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BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance.

ABSTRACT: The major histocompatibility complex (H-2d) and non-major histocompatibility complex genetic backgrounds make the BALB/c strain highly susceptible to inflammatory arthritis and spondylitis. Although different BALB/c colonies develop proteoglycan-induced arthritis and proteoglycan-induced spondylitis in response to immunization with human cartilage proteoglycan, they show significant differences in disease penetrance despite being maintained by the same vendor at either the same or a different location.BALB/c female mice (24 to 26 weeks old after 4 weeks of acclimatization) were immunized with a suboptimal dose of cartilage proteoglycan to explore even minute differences among 11 subcolonies purchased from five different vendors. In vitro-measured T-cell responses, and serum cytokines and (auto)antibodies were correlated with arthritis (and spondylitis) phenotypic scores. cDNA microarrays were also performed using spleen cells of naïve and immunized BALB/cJ and BALB/cByJ mice (both colonies from The Jackson Laboratory, Bar Harbor, ME, USA), which represent the two major BALB/c sublines.The 11 BALB/c colonies could be separated into high (n = 3), average (n = 6), and low (n = 2) responder groups based upon their arthritis scores. While the clinical phenotypes showed significant differences, only a few immune parameters correlated with clinical or histopathological abnormalities, and seemingly none of them affected differences found in altered clinical phenotypes (onset time, severity or incidence of arthritis, or severity and progression of spondylitis). Affymetrix assay (Affymetrix, Santa Clara, CA, USA) explored 77 differentially expressed genes (at a significant level, P < 0.05) between The Jackson Laboratory's BALB/cJ (original) and BALB/cByJ (transferred from the National Institutes of Health, Bethesda, MD, USA). Fourteen of the 77 differentially expressed genes had unknown function; 24 of 77 genes showed over twofold differences, and only 8 genes were induced by immunization, some in both colonies.Using different subcolonies of the BALB/c strain, we can detect significant differences in arthritis phenotypes, single-nucleotide polymorphisms (SNPs), and a large number of differentially expressed genes, even in non-immunized animals. A number of the known genes (and SNPs) are associated with immune responses and/or arthritis in this genetically arthritis-prone murine strain, and a number of genes of as-yet-unknown function may affect or modify clinical phenotypes of arthritis and/or spondylitis.

SUBMITTER: Farkas B

PROVIDER: S-EPMC2688253 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance.

Farkas Balint B Boldizsar Ferenc F Tarjanyi Oktavia O Laszlo Anna A Lin Simon M SM Hutas Gabor G Tryniszewska Beata B Mangold Aaron A Nagyeri Gyorgy G Rosenzweig Holly L HL Finnegan Alison A Mikecz Katalin K Glant Tibor T TT

Arthritis research & therapy 20090216 1

<h4>Introduction</h4>The major histocompatibility complex (H-2d) and non-major histocompatibility complex genetic backgrounds make the BALB/c strain highly susceptible to inflammatory arthritis and spondylitis. Although different BALB/c colonies develop proteoglycan-induced arthritis and proteoglycan-induced spondylitis in response to immunization with human cartilage proteoglycan, they show significant differences in disease penetrance despite being maintained by the same vendor at either the s ...[more]

PMID: 19220900

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Project description:BackgroundAnkylosing spondylitis (AS) is characterised by immune-mediated arthritis and osteoproliferation, ultimately leading to joint ankylosis. Whether inflammation is necessary for osteoproliferation is controversial, fuelled by the unclear efficacy of anti-inflammatory treatments on radiographic progression. In proteoglycan-induced spondylitis (PGISp), a mouse model of AS, inflammation is the prerequisite for osteoproliferation as osteoproliferation was only observed following inflammation-driven intervertebral disc (IVD) destruction. We hypothesised that early intervention with a potent anti-inflammatory therapy would protect IVD integrity and consequently alter disease progression.MethodsPGISp mice received vehicle or a combination of etanercept (ETN) plus prednisolone (PRD) therapy for 2 or 6 weeks initiated at an early disease stage. Peripheral arthritis was scored longitudinally. Spinal disease was assessed using a semi-quantitative histological scoring regimen including inflammation, joint destruction and excessive tissue formation.ResultsETN + PRD therapy significantly delayed the onset of peripheral arthritis. IVD integrity was significantly protected when treatment was commenced in early disease. Six-weeks of treatment resulted in trends towards reductions in intervertebral joint damage and excessive tissue formation. IVD score distribution was dichotomized, likely reflecting the extent of axial disease at initiation of therapy. In the sub-group of mice with high IVD destruction scores, ETN + PRD treatment significantly reduced IVD destruction severity, inflammation and bone erosion and reduced cartilage damage and excessive tissue formation.ConclusionsEarly intervention with anti-inflammatory treatment not only improved inflammatory symptoms but also ameliorated structural damage of spine in PGISp mice. This preclinical observation suggests that early anti-inflammatory intervention may slow radiographic progression in AS patients.

Project description:BackgroundRheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients.MethodsWe used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)-containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA.ResultsSplenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma.ConclusionsWe identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T-cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitope-induced T-cell activation or antibody deposition may occur in the joints of RA patients.

Project description:IntroductionPatients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS) may receive suboptimal care, and differences in care by race/ethnicity, sex, and insurance coverage are not well studied.MethodsThis was a descriptive, retrospective cross-sectional US claims database analysis utilizing the Medicaid multi-state segment of the IBM® MarketScan® Commercial Claims and Encounters Supplemental Database and Optum Insight Clinformatics® Data Mart database for 2019. Patients aged ≥ 18 years with PsA or AS and continuous medical and pharmacy coverage were included. Outcomes evaluated were prevalence and percentage of patients receiving biologic disease-modifying antirheumatic drugs (bDMARDs)/targeted synthetic DMARDs (tsDMARDs) or visiting a rheumatologist. Outcomes were stratified by race/ethnicity, sex, and insurance coverage, with outcomes determined for commercial insurance, Medicare, and Medicaid enrollees. Differences observed in outcomes were numerical in nature.ResultsPrevalences of PsA and AS were highest for Medicare enrollees (320 and 156 per 100,000 persons [0.32 and 0.16%], respectively) and lowest for Medicaid enrollees (132 and 71 per 100,000 persons [0.13 and 0.07%], respectively). White patients had the greatest prevalence versus patients of other races/ethnicities. Females had a higher prevalence of PsA than males, while AS prevalence was generally lower for females versus males for each insurance category. The percentage of patients prescribed bDMARDs/tsDMARDs was highest for commercial insurance enrollees (PsA 63%, AS 43%) and lowest for Medicare enrollees (PsA 21%, AS 11%). The proportion of patients who saw a rheumatologist was lower for Medicaid enrollees (PsA 12%, AS 10%) than for commercial insurance or Medicare enrollees (PsA 68%, 55%; AS 67%, 42%). For commercial insurance and Medicare enrollees, the percentage of patients visiting a rheumatologist was similar by race/ethnicity but higher for females versus males.ConclusionsThe prevalence and treatment of PsA and AS differs by race/ethnicity, insurance coverage, and sex in the USA. Efforts for improving access to care are needed to improve outcomes among all patients.

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BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance.

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BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance.

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