Molecular mimicry and autoimmunity.
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Animals↗
Biomedical subjects
R D Inman
Publications and source records attributed to R D Inman.
Tumor necrosis factor receptor p55 controls the severity of arthritis in experimental Yersinia enterocolitica infection.
OBJECTIVE: To dissect the host defense mechanisms in relation to the development of Yersinia-associated arthritis by evaluating the impact of tumor necrosis factor receptor p55 (TNFRp55) deficiency on Yersinia enterocolitica infection. METHODS: TNFRp55-/- and C57BL/6 mice were inoculated intravenously with arthritogenic strain 8081 of Yenterocolitica serotype 0:8. Mice were observed daily for generating survival curves and monitoring arthritis. In subsequent sets of experiments, mice were sacrificed at day 14 after infection for examination of histopathology of joints, bacterial clearance, macrophage microbicidal activity, nitric oxide (NO) production, oxidative burst generation, and cytokine production. RESULTS: There was an 80% mortality rate in TNFRp55-/- mice compared with 25% in the controls at 8 weeks after inoculation with 70 colony-forming units of Y. enterocolitica 0:8. Histologic examination of joint tissues revealed that TNFRp55-/- mice developed more severe arthritis, including cartilage degradation and bony destruction, than controls at day 14 after infection. The more extensive joint pathology in TNFRp55-/- mice was correlated with the higher bacterial load in liver, spleen, and lungs, and with the increased levels of interleukin-10. TNFRp55-/- mice displayed impaired intracellular killing of bacteria by macrophages. This was associated with decreased NO production and impaired oxidative burst activity. CONCLUSION: This study demonstrates that TNF signaling through TNFRp55 controls the severity of Yersinia-induced arthritis and implicates TNF-mediated macrophage microbicidal activity as a central event in this process.
Animals↗
Classification criteria for reactive arthritis.
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Antibodies, Bacterial↗
Synoviocyte-packaged Chlamydia trachomatis induces a chronic aseptic arthritis.
The basic mechanisms underlying reactive arthritis and specifically the joint injury that follows intra-articular Chlamydia trachomatis infection have not been defined. The present study addresses this question through the development of an experimental model. Stable cell lines were generated from synoviocytes harvested from the knee joints of Lewis rats. The synoviocytes were cocultivated with C. trachomatis to allow invasion by the microbe and were then transferred by intra-articular injection into the knee joints of Lewis rats. The ensuing arthritis could be subdivided into an early phase (</= 14 d) and a late phase. The early phase was characterized by intense, primarily neutrophilic, synovitis; accelerated cartilage injury; dissemination of Chlamydia to liver and spleen; and viable Chlamydia in the joints. The late phase was marked by mixed mononuclear lymphocyte infiltration in the joint; dysplastic cartilage injury and repair; absence of viable organisms; and development of a distinctive humoral response. Western blot analysis comparing reactive arthritis patients to the experimental model indicates that candidate arthritogenic chlamydial antigens are comparable between the two. This model demonstrates that an intense synovitis can be induced by this intracellular pathogen, and that chronic inflammation can persist well beyond the culture-positive phase. Furthermore, these data show that the synoviocyte is a suitable host cell for C. trachomatis and can function as a reservoir of microbial antigens sufficient to perpetuate joint injury.
Animals↗
Experimental autoimmune uveitis in HLA-B27 transgenic mice.
The major histocompatibility complex (MHC) gene, HLA-B27 is strongly associated with auto-immune uveitis and spondyloarthropathies in humans. Experimental mouse models of autoimmune uveitis involve systemic immunization with the retinal autoantigen interphotoreceptor retinoid binding protein (IRBP). To assess possible roles of HLA-B27 in autoimmune uveitis, as well as to investigate a possible new animal model of human uveitis, inbred strains of C57BL/6 and C57BL/6 possessing the human HLA-B27 or HLA-A2 transgene were immunized with IRBP emulsified in complete Freund's adjuvant (CFA). Dilated eye examinations were performed to assess the timing and clinical course of any ensuing uveitis. Mice were sacrificed 3 to 4 weeks postinjection and the eyes submitted for histopathologic analysis. CFA alone did not produce any clinical uveitis. Fifty percent of eyes from the background C57BL/6 strain developed uveitis as early as 10 days postinjection. Of the eyes demonstrating uveitis, an average clinical score of 2.5 was present. Pathologically, a moderate scleritis and anterior uveitis was present. Fifty percent of A2 transgenic eyes developed uveitis as early as 14 days postinjection with an average clinical score of 2.0. Pathologically, a mild vitritis was present. Uveitis developed in only 20% of B27 transgenic mice and reached a peak on day 28. The average EAU score in diseased animals was 4.5. A dense retinitis and panuveitis was associated with severe vitritis. We conclude that the presence of the B27 gene is associated with a decreased incidence and slower rate of onset of EAU following immunization with IRBP; however, EAU may be more severe in the HLA-B27 expressing animals who do develop disease.
Animals↗
Immunogenetic and microbial factors in acute anterior uveitis.
OBJECTIVE: To characterize the rheumatic diseases associated with acute anterior uveitis and examine the potential role of Yersinia enterocolitica in the pathogenesis of acute anterior uveitis. METHODS: 44 patients with acute anterior uveitis were assessed for evidence of an underlying rheumatic syndrome by history and examination. HLA profiles were identified by serologic and molecular techniques. Serological analysis of patients' sera for the presence of antibodies to Y. enterocolitica was by Western blot. RESULTS: 30 of the 44 patients had musculoskeletal symptoms. Of these, 8 had ankylosing spondylitis, 4 reactive arthritis, 2 undifferentiated spondyloarthropathy (SpA), 2 inflammatory bowel disease, one seronegative polyarthritis, and 13 mechanical back pain. Of 42 patients typed, 29 (69%) were HLA B27 positive and an additional 7 patients expressed a crossreactive group antigen (86% of total group B27 or CREG positive). Western blot analysis of the sera revealed increased frequency of antibodies to Yersinia compared with a control population. Antibodies directed against the 36 and 27 kDa Yersinia antigens were recognized with greater frequency (p < 0.05) in patients with acute anterior uveitis than in controls. IgG reactivity was more pronounced than IgA reactivity. Adsorption studies showed significant cross reactivity of anti-Yersinia antibodies with Salmonella typhimurium. Among the patients with acute anterior uveitis anti-Yersinia reactivity did not correlate with the HLA profile, nor with the presence of an underlying rheumatic disease. CONCLUSION: SpA represent the commonest underlying rheumatic disorders associated with acute anterior uveitis. The majority of patients with acute anterior uveitis possess HLA-B27 regardless of whether there is underlying SpA. Patients with acute anterior uveitis show increased frequency of anti-Yersinia antibodies compared with controls. Many of these antibodies appear to be directed against antigenic determinants shared among gram negative bacteria and thus cannot constitute definitive evidence for a causal role specifically for Yersinia in acute anterior uveitis. Acute anterior uveitis represents an interplay of host susceptibility and microbial triggers, as is the case for the SpA in general.
Acute Disease↗
Helicobacter pylori and nonsteroidal antiinflammatory drugs: partners in crime?
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Anti-Inflammatory Agents, Non-Steroidal↗
Unilateral hemochromatosis arthropathy on a neurogenic basis.
We describe a 42-year-old man with right hemiplegia from cerebral palsy who presented with chronic left arm pain. Examination revealed 12 active joints, predominantly in the left hand. Radiographs showed characteristic changes of an advanced secondary osteoarthritic process in the left hand and only minimal changes on the right. Bone scan confirmed unilateral activity. Subsequent investigations diagnosed hemochromatosis. Unilateral arthropathy of hemochromatosis on a neurogenic basis has not been previously reported.
Adult↗
Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter's syndrome). A Department of Veterans Affairs Cooperative Study.
OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective in the treatment of reactive arthritis (ReA) that has been unresponsive to nonsteroidal antiinflammatory drug (NSAID) therapy. METHODS: One hundred thirty-four patients with ReA who had failed to respond to NSAIDs were recruited from 19 clinics, randomized (double-blind) to receive either SSZ or placebo, and followed up for 36 weeks. The definition of treatment response was based on joint pain/tenderness and swelling scores and physician and patient global assessments. RESULTS: Longitudinal analysis revealed improvement in the patients taking SSZ compared with those taking placebo, which appeared at 4 weeks and continued through the trial (P = 0.02). At the end of treatment, response rates were 62.3% for SSZ treatment compared with 47.7% for placebo treatment. The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints. CONCLUSION: SSZ at a dosage of 2,000 mg/day is well tolerated and effective in patients with chronically active ReA.
Adult↗
Comparative microbicidal activity of synovial fluid on arthritogenic organisms.
There is strong circumstantial evidence to support the concept that local microbial antigens play a key role in the synovitis of reactive arthritis (ReA) patients. It is not at all clear whether these antigens reflect the sequelae of previously viable organisms once resident in the joint. To address the microbicidal activity of synovial fluid (SF) we performed quantitative cultures of arthritogenic organisms (Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae) and controls (Escherichia coli, Staphylococcus aureus) in the presence of SF from patients with ReA. There was a dramatic inhibitory effect of SF on the Gram-negative organisms (mean 1.35x10(5) organisms at 3h; 0 organisms at 24 h) in contrast to Staph. aureus (1.61x10(5) at 3h; 5.70x10(5) at 24 h). This SF bactericidal phenomenon was observed in 11/11 ReA patients, 5/8 rheumatoid arthritis (RA) patients and 1/8 osteoarthritis (OA) patients. Using a sandwich ELISA, we measured SF levels of bactericidal/permeability-increasing protein (BPI). BPI was detectable in all ReA SF (range 4.6-333ng/ml)) and RA SF (range 343-2570ng/ml), but was absent in 5/6 OA SF tested. Anti-BPI antibodies, however, did not fully neutralize the bactericidal activity of inflammatory SF. In contrast to the SF effects observed on Gram-negative bacteria, Chlamydia trachomatis cultured within HeLa cells thrived in the presence of SF. Indeed extracellular Chlamydia could easily be passaged through cultured synovial fibroblasts in the presence of SF. These findings indicate that the potent microbicidal activity of SF may account for the failure to recover viable organisms from the joint in ReA. Chlamydia alone amongst these organisms demonstrates resistance to microbicidal effect of SF, which may relate to the pathogenesis of Chlamydia-induced arthritis.
Antimicrobial Cationic Peptides↗
Peri-colic diverticular mass of the sigmoid colon presenting in A strangulated inguinal hernia.
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Aged↗
Analysis of T cell receptor gamma transcripts in right and left knee synovial fluids of patients with rheumatoid arthritis.
OBJECTIVE: To establish the extent of clonal expansion of T cell receptor (TCR) gamma delta + T cells in synovial fluid (SF), and the sharing of the clones between affected knee joints from patients with rheumatoid arthritis (RA). METHODS: We quantified, using the polymerase chain reaction (PCR), the level of expression from each of the 4 V gamma gene families. We resolved PCR products on denaturing polyacrylamide gels to measure the proportion of mRNA transcripts contributed by clonally expanded gamma delta T cells. We subcloned and sequenced 509 cDNA clones derived from 8 SF and one peripheral blood sample from 2 patients with RA and one patient with juvenile onset RA to fully characterize the populations of T cell receptor gamma mRNA sequences. RESULTS: We found in each patient disproportionate expression of a subpopulation of T cell receptor gamma mRNA transcripts. Some of these transcripts are expressed by T cells found in both joints. CONCLUSION: Synovial TCR gamma delta + T cells are oligoclonal and some of these T cell clones are common to SF of both joints. The finding of identical T cell sequences from SF of both affected joints from each patient points to a role for gamma delta + T cells in disease progression.
Amino Acid Sequence↗
Post-Salmonella reactive arthritis: late clinical sequelae in a point source cohort.
PURPOSE: To define the natural history of post-Salmonella-infection reactive arthritis (ReA) in a point source cohort concurrently exposed to the same microorganism, and to determine any relationship between anti-Salmonella humoral immune response to the organism and clinical outcome at 5 years. PATIENTS AND METHODS: A cohort of 423 Ontario Provincial Police officers with a clinical diagnosis of Salmonella food poisoning were defined in 1984. Five years following the food poisoning, a mail and telephone survey was carried out to determine all those who developed ReA within 3 months of the onset of dysentery. Medical and physiotherapy charts from an earlier study on the same cohort were incorporated. All patients with a history compatible with reactive arthritis were interviewed and examined. Serum was taken to determine the presence of isotypic antibodies to the lipopolysaccharide of the causative Salmonella typhimurium. RESULTS: Twenty-seven of the 423 individuals with dysentery were identified as developing acute ReA. In one third of them, the arthritis resolved within 4 months of onset. Two thirds continued to have subjective complaints, mostly of minor significance. However, symptoms were severe enough to force a change in work for 4 patients. Another 4 patients had objective damage to joints radiographically. Objective changes to joints were documented on physical examination in 37% of ReA patients 5 years following onset of disease. IgA antilipopolysaccharide antibodies correlated with the severity and duration of disease. Tests of cellular immune function did not correlate with clinical variables. CONCLUSIONS: Chronic symptoms persist 5 years after the onset of ReA in the majority of patients. Joint damage by physical examination and radiographic assessment correlate with functional disability. Some early clinical features of disease, including prolonged diarrhea during the acute illness, may predict a worse outcome. IgA antilipopolysaccharides may serve as a disease marker for late post-Salmonella-infection ReA.
Acute Disease↗
Acute anterior uveitis: clinical and experimental aspects.
Acute anterior uveitis (AAU) or iritis is an inflammatory disorder of the anterior structures of the eye that may be associated with a number of disease entities. A significant proportion of patients will have no evidence of an underlying disorder and are labeled as idiopathic. Within this group approximately 50% will possess the human leukocyte antigen, HLA-B27, and some will have an associated spondyloarthropathy such as ankylosing spondylitis or Reiter's syndrome. Nevertheless, a number of HLA-B27-positive patients have no apparent underlying rheumatic disorder. The potential interplay of HLA-B27 and certain infective agents in the pathogenesis of AAU is discussed with particular reference to Yersinia species. Presentation of a uveitogenic peptide, similar to the arthritogenic peptide model in spondyloarthropathies, may be a mechanism involved in the development of AAU. Experimental models in animals have increased our understanding of the roles of retinal proteins and bacterial peptides, as well as T cells and cytokines, in the pathogenesis of uveitis. As in animal models of arthritis, certain retinal peptides (in conjunction with adjuvant therapy) can induce uveitis in animals. The treatment of isolated AAU usually involves topical medication and the prognosis is good. Occasional cases, especially those associated with systemic disorders, may require the addition of systemic corticosteroids or other immunosuppressive medications.
Acute Disease↗
Etiopathogenesis of reactive arthritis and ankylosing spondylitis.
Advances in molecular biology have brought more refined techniques to the study of the structure and function of HLA molecules and the biology of arthritogenic bacteria. Site-directed mutations in HLA and bacterial genes have focused attention on amino acids that are playing a critical role in the dynamic interaction of host and pathogen. The role of HLA-B27 in conferring disease susceptibility is being evaluated in both human disease and in B27 transgenic animal models. The continued interchange between clinical research in the spondyloarthropathies and the in vitro systems analyzing the immunology and microbiology of these diseases has maintained a high level of interest in this field of arthritis research.
Animals↗
The effect of the medial collar in total hip arthroplasty with porous-coated components inserted without cement. An in vivo canine study.
We performed an in vivo study in a canine model to compare the results of the use of a porous-coated collared femoral component with those of the use of a porous-coated collarless femoral component in total hip arthroplasties without cement. Our study focused on the comparative proximal strain pattern, bone ingrowth, and cortical porosity of the two types of prostheses. We used a trochanteric wire marker to measure subsidence. The use of the limb was assessed with gait analysis. Twelve weeks after the operation, the collarless components had significantly greater bone ingrowth proximally (p = 0.003) and were associated with significantly lower cortical porosity (p = 0.006). There were no differences between the groups with regard to either axial or hoop strain. While the group that had a collarless prosthesis had significantly less proximal-medial radiolucency (p = 0.03), there were no differences between the groups with regard to subsidence.
Animals↗
Metastatic adenocarcinoma mimicking unilateral sacroiliitis.
Back pain is a common clinical syndrome that may be the expression of an uncommon pathological process. We describe an unusual case of adenocarcinoma mimicking unilateral sacroiliitis. When progressive symptoms are unresponsive to conventional therapy, diagnosis should always be reconsidered, with appropriate imaging studies. We discuss mechanisms of joint space involvement and review the literature.
Adenocarcinoma↗
ME1 epitope of HLA-B27 confers class I-mediated modulation of gram-negative bacterial invasion.
We have previously demonstrated that the presence of the MHC class I molecule, HLA-B27, on the surface of transfected fibroblasts differentially alters Gram-negative bacterial invasion as compared with class I alleles that are not implicated in the seronegative spondyloarthropathies. We have now extended this analysis to show that fibroblasts transfected with HLA-B7, a cross-reactive allele with HLA-B27, also demonstrate a similar altered bacterial invasion phenotype. The decrease in the ability of the bacteria to penetrate the HLA-B27 and HLA-B7 transfectants is an invasion-mediated event, as demonstrated by differential invasion events using Escherichia coli transfected with the inv gene of Yersinia enterocolitica. The lysine at position 70, although unique to the HLA-B27 subtypes, is shown to be not involved in mediating the decrease in invasion. However, the ME1 epitope is the critical factor in determining allele-specific alteration in invasion on the basis of the following: 1) ME1 mAb preincubation reverses the decrease; 2) ME1-binding alleles act like HLA-B27; 3) a class I allele that is intermediate in ME1 binding (HLA-B14) also demonstrates a relative decrease in invasion; and 4) mutation at residue 67 (C-->Y) in HLA-B27, which eliminates the ME1 epitope, normalizes the decreased invasion seen in the native HLA-B27-transfected cells. Thus, the ME1 epitope relates to the disease susceptibility for reactive arthritis that is conferred by both HLA-B27 and cross-reactive group Ags.
Animals↗