Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice

Rheumatoid arthritis (RA) is a common autoimmune disease that afflicts the synovium of diarthrodial joints. The pathogenic mechanisms inciting this disease are not fully characterized, but may involve the loss of tolerance to posttranslationally modified (citrullinated) antigens. We have demonstrated that this modification leads to a selective increase in antigenic peptide affinity for major histocompatibility complex (MHC) class II molecules that carry the RA-associated shared epitope, such as HLA-DRB1*0401 (DR4). We describe the induction of arthritis in DR4-IE transgenic (tg) mice with citrullinated fibrinogen, a protein commonly found in inflamed synovial tissue and a frequent target of autoantibodies in RA patients. The disease induced in these mice was characterized by synovial hyperplasia followed by ankylosis, but lacked a conspicuous polymorphonuclear cell infiltrate. Immunological analysis of these mice through T cell epitope scanning and antibody microarray analysis identified a unique profile of citrulline-specific reactivity that was not found in DR4-IE tg mice immunized with unmodified fibrinogen or in wild-type C57BL/6 mice immunized with citrullinated fibrinogen, two conditions where arthritis was not observed. These observations directly implicate citrullinated fibrinogen as arthritogenic in the context of RA-associated MHC class II molecules

Severe necrotizing pancreatitis following combined hepatitis A and B vaccination

Necrotizing pancreatitis is a severe form of pancreatitis and is associated with substantial morbidity and mortality. We report a case of necrotizing pancreatitis that developed following combined hepatitis A and B vaccination. No other causes of pancreatitis could be determined. Although confirming the diagnosis is challenging, 3 main factors suggest a possible link to the vaccine: the chronology of the events, the patient's human leukocyte antigen genotype and the incongruent immune response to the vaccine components. This report serves to alert physicians to the possible development of necrotizing pancreatitis after vaccination

Systematic review of nondermatophyte mold onychomycosis: diagnosis, clinical types, epidemiology, and treatment

Nondermatophyte mold (NDM) onychomycosis is difficult to diagnose given that NDMs are common contaminants of the nails and of the mycology laboratory. Diagnostic criteria and definition of cure are inconsistent between studies, which may affect the quality of published data. We identified 6 major criteria used in the literature: identification of the NDM in the nail by microscopy (using potassium hydroxide preparation), isolation in culture, repeated isolation in culture, inoculum counting, failure to isolate a dermatophyte in culture, and histology. Most studies used 3 or more of these (range = 1-5). We recommend using at least 3 of the criteria to rule out contamination; these should include potassium hydroxide preparation for direct microscopy and isolation of the organism in culture. We review geographic distribution and clinical presentations associated with different NDMs. The treatment with the greatest quantity of data and highest reported cure rates is terbinafine, for the treatment of Scopulariopsis brevicaulis and Aspergillus species infections. Topicals such as ciclopirox nail lacquer may also be effective (data originating from Scopulariopsis brevicaulis and Acremonium species infections), especially when combined with chemical or surgical avulsion of the nail. We recommend that future studies use (and clearly indicate) at least 3 of the main criteria for diagnosis, and report the clinical type of onychomycosis and the isolated organism. When evaluating different treatments, we suggest that authors clearly define their efficacy outcomes

Association of severe inflammatory polyarthritis in primary Sjögren\u27s syndrome: Clinical, serologic, and HLA analysis

Objective. To evaluate the clinical, serologic, and MHC class II antigen characteristics of a group of patients with primary Sjögren\u27s syndrome (SS) and severe arthritis. Methods. A case-control study comparing 35 patients with primary SS: 17 with inflammatory arthritis, 18 without arthritis. Results.All patients fulfilled criteria for primary SS. There were no demographic or clinical features other than inflammatory arthritis, often erosive, that distinguished patients with arthritis from those without. All patients had anti-Ro/SSA autoantibodies, most had anti-La/SSB autoantibodies, and a high percentage of these patients had anti-citrullinated peptide antibodies absent in those without inflammatory arthritis. HLA typing revealed that most patients with anti-citrulline antibodies expressedMHC class II molecules with the shared epitope (SE). The presence of DRB1*0301 linked to the expression of anti-Ro/SSA autoantibodies did not influence the level or frequency of anti-citrulline antibodies in these patients. Conclusion. Severe arthritis with features resembling rheumatoid arthritis including erosive disease can occur in primary SS, particularly among those with anti-citrulline antibodies and the SE. The Journal of Rheumatology Copyright © 2009. All rights reserved

CTLA-4Ig blocks the development and progression of citrullinated fibrinogen-induced arthritis in DR4-transgenic mice

Objective. To assess the role of T cells in the mouse model of citrullinated human fibrinogen - induced rheumatoid arthritis (RA) using CTLA-4Ig, an agent that blocks T cell costimulation, which is required for T cell activation. Methods. Humanized HLA-DRβ1*0401 - transgenic (DR4-Tg) mice were immunized with Cit - human fibrinogen to induce arthritis. Prior to, and at the onset or peak of, arthritis, the DR4-Tg mice were treated with CTLA-4Ig or control human IgG1 or were left untreated. Arthritis development and progression were monitored by measuring ankle swelling with calipers and by assessing histopathologic changes. The immune responses to the citrullinated antigens and the corresponding unmodified antigens, as well as the arthritogenicity of lymphocytes from these mice, were examined. The latter was performed using lymphocyte transfers from CTLA-4Ig - treated or control mice via intraperitoneal injection into naive DR4-Tg mice. Recipient mice also received an intraarticular injection of Cit - human fibrinogen, unmodified human fibrinogen, or vehicle. Results. CTLA-4Ig - treated, but not human IgG1-treated, arthritic mice had significantly reduced ankle swelling and pathologic joint damage. Treatment with CTLA-4Ig, but not human IgG1, suppressed Cit - human fibrinogen - induced T cell activation, including citrulline-specific T cell activation, when given prior to disease onset. Transfer of splenic lymphocytes from untreated or human IgG1 - treated arthritic mice caused arthritis in recipients, and this occurred when Cit - human fibrinogen, but not unmodified fibrinogen, was deposited into the joint. Splenocytes from CTLA-4Ig - treated mice were unable to transfer arthritis. Conclusion. Activated citrulline-specific T cells play a direct role in the development and progression of arthritis in this model of Cit-human fibrinogen-induced RA. © 2010, American College of Rheumatology

Immunization with porphyromonas gingivalis enolase induces autoimmunity to mammalian α-enolase and arthritis in DR4-IE-transgenic mice

Objective To examine the hypothesis that the subset of rheumatoid arthritis (RA) characterized by antibodies to citrullinated α-enolase is mediated by Porphyromonas gingivalis enolase in the context of DR4 alleles. Methods Recombinant human α-enolase and P gingivalis enolase, either citrullinated or uncitrullinated, were used to immunize DR4-IE-transgenic mice and control mice (class II major histocompatibility complex-deficient [class II MHC -/-] and C57BL/6 wild-type mice). Arthritis was quantified by measurement of ankle swelling in the hind paws and histologic examination. Serum IgG reactivity with α-enolase and citrullinated α-enolase was assayed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Antibodies to peptide 1 of citrullinated α-enolase (CEP-1) and its arginine-bearing control peptide, REP-1, were also assessed by ELISA. Results Significant hind-ankle swelling (≥0.3 mm) occurred in DR4-IE-transgenic mice immunized with citrullinated human α-enolase (9 of 12 mice), uncitrullinated human α-enolase (9 of 12 mice), citrullinated P gingivalis enolase (6 of 6 mice), and uncitrullinated P gingivalis enolase (6 of 6 mice). Swelling peaked on day 24. None of the control groups developed arthritis. The arthritic joints showed synovial hyperplasia and erosions, but there was a paucity of leukocyte infiltration. Antibodies to human α-enolase, both citrullinated and unmodified, and to CEP-1 and REP-1 were detectable in all immunized mice except the class II MHC -/- control mice. Conclusion This is the first animal model that links an immune response to P gingivalis enolase to an important subset of RA, defined by antibodies to citrullinated α-enolase in the context of DR4. The fact that arthritis and anti-CEP-1 antibodies were induced independent of citrullination of the immunizing antigen suggests that the unmodified form of α-enolase may be important in initiating the corresponding subset of human RA. © 2011 by the American College of Rheumatology

Preventing and curing citrulline-induced autoimmune arthritis in a humanized mouse model using a Th2-polarizing iNKT cell agonist

Invariant natural killer T (iNKT) cells are innate lymphocytes with unique reactivity to glycolipid antigens bound to non-polymorphic CD1d molecules. They are capable of rapidly releasing pro- and/or anti-inflammatory cytokines and constitute attractive targets for immunotherapy of a wide range of diseases including autoimmune disorders. In this study, we have explored the beneficial effects of OCH, a Th2-polarizing glycolipid agonist of iNKT cells, in a humanized mouse model of rheumatoid arthritis (RA) in which citrullinated human proteins are targeted by autoaggressive immune responses in mice expressing an RA susceptibility human leukocyte antigen (HLA) DR4 molecule. We found for the first time that treatment with OCH both prevents and cures citrulline-induced autoimmune arthritis as evidenced by resolved ankle swelling and reversed histopathological changes associated with arthritis. Also importantly, OCH treatment blocked the arthritogenic capacity of citrullinated antigen-experienced splenocytes without compromising their global responsiveness or altering the proportion of splenic naturally occurring CD4 CD25 FoxP3 regulatory T cells. Interestingly, administering the Th1-promoting iNKT cell glycolipid ligand α-C-galactosylceramide into HLA-DR4 transgenic mice increased the incidence of arthritis in these animals and exacerbated their clinical symptoms, strongly suggesting a role for Th1 responses in the pathogenesis of citrulline-induced arthritis. Therefore, our findings indicate a role for Th1-mediated immunopathology in citrulline-induced arthritis and provide the first evidence that iNKT cell manipulation by Th2-skewing glycolipids may be of therapeutic value in this clinically relevant model, a finding that is potentially translatable to human RA. © 2012 Australasian Society for Immunology Inc

Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis

Objective. To examine the association between aberrant IgG galactosylation and disease parameters in rheumatoid arthritis (RA). Methods. Analysis of N-glycan in serum samples from multiple cohorts was performed. The IgG N-glycan content and the timing of N-glycan aberrancy relative to disease onset were compared in healthy subjects and in patients with RA. Correlations between aberrant galactosylation and disease activity were assessed in the RA cohorts. The impact of disease activity, sex, age, anticyclic citrullinated peptide (anti-CCP) antibody titer, disease duration, and C-reactive protein level on aberrant galactosylation was determined using multivariate analysis. The N-glycan content was also compared between epitope affinity-purified autoantibodies and the remaining IgG repertoire in RA patients. Results. Our results confirm the aberrant galactosylation of IgG in RA patients as compared with healthy controls (mean ± SD 1.36 ± 0.43 versus 1.01 ± 0.23; P \u3c 0.0001). We observed a significant correlation between levels of aberrant IgG galactosylation and disease activity (Spearman\u27s ρ = 0.37, P \u3c 0.0001). This correlation was higher in women (Spearman\u27s ρ = 0.60, P \u3c 0.0001) than in men (Spearman\u27s ρ = 0.16, P = 0.10). Further, aberrant IgG galactosylation substantially predated the onset of arthritis and the diagnosis of RA (3.5 years) and resided selectively in the anticitrullinated antigen fraction. Conclusion. Our findings identify aberrant IgG galactosylation as a dysregulated component of the humoral immune response in RA that begins prior to disease onset, associates with disease activity in a sex-specific manner, and resides preferentially in auto-antibodies. © 2010, American College of Rheumatology