme arthritis in humans.Arthritis is a frequent complication of Borreliu burgdorferi infection. Up to 60% of patients with untreated erythema chronicum migrans develop Lyme arthritis. About half of these patients experience intermittent attacks of inflammation and 10% develop chronic arthritis (1). In one study, bacteria were demonstrated in discrete foci within the structures of arthritic joints (2), and successful cultivation of Borreliu from synovial fluid has also been reported in a limited number of cases (3-5). Nevertheless, whether the induction and maintainance of Lyme arthritis requires the presence of bacteria or their products within the affected joints remains an unanswered question. There are approaches for establishing animal models of Lyme arthritis using live organisms. In rats and mice, the severity of arthritis following infection was found to be age dependent; young animals developed more severe inflammation (6,7). Arthritis has also been induced by injecting B burgdorferi into the joints of irradiated hamsters (8). In immunodeficient SCID mice, Borreliu infection leads to persistent spirochetemia, accompanied by multiple organ manifestations, including chronic joint inflammation (9). These models have increased our understanding of the biology of Lyme disease. It appears that arthritis develops best when the host animal's immune system is either immature or blatantly compromised. The underlying immunopathogenic mechanisms leading to Lyme arthritis in the presence of an intact immune system have not yet been clarified.Previous studies of rodents have shown that cationic antigens, including bacterial products, can be potent inducers of allergic arthritis (10-13); anionic antigens are not effective in this experimental setting (for review, see ref. 13). Postulating that the inflammatory process characteristic of Lyme arthritis may be an antigen-driven event, we sought putative cationic arthritogens from B burgdorferi. The most abundant cationic molecules possessed by B burgdorferi are the outer surface proteins (Osps) (14,15), which are also the immunodominant antigens in chronic borrelial infection (15,16). We were able to show that the Osps, in complexed form, are capable of inducing severe joint disease in healthy adult rats. MATERIALS AND METHODSAntigens. The Osp complex was prepared from B burgdorferi in aqueous form, as described previously (17). Briefly, late log cultures of B burgdorferi strains GeHo (a Freiburg area skin isol...
Cationic antigens are known to have considerable arthritogenic potential in experimental systems. During a systematic search for suitable, naturally occurring candidates an intracellular protein was isolated from the ribosomal pellet of Yersinia enterocolitica 0:3, a bacterial strain associated with reactive arthritis in humans. The protein is highly cationic, contains two 19-kD polypeptide chains linked by a disulfide bond, and reveals a strong tendency for spontaneous aggregation. It is suggested to be a nucleic acid binding protein. We tested this antigen for its ability to induce arthritis after intra-articular challenge in preimmunized rats. An acute inflammatory phase followed by transition to chronicity was observed both by technetium-99m scintigraphy and from histology. Massive polymorphonuclear leucocyte infiltration of the synovium was seen early on and fibrosis and thickening of the joint capsule occurred in later stages. Control groups showed no evidence of inflammation. Western blot and ELISA analysis of unselected sera from Yersinia enterocolitica 0:3-infected patients revealed antibodies to the antigen in the majority of cases, whereas healthy individuals rarely reacted. This is the first report of a naturally occurring cationic antigen capable of inducing immunologic tissue injury; it justifies the speculation that cationic antigens from prokaryotic cells could trigger reactive arthritis.in humans. (J. Clin. Invest. 1991. 87:632-642.)
Histone can mediate the binding of free DNA to the glomerular capillary wall. We tested whether histone could mediate the deposition of preformed DNA-anti-DNA immune complex (IC). IC were generated using monoclonal anti-DNA Ab and excess of small size 125I-DNA; after further digestion with DNase the IC, containing 5 micrograms DNA (now 20 to 60 bp), was injected into the left kidney of rats. When given alone, only about 0.2% of the IC bound in glomeruli. Prior injection of 200 micrograms of core histones (H2A,H2B,H3,H4) resulted in high glomerular binding of the IC; 18.1% of the injected dose (measured as 125I-DNA) was bound at 15 minutes. Mouse immunoglobulin, representing the IC, could be seen in a capillary pattern. C3 was also present in a similar pattern, showing that complement had been activated. Discrete electron-dense deposits were seen in a subendothelial and subepithelial localization at 15 minutes. Although about 1 microgram of DNA was deposited in the glomeruli, it could not be detected by indirect immunofluorescence or intercalating dyes. These studies provide direct evidence that histones can mediate the binding of particular circulating DNA-anti-DNA immune complexes to the glomerular capillary wall in vivo. If small size DNA fragments (< 100 bp) are involved in lupus nephritis, our results provide a possible explanation for the frequent failure to detect DNA deposits in renal biopsies from SLE patients.
SUMMARYTwo types of lupus mice, NZB/NZW F, female hybrids and mice with graft-versus-host disease (GVHD), were studied. Histones H3 and H2A were detected by immunofluorescence in glomeruli of 22/22 proteinuric GVHD and 8/12 proteinuric NZB/W F, female mice; in non-proteinuric animals, 3/5 GVHD and 2/27 NZB/W F, female were positive. Using antibodies to histone peptides it was shown that mainly the N-terminal regions of histones H3 and H2A were exposed in glomerular deposits. Western blot analysis revealed antibodies to histone subfractions in sera of 33/34 lupus mice that developed proteinuria. This study provides evidence that histones are involved in the pathogenesis of lupus nephritis.
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