301 research outputs found
Heavy metal exposure reverses genetic resistance to Chlamydia-induced arthritis
Abstract
Introduction
We have previously observed that Brown Norway (BN) rats display a relative resistance to experimental Chlamydia-induced arthritis. In the present study, we examine an environmental toxin, mercuric chloride (HgCl2), as a modulator of this innate resistance to arthritis.
Methods
To assess the effect of the heavy metal exposure, one group of rats received two subcutaneous injections of HgCl2 (1 mg/kg) 48 hours apart. Seven days later, the animals received the intra-articular injection of synoviocyte-packaged Chlamydia.
Results
Histopathology revealed that BN rats receiving only Chlamydia had a minimal cellular infiltration in the joint, which was predominantly mononuclear in character. In contrast, mercury-exposed rats had a marked exacerbation of the histopathological severity of the arthritis, and the infiltration was predominantly neutrophilic. Mercury exposure was also associated with marked enhancement in IgE levels and an alteration in IgG2a/IgG1 ratio, reflecting a Th2 shift. The local cytokine profile in the joint was markedly altered after mercury exposure, with a suppression of tumour necrosis factor-alpha and interferon-gamma but an enhancement of vascular endothelial growth factor. This was associated with decreased host clearance capacity reflected in enhanced bacterial load in both the spleen and the joint and was accompanied by enhanced detection of microbial antigens in the synovial tissues by immunohistological staining.
Conclusions
Genetically defined cytokine production in the joint defines the severity of reactive arthritis by dictating the local clearance of the pathogen. This interplay can be altered dramatically by heavy metal exposure, which results in suppression of protective cytokines in the microenvironment of the joint
ANKH variants associated with ankylosing spondylitis: gender differences
The ank (progressive ankylosis) mutant mouse, which has a nonsense mutation in exon 12 of the inorganic pyrophosphate regulator gene (ank), exhibits aberrant joint ankylosis similar to human ankylosing spondylitis (AS). We previously performed family-based association analyses of 124 Caucasian AS families and showed that novel genetic markers in the 5' flanking region of ANKH (the human homolog of the murine ank gene) are modestly associated with AS. The objective of the present study was to conduct a more extensive evaluation of ANKH variants that are significantly associated with AS and to determine whether the association is gender specific. We genotyped 201 multiplex AS families with nine ANKH intragenetic and two flanking microsatellite markers, and performed family-based association analyses. We showed that ANKH variants located in two different regions of the ANKH gene were associated with AS. Results of haplotype analyses indicated that, after Bonferroni correction, the haplotype combination of rs26307 [C] and rs27356 [C] is significantly associated with AS in men (recessive/dominant model; P = 0.004), and the haplotype combination of rs28006 [C] and rs25957 [C] is significantly associated with AS in women (recessive/dominant model; P = 0.004). A test of interaction identified rs26307 (i.e. the region that was associated in men with AS) as showing a difference in the strength of the association by gender. The region associated with AS in women only showed significance in the test of interaction among the subset of families with affected individuals of both genders. These findings support the concept that ANKH plays a role in genetic susceptibility to AS and reveals a gender–genotype specificity in this interaction
Notochordal cells protect nucleus pulposus cells from degradation and apoptosis: implications for the mechanisms of intervertebral disc degeneration
Abstract
Introduction
The relative resistance of non-chondrodystrophic (NCD) canines to degenerative disc disease (DDD) may be due to a combination of anabolic and anti-catabolic factors secreted by notochordal cells within the intervertebral disc (IVD) nucleus pulposus (NP). Factors known to induce DDD include interleukin-1 beta (IL-1ß) and/or Fas-Ligand (Fas-L). Therefore we evaluated the ability of notochordal cell conditioned medium (NCCM) to protect NP cells from IL-1ß and IL-1ß +FasL-mediated cell death and degeneration.
Methods
We cultured bovine NP cells with IL-1ß or IL-1ß+FasL under hypoxic serum-free conditions (3.5% O2) and treated the cells with either serum-free NCCM or basal medium (Advanced DMEM/F-12). We used flow cytometry to evaluate cell death and real-time (RT-)PCR to determine the gene expression of aggrecan, collagen 2, and link protein, mediators of matrix degradation ADAMTS-4 and MMP3, the matrix protection molecule TIMP1, the cluster of differentiation (CD)44 receptor, the inflammatory cytokine IL-6 and Ank. We then determined the expression of specific apoptotic pathways in bovine NP cells by characterizing the expression of activated caspases-3, -8 and -9 in the presence of IL-1ß+FasL when cultured with NCCM, conditioned medium obtained using bovine NP cells (BCCM), and basal medium all supplemented with 2% FBS.
Results
NCCM inhibits bovine NP cell death and apoptosis via suppression of activated caspase-9 and caspase-3/7. Furthermore, NCCM protects NP cells from the degradative effects of IL-1ß and IL-1ß+Fas-L by up-regulating the expression of anabolic/matrix protective genes (aggrecan, collagen type 2, CD44, link protein and TIMP-1) and down-regulating matrix degrading genes such as MMP-3. Expression of ADAMTS-4, which encodes a protein for aggrecan remodeling, is increased. NCCM also protects against IL-1+FasL-mediated down-regulation of Ank expression. Furthermore, NP cells treated with NCCM in the presence of IL-1ß+Fas-L down-regulate the expression of IL-6 by almost 50%. BCCM does not mediate cell death/apoptosis in target bovine NP cells.
Conclusions
Notochordal cell-secreted factors suppress NP cell death by inhibition of activated caspase-9 and -3/7 activity and by up-regulating genes contributing anabolic activity and matrix protection of the IVD NP. Harnessing the restorative powers of the notochordal cell could lead to novel cellular and molecular strategies in the treatment of DDD
Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 104-week results of the GO-RAISE study
Pathophysiology and treatment of rheumatic disease
results of the randomized, placebo-controlled GO-RAISE study
Background In the present study, we evaluated relationships between serum
biomarkers and clinical/magnetic resonance imaging (MRI) findings in
golimumab-treated patients with ankylosing spondylitis. Methods In the GO-
RAISE study, 356 patients with ankylosing spondylitis randomly received either
placebo (n = 78) or golimumab 50 mg or 100 mg (n = 278) injections every 4
weeks through week 24 (placebo-controlled); patients continuing GO-RAISE
received golimumab through week 252. Up to 139/125 patients had sera collected
for biomarkers/serial spine MRI scans (sagittal plane, 1.5-T scanner). Two
blinded readers employed modified ankylosing spondylitis spine magnetic
resonance imaging score for activity (ASspiMRI-a) and ankylosing spondylitis
spine magnetic resonance imaging score for chronicity. Spearman correlations
(r s) were assessed between serum biomarkers (n = 73) and Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI), C-reactive-protein (CRP)-based
Ankylosing Spondylitis Disease Activity Score (ASDAS), modified Stokes
Ankylosing Spondylitis Spine Score (mSASSS), and ASspiMRI scores. Serum
biomarkers predicting postbaseline spinal fatty lesion development and
inflammation were analyzed by logistic regression. Results Significant,
moderately strong correlations were observed between baseline inflammatory
markers interleukin (IL)-6, intracellular adhesion molecule-1, complement
component 3 (C3), CRP, haptoglobin, and serum amyloid-P and baseline ASDAS (r
s = 0.39–0.66, p ≤ 0.01). Only baseline leptin significantly correlated with
ASDAS improvement at week 104 (r s = 0.55, p = 0.040), and only baseline IL-6
significantly predicted mSASSS week 104 change (β = 0.236, SE = 0.073, p =
0.002, model R 2 = 0.093). By logistic regression, baseline leptin, C3, and
tissue inhibitor of metalloproteinase (TIMP)-1 correlated with new fatty
lesions per spinal MRI at week 14 and week 104 (both p < 0.01). Changes in
serum C3 levels at week 4 (r s = 0.55, p = 0.001) and week 14 (r s = 0.49, p =
0.040) significantly correlated with BASDAI improvement at week 14. Baseline
IL-6 and TIMP-1 (r s = −0.63, −0.67; p < 0.05) and reductions at week 4 in
IL-6 (r s = 0.61, p < 0.05) and C3 (r s = 0.72; p < 0.05) significantly
correlated with week 14 ASspiMRI-a improvement. Conclusions Extensive serum
biomarker multiparametric analyses in golimumab-treated patients with
ankylosing spondylitis demonstrated few correlations with disease activity or
MRI changes; IL-6 weakly correlated with radiographic progression
Serum markers associated with clinical improvement in patients with ankylosing spondylitis treated with golimumab
Pathophysiology and treatment of rheumatic disease
Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN)
OBJECTIVES: The ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-alpha (IL-6Ralpha), in patients with ankylosing spondylitis (AS).
METHODS: Patients with active AS despite conventional treatment were randomised to placebo, or one of five subcutaneous dose regimens of sarilumab (100, 150 or 200 mg every other week, or 100 or 150 mg every week), for 12 weeks. The primary efficacy end point was the percentage of patients achieving the Axial SpondyloArthritis international Society (ASAS) 20 response criteria at week 12. Secondary endpoints included ASAS40 response, ASAS partial remission, AS Disease Activity Score, high-sensitivity C-reactive protein (hs-CRP) value, and safety.
RESULTS: Baseline demographic and disease characteristics of the 301 patients enrolled were similar across treatment groups. At week 12, there was no statistically significant difference in ASAS20 response rate between placebo (ASAS20 = 24.0%) and any sarilumab dose group. A significantly greater reduction in hs-CRP value was achieved with the higher sarilumab doses versus placebo. No other statistically significant differences were evident for secondary efficacy endpoints.The most common treatment-emergent adverse events reported for sarilumab included infections (non-serious), neutropenia, and increase in alanine aminotransferase. No cases of tuberculosis, opportunistic, or fungal infections, or bowel perforations were reported. Seven patients experienced a treatment-emergent serious adverse event (all in sarilumab treatment groups). No deaths occurred.
CONCLUSIONS: The ALIGN study shows that IL-6Ralpha blockade with sarilumab was not an effective treatment for AS. Sarilumab was generally well tolerated with a manageable safety profile
Preventing autoimmune arthritis using antigen-specific immature dendritic cells: a novel tolerogenic vaccine
Conventional treatments for autoimmune diseases have relied heavily on nonspecific immune suppressants, which possess a variety of adverse effects without inhibiting the autoimmune process in a specific manner. In the present study we demonstrate the effectiveness of antigen-specific, maturation-resistant, tolerogenic dendritic cells (DC) in suppressing collagen-induced arthritis, a murine model of rheumatoid arthritis. Treatment of DC progenitors with the NF-κB inhibiting agent LF 15-0195 (LF) resulted in a population of tolerogenic DC that are characterized by low expression of MHC class II, CD40, and CD86 molecules, as well as by poor allostimulatory capacity in a mixed leukocyte reaction. Administering LF-treated DC pulsed with keyhole limpet hemocyanin antigen to naïve mice resulted hyporesponsiveness specific for this antigen. Furthermore, administration of LF-treated DC to mice with collagen-induced arthritis resulted in an improved clinical score, in an inhibited antigen-specific T-cell response, and in reduced antibody response to the collagen. The efficacy of LF-treated DC in preventing arthritis was substantiated by histological examination, which revealed a significant decrease in inflammatory cell infiltration in the joints. In conclusion, we demonstrate that in vitro-generated antigen-specific immature DC may have important potential as a tolerogenic vaccine for the treatment of autoimmune arthritis
Golimumab reduces spinal inflammation in ankylosing spondylitis: MRI results of the randomised, placebo- controlled GO-RAISE study
Pathophysiology and treatment of rheumatic disease
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