Publications by authors named "Veronique Duchatelle"

18 Publications

  • Page 1 of 1

Interventricular septum mass presenting as a late acute coronary syndrome with ST-segment elevation: a case report.

Eur Heart J Case Rep 2021 May 12;5(5):ytab164. Epub 2021 May 12.

Radiology Department, Hopital Saint-Joseph, 185 Rue Raymond Losserand, 75014 Paris, France.

Background: Intracardiac masses are relatively rare but the diagnosis can be challenging for the cardiologist and the clinical presentation can be misleading. While most of the cardiac masses are benign, malignant masses are mostly metastatic tumours.

Case Summary: An 81-year-old man was admitted to the cardiology department for congestive heart failure with the complaint of recent dyspnoea. The initial electrocardiogram was suggestive of a late presentation of an anterior myocardial infarction. Blood test showed mild and stable elevation of troponin and brain natriuretic peptide. Doppler-echocardiography revealed an interventricular septal thickening. Contrast echocardiography revealed a mass with a possibly necrotic centre and peripheral hypervascularization. Cardiac computed tomography (CT) confirmed the existence of a cardiac tumour with a hypodense centre and also revealed the presence of a large tumour of the lung's left lower lobe with multiple enlarged lymph nodes associated with possible left adrenal gland metastasis. Computed tomography-guided percutaneous biopsy of the pulmonary mass demonstrated a squamous cell lung cancer which was likely the primary cancer. The patient was discharged home waiting for chemotherapy to start but died a few days later at home of an unknown cause.

Discussion: Diagnosis of intracardiac mass is difficult, often requiring multiple imaging modalities. Contrast-enhanced echocardiography may help early diagnosis and can be easily implemented with other imaging modalities such as cardiac magnetic resonance imaging or CT.
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http://dx.doi.org/10.1093/ehjcr/ytab164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189305PMC
May 2021

Peripheral arterial disease and systematic detection of circulating tumor cells: rationale and design of the DETECTOR prospective cohort study.

BMC Cardiovasc Disord 2019 09 13;19(1):212. Epub 2019 Sep 13.

Groupe Hospitalier Paris Saint Joseph, 185 rue Raymond Losserand, 75 014, Paris, France.

Background: Smoking is a strong risk factor for cancer and atherosclerosis. Cancer mortality, especially from lung cancer, overtakes cardiovascular (CV) death rate in patients with peripheral arterial disease (PAD). Only a few patients with lung cancer after PAD management may benefit from surgical excision. Circulating tumor cells (CTC) associated with low-dose chest CT (LDCT) may improve early cancer detection. This study focuses on a screening strategy that can address not only lung cancer but all tobacco-related cancers in this high-risk population.

Methods: DETECTOR Project is a prospective cohort study in two French University hospitals. Participants are smokers or former smokers (≥30 pack-years, quitted ≤15 years), aged ≥55 to 80 years, with atherosclerotic PAD or abdominal aortic aneurysm. After the first screening round combining LDCT and CTC search on a blood sample, two other screening rounds will be performed at one-year interval. Incidental lung nodule volume, volume doubling time and presence of CTC will be taken into consideration for adapted diagnostic management. In case of negative LDCT and presence of CTC, a contrast enhanced whole-body PET/CT will be performed for extra-pulmonary malignancy screening. Psychological impact of this screening strategy will be evaluated in population study using a qualitative methodology. Assuming 10% prevalence of smoking-associated cancer in the studied population, a total of at least 300 participants will be enrolled.

Discussion: Epidemiological data underline an increase incidence in cancer and related death in the follow-up of patients with PAD, compared with the general population, particularly for tobacco-related cancers. The clinical benefit of a special workup for neoplasms in patients with PAD and a history of cigarette smoking has never been investigated. By considering CTCs detection in this very high-risk selected PAD population for tobacco-induced cancer, we expect to detect earlier pulmonary and extra-pulmonary malignancies, at a potentially curable stage.

Trial Registration: The study was registered in the French National Agency for Medicines and Health Products Safety (No N° EUDRACT_ID RCB: 2016-A00657-44) and was approved by the ethics Committee for Persons Protection (IRB number 1072 and n° initial agreement 2016-08-02; ClinicalTrials.gov identifier NCT02849041).
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http://dx.doi.org/10.1186/s12872-019-1193-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743149PMC
September 2019

Chronic NO Restriction in Hypertensive Rats Increases Abdominal but Not Thoracic Aortic Intrinsic Stiffness via an Augmentation in Profibrotic Materials.

Int J Hypertens 2019 19;2019:8070198. Epub 2019 Mar 19.

Servier Research Institute, Cardiovascular Discovery Research Unit Suresnes, France.

The spontaneously hypertensive rat model with reduced NO synthesis (SHRLN) shares features with aging and hypertension in humans, among other a severe aortic stiffening. The present study aimed to compare thoracic (TA) and abdominal (AA) aortic stiffness in the SHRLN (treated 5 weeks with L-NAME), SHR, and normotensive Wistar Kyoto (WKY). Dynamic properties of TA and AA were measured in the same rats, using echotracking recording of aortic diameter coupled with blood pressure (BP). Measurements were performed first at operating BP and then after BP reduction in hypertensive rats, thus in isobaric conditions. Histological staining and immunohistochemistry were used for structural analysis at both sites. At operating pressure, BP and pulse pressure (PP) were higher in SHRLN compared with SHR. Stiffness index was also increased and distensibility decreased in both TA and AA in SHRLN. At WKY-matched blood pressure, isobaric AA parameters remained specifically altered in SHRLN, whereas TA recovered to values identical to WKYs. Collagen, fibronectin, 5-selectin, and FAK were increased in SHRLN compared with SHR or WKY. Nevertheless, only the strong accumulations of fibronectin and collagen at the AA site in SHRLN were associated with intrinsic stiffening. In conclusion, we confirm that NO restriction associated with hypertension induces a severe pathological phenotype and shows that L-NAME induced stiffening is more pronounced in AA than in TA as a result of greater fibrosis.
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http://dx.doi.org/10.1155/2019/8070198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444237PMC
March 2019

[A persistent lesion of the anus].

Rev Prat 2018 May;68(5):531-535

Service de proctologie médico-chirurgicale, institut Léopold- Bellan, groupe hospitalier Paris-Saint-Joseph, Paris, France.

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May 2018

Modulation of lung cancer cell plasticity and heterogeneity with the restoration of cisplatin sensitivity by neurotensin antibody.

Cancer Lett 2019 03 21;444:147-161. Epub 2018 Dec 21.

INSERM UMRS 1007, Paris Descartes University, 75270, Paris Cedex 06, France. Electronic address:

Overall survival of patients with metastatic non-small cell lung cancer (NSCLC) has significantly improved with platinum-based salt treatments and recently with targeted therapies and immunotherapies. However, treatment failure occurs due to acquired or emerging tumor resistance. We developed a monoclonal antibody against the proform of neurotensin (LF-NTS mAb) that alters the homeostasis of tumors overexpressing NTSR1. Neurotensin is frequently overexpressed along with its high affinity receptor (NTSR1) in tumors from epithelial origins. This ligand/receptor complex contributes to the progression of many tumor types by activation of the cellular effects involved in tumor progression (proliferation, survival, migration, and invasion). We demonstrate that LF-NTS mAb operates on the plasticity of tumor cells overexpressing NTSR1 and lowers their aggressiveness. The mAb enables the restoration of platinum-based therapies responsiveness, while also decreasing metastatic processes. Efficacy dosage with long-term treatment showed no obvious adverse events, while demonstrating improvement in the performance status. Our data suggests that LF-NTS mAb is an ideal candidate to be safely added to the conventional standard of care in order to improve its efficacy.
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http://dx.doi.org/10.1016/j.canlet.2018.12.007DOI Listing
March 2019

Differential Stiffening between the Abdominal and Thoracic Aorta: Effect of Salt Loading in Stroke-Prone Hypertensive Rats.

J Vasc Res 2018 8;55(3):144-158. Epub 2018 Jun 8.

Cardiovascular Discovery Research Unit Suresnes, Servier Research Institute, Suresnes, France.

Central artery stiffening is recognized as a cardiovascular risk. The effects of hypertension and aging have been shown in human and animal models but the effect of salt is still controversial. We studied the effect of a high-salt diet on aortic stiffness in salt-sensitive spontaneously hypersensitive stroke-prone rats (SHRSP). Distensibility, distension, and β-stiffness were measured at thoracic and abdominal aortic sites in the same rats, using echotracking recording of the aortic diameter coupled with blood pressure (BP), in SHRSP-salt (5% salted diet, 5 weeks), SHRSP, and normotensive Wistar-Kyoto (WKY) rats. Hemodynamic parameters were measured at BP matched to that of WKY. Histological staining and immunohistochemistry were used for structural analysis. Hemodynamic isobaric parameters in SHRSP did not differ from WKY and only those from the abdominal aorta of SHRSP-salt presented decreased distensibility and increased stiffness compared with WKY and SHRSP. The abdominal and thoracic aortas presented similar thickening, increased fibrosis, and remodeling with no change in collagen content. SHRSP-salt presented a specific increased elastin disarray at the abdominal aorta level but a decrease in elastin content in the thoracic aorta. This study demonstrates the pro-stiffening effect of salt in addition to hypertension; it shows that only the abdominal aorta presents a specific pressure-independent stiffening, in which elastin disarray is likely a key mechanism.
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http://dx.doi.org/10.1159/000488877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106143PMC
August 2018

Validity of Targeted Next-Generation Sequencing in Routine Care for Identifying Clinically Relevant Molecular Profiles in Non-Small-Cell Lung Cancer: Results of a 2-Year Experience on 1343 Samples.

J Mol Diagn 2018 07 19;20(4):550-564. Epub 2018 May 19.

INSERM UMR-S1147, Sorbonne Paris Cité University, Paris, France; Department of Biochemistry, Unit of Pharmacogenetic and Molecular Oncology, Georges Pompidou European Hospital, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

Theranostic assays are based on single-gene testing, but the ability of next-generation sequencing (NGS) to interrogate numerous genetic alterations will progressively replace single-gene assays. Although NGS was evaluated to screen for theranostic mutations, its usefulness in clinical practice on large series of samples remains to be demonstrated. NGS performance was assessed following guidelines. TaqMan probes and NGS were compared for their ability to detect EGFR and KRAS mutations, and NGS mutation profiles were analyzed on a large series of non-small-cell lung cancers (n = 1343). The R correlation between expected and measured allelic ratio, using commercial samples, was >0.96. Mutation detection threshold was 2% for 10 ng of DNA input. κ Scores for TaqMan versus NGS were 0.99 (95% CI, 0.97-1.00) for EGFR and 0.98 (95% CI, 0.97-1.00) for KRAS after exclusion of rare EGFR (n = 40) and KRAS (n = 60) mutations. NGS identified 693 and 292 mutations in validated and potential oncogenic drivers, respectively. Significant associations were found between EGFR and PI3KCA or CTNNB1 and between KRAS and STK11. Potential oncogenic driver mutations or gene amplifications were more frequent in validated oncogenic driver nonmutated samples. This work is a proof of concept that targeted NGS is accessible in routine screening, including large screening, at reasonable cost. Clinical data should be collected and implemented in specific databases to make molecular data meaningful for direct patients' benefit.
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http://dx.doi.org/10.1016/j.jmoldx.2018.04.002DOI Listing
July 2018

SBP, DBP, and pulse blood pressure variability are temporally associated with the increase in pulse wave velocity in a model of aortic stiffness.

J Hypertens 2016 Apr;34(4):666-75

aInstitut de Recherches Servier, SuresnesbCenter of Clinical Research, Groupe Hospitalier Paris Saint-JosephcHôtel-Dieu Hospital, Diagnosis Center and Université René Descartes, UFR MédecinedDepartment of PathologyeDepartment of Pharmacy, Groupe Hospitalier Paris Saint-Joseph, Paris, France*Christine Vayssettes-Courchay and Yvonnick Bézie contributed equally to the writing of this article.

Background: Enhanced aortic stiffness and blood pressure variability (BPV) are independent risk factors for cardiovascular disease and all-cause mortality in man. They are also correlated with increased blood pressure (BP) and/or arterial remodeling. However, the interplay between BP and BPV on the stiffening process is still unclear. Our objectives were to determine the temporal evolution of both BPV and pulse wave velocity (PWV), a surrogate measure of arterial stiffness, using an animal model of remodeling-dependent aortic stiffening.

Method: We thus, developed a new telemetric technique allowing continuous measurement of PWV in conscious, unrestrained rats. Studies were performed in spontaneously hypertensive rats (SHR) treated for 2 weeks with N-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor (SHR-LN). BPV was evaluated conventionally or with a new device composed of two pressure transducers in two different sets of rats. This allowed a continuous monitoring of telemetered PWV, systolic (SPV), diastolic (DPV), and pulse pressure variability (PPV). Aortic structure was then characterized by immunohistochemical analysis.

Results: SPV, DPV, and PPV were increased in SHR-LN, when calculated by 24-h SD or using average real variability a parameter used to assess short-term variability in man. We observed rapid and simultaneous increases in BP, SPV, and PWV. Interestingly, PPV was the most increased parameter resulting mainly from different time course of SPV and DPV. Structural alterations of the aortic wall were observed, with a eutrophic inward remodeling and accumulation of fibronectin and its two main receptors (α5 and αv integrins).

Conclusion: This offers unequivocal evidence of a significant relationship between PWV, BPV, and arterial structure.
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http://dx.doi.org/10.1097/HJH.0000000000000838DOI Listing
April 2016

Seminal vesicle metastasis of cutaneous malignant melanoma: An unusual and challenging presentation.

Can Urol Assoc J 2015 Mar-Apr;9(3-4):E220-3

Department of Urology, Hopital Saint Joseph, Paris, France;

Malignant melanoma is a tumour, which usually involves skin melanocytes. Involvement of the male genitourinary (GU) system by melanoma is an uncommon and challenging diagnosis. We report the first case of seminal vesicle metastasis from a primary cutaneous melanoma in a 58-year-old man, with hemospermia as the only clinical sign. This case highlights the role of multiparametric magnetic resonance imaging, as a more sensitive assessment to early detect metastatic melanoma in the GU system. The patient underwent a robot-assisted laparoscopic bilateral seminal vesiculectomy, which had good functional and oncological results and is still in complete remission at the 1-year follow-up.
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http://dx.doi.org/10.5489/cuaj.2172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455645PMC
June 2015

Pancreatic adenocarcinoma: MRI conspicuity and pathologic correlations.

Abdom Imaging 2015 Jan;40(1):85-94

Radiology Department, Fondation Hôpital Saint-Joseph, 185 rue Raymond Losserand, 75014, Paris, France,

Purpose: To identify the MRI sequences producing the greatest pancreatic adenocarcinoma conspicuity and to assess correlations linking MRI signal intensity and apparent diffusion coefficient to histopathological findings.

Methods: We retrospectively included 22 patients with pancreatic adenocarcinoma who underwent MRI (1.5 or 3 T) before surgical resection. Fat-suppressed (FS) T1- and T2-weighted sequences; 3D FS dynamic T1-weighted gadolinium-enhanced gradient-echo (GRE) imaging at the arterial, portal, and delayed phases; and diffusion-weighted imaging (DWI) with b values of 600-800 s/mm(2) were reviewed. On each sequence, we assessed tumor conspicuity both qualitatively (3-point scale) and quantitatively (tumor-to-proximal and -distal pancreas contrast ratios), and we performed paired Wilcoxon tests to compare these data across sequences. We evaluated correlations between histopathological characteristics and MRI features.

Results: 21/22 (95%) tumors were hypointense by 3D FS T1 GRE arterial phase imaging, which produced the greatest tumor conspicuity (p ≤ 0.02). By DWI, 5/20 (25%) of tumors were isointense. The correlation between size by histology and MRI was strongest with DWI. A progressive enhancement pattern was associated with extensive and dense fibrous stroma (p ≤ 0.03).

Conclusions: 3D FS T1 GRE arterial phase imaging produces greater pancreatic adenocarcinoma conspicuity compared to DWI but underestimates tumor size. DWI provides the best size evaluation but fails to delineate the tumor in one-fourth of cases.
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http://dx.doi.org/10.1007/s00261-014-0196-8DOI Listing
January 2015

Increased stiffness and cell-matrix interactions of abdominal aorta in two experimental nonhypertensive models: long-term chemically sympathectomized and sinoaortic denervated rats.

J Hypertens 2014 Mar;32(3):652-8

aINSERM, U955, Créteil bINSERM, U1116, Nancy cDiagnosis Center and Université René Descartes, Hôtel-Dieu Hospital, UFR Médecine, Paris, France dDepartment of Anatomy and Developmental Biology, University College London, London, UK eDepartment of Pathology, Groupe Hospitalier Paris Saint-Joseph fUPMC Univ Paris 06 gCNRS UMR 7190 hDepartment of Pharmacy, Groupe Hospitalier Paris Saint-Joseph, Paris, France *P.C. and Y.B. contributed equally to the writing of the article.

Rationale: Sinoaortic denervated (SAD) and chemically sympathectomized (SNX) rats are characterized by a decrease in arterial distensibility without hypertension and would, thus, be relevant for analyzing arterial wall stiffening independently of blood pressure level. The fibronectin network, which plays a pivotal role in cell-matrix interactions, is a major determinant of arterial stiffness. We hypothesized that in SAD and SNX rats, arterial stiffness is increased, due to alterations of cell-matrix anchoring leading to spatial reorganization of the extracellular matrix.

Methods: The intrinsic elastic properties of the arterial wall were evaluated in vivo by the relationship between incremental elastic modulus determined by echotracking and circumferential wall stress. The changes of cell-extracellular matrix links in the abdominal aorta were evaluated by studying fibronectin, vascular integrin receptors, and ultrastructural features of the aorta by immunochemistry.

Results: In both experimental conditions, wall stiffness increased, associated with different modifications of cell-extracellular matrix adhesion. In SAD rats, increased media cross-sectional area was coupled with an increase of muscle cell attachments to its extracellular matrix via fibronectin and its α5-β1 integrin. In SNX rats, reduced media cross-sectional area was associated with upregulation of αv-β3 integrin and more extensive connections between dense bands and elastic fibers despite the disruption of the elastic lamellae.

Conclusion: In aorta of SNX and SAD rats, a similar arterial stiffness is associated to different structural alterations. An increase in αvβ3 or α5β1 integrins together with the already reported increase in the proportion of less distensible (collagen) to more distensible (elastin) components in both models contributes to remodeling and stiffening of the abdominal aorta.
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http://dx.doi.org/10.1097/HJH.0000000000000073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097123PMC
March 2014

A case of adrenal metastasis in seminoma.

Case Rep Urol 2013 21;2013:495743. Epub 2013 Aug 21.

Department of Urology, Paris Saint Joseph Hospital Group, 185 Rue Raymond Losserand, 75014 Paris, France.

We report an uncommon case of testicular cancer with adrenal metastasis without retroperitoneal or distant metastatic disease. This situation is highly unusual. In fact, no similar case was reported in the literature. Our case is the first adrenalectomy that has been performed for secondary localization of testicular cancer. After eighteen-month followup, the patient was doing well, with no evidence of disease.
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http://dx.doi.org/10.1155/2013/495743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763588PMC
September 2013

[Diagnostic issues of prostate biopsies. Case 2. Atypical adenomatous hyperplasia (adenosis)].

Ann Pathol 2012 Apr 23;32(2):114-7. Epub 2012 Mar 23.

Service de pathologie, hôpital Saint-Joseph, Paris, France.

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http://dx.doi.org/10.1016/j.annpat.2012.02.003DOI Listing
April 2012

[Diagnostic issues of prostate biopsies. Case 1. Limited adenocarcinoma].

Ann Pathol 2012 Apr 29;32(2):107-13. Epub 2012 Mar 29.

Service de pathologie, hôpital Saint-Joseph, Paris, France.

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http://dx.doi.org/10.1016/j.annpat.2012.02.013DOI Listing
April 2012

Prolonged cholestasis and ductopenia associated with tenoxicam.

J Hepatol 2003 Jul;39(1):125-8

Department of Pathology, Beaujon Hospital, 100 Boulevard du Général Leclerc, 92118 Clichy Cedex, France.

Cholestatic liver diseases leading to progressive destruction of intra-hepatic bile ducts and ductopenia encompass multiple etiologies. Pathophysiology and natural history of drug-induced cholangiopathies remain unclear. We report a case of prolonged ductopenia attributed to Tenoxicam (Tilcotil o--a non-steroidal anti-inflammatory drug of the oxicam family) ingested at therapeutic dose. A 36 year-old male patient was admitted for jaundice and Lyell syndrome starting 1 week after the ingestion of Tenoxicam. Liver biopsy showed cholestasis, non-suppurative cholangitis and polymorphous inflammatory infiltrate of the portal tracts (round cells, macrophages an eosinophils). Treatment with ursodesoxycholic acid and cholestyramine was instituted and the patient was asymptomatic 1 year after. Three years later mild biological cholestasis persisted and ductopenia was evidenced on liver biopsy. In this report we found that: (1) The toxicity of tenoxicam was probably mediated by an immunoallergic mechanism (Lyell syndrome and eosinophils on histology); (2) ductopenia was secondary to inflammatory cholangitis. Factors responsible for this chronic evolution are still unknown (genetic predisposition, vascular factors, etc.); and (3) the presence of ductopenia contrasted with the "clinical recovery" of the disease suggesting accessory bile drainage by cholangioles or partial reconstruction of the biliary tree.
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http://dx.doi.org/10.1016/s0168-8278(03)00081-3DOI Listing
July 2003

Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis.

J Exp Med 2002 Jul;196(1):77-85

Section on Immunology and Immunogenetics, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

In spontaneous inflammatory arthritis of K/BxN T cell receptor transgenic mice, the effector phase of the disease is provoked by binding of immunoglobulins (Igs) to joint surfaces. Inflammatory cytokines are known to be involved in human inflammatory arthritis, in particular rheumatoid arthritis, although, overall, the pathogenetic mechanisms of the human affliction remain unclear. To explore the analogy between the K/BxN model and human patients, we assessed the role and relative importance of inflammatory cytokines in K/BxN joint inflammation by transferring arthritogenic serum into a panel of genetically deficient recipients. Interleukin (IL)-1 proved absolutely necessary. Tumor necrosis factor (TNF)-alpha was also required, although seemingly less critically than IL-1, because a proportion of TNF-alpha-deficient mice developed robust disease. There was no evidence for an important role for IL-6. Bone destruction and reconstruction were also examined. We found that all mice with strong inflammation exhibited the bone erosion and reconstruction phenomena typical of K/BxN arthritis, with no evidence of any particular requirement for TNFalpha for bone destruction. The variability in the requirement for TNF-alpha, reminiscent of that observed in treated rheumatoid arthritis patients, did not appear genetically programmed but related instead to subtle environmental changes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194010PMC
http://dx.doi.org/10.1084/jem.20020439DOI Listing
July 2002

Arthritogenic monoclonal antibodies from K/BxN mice.

J Exp Med 2002 Apr;195(8):1071-7

Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), 67000 Strasbourg, France.

Arthritis in the K/BxN mouse model is provoked by pathogenic antibodies (Abs) directed against a ubiquitously expressed protein, glucose-6-phosphate isomerase (GPI). To begin dissecting the repertoire of arthritogenic immunoglobulins (Igs) in the K/BxN model, and to provide a basis for comparison with RA patients we have generated anti-GPI monoclonal Abs (mAbs) from spontaneously activated B cells in the lymphoid organs of arthritic mice. B cell clones with anti-GPI specificities were present at extraordinarily high frequencies in the spleen, and less frequently in other lymphoid organs and in the synovial fluid. None of the anti-GPI mAbs induced arthritis when injected individually into healthy recipients, but most were effective when combined in pairs or larger pools. Arthritogenic combinations depended on mAbs of the IgG1 isotype, which bound to GPI with Kd in the 10(-9) M range, with no indication of cooperative binding between complementing pairs. Pathogenicity was not associated with recognition of a particular epitope, but the ability to form mAb/GPI multimers by simultaneous recognition of different epitopes was clearly required, consistent with the known role of complement and FcRs in this model. Sequence analysis revealed structural similarities amongst the mAbs, indicating that a particular subset of B cells may evade tolerance in K/BxN mice, and that affinity maturation by somatic mutation likely takes place. These results confirm that GPI itself, rather than a cross-reactive molecule, is the target of pathogenic Igs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193697PMC
http://dx.doi.org/10.1084/jem.20011941DOI Listing
April 2002

Arthritis critically dependent on innate immune system players.

Immunity 2002 Feb;16(2):157-68

Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA 02215, USA.

K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, similar to rheumatoid arthritis. Disease in these animals is focused specifically on the joints but stems from autoreactivity to a ubiquitously expressed antigen, glucose-6-phosphate isomerase (GPI). T and B cells are both required for disease initiation, but anti-GPI immunoglobulins (Igs), alone, can induce arthritis in lymphocyte-deficient recipients. Here, we show that the arthritogenic Igs act through both Fc receptors (in particular, FcgammaRIII) and the complement network (C5a). Surprisingly, the alternative pathway of complement activation is critical, while classical pathway components are entirely dispensable. We suggest that autoimmune disease, even one that is organ specific, can occur when mobilization of an adaptive immune response results in runaway activation of the innate response.
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http://dx.doi.org/10.1016/s1074-7613(02)00275-3DOI Listing
February 2002