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1.
Genes (Basel) ; 13(10)2022 Sep 24.
Article in English | MEDLINE | ID: mdl-36292599

ABSTRACT

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family involved in various diseases including brain inflammatory pathologies such as multiple sclerosis. It has been demonstrated that TWEAK can induce cerebrovascular permeability in an in vitro model of the blood-brain barrier. The molecular mechanisms playing a role in TWEAK versus TNFα signaling on cerebral microvascular endothelial cells are not well defined. Therefore, we aimed to identify gene expression changes in cultures of human brain microvascular endothelial cells (hCMEC/D3) to address changes initiated by TWEAK exposure. Taken together, our studies highlighted that gene involved in leukocyte extravasation, notably claudin-5, were differentially modulated by TWEAK and TNFα. We identified differential gene expression of hCMEC/D3 cells at three timepoints following TWEAK versus TNFα stimulation and also found distinct modulations of several canonical pathways including the actin cytoskeleton, vascular endothelial growth factor (VEGF), Rho family GTPases, and phosphatase and tensin homolog (PTEN) pathways. To our knowledge, this is the first study to interrogate and compare the effects of TWEAK versus TNFα on gene expression in brain microvascular endothelial cells.


Subject(s)
Multiple Sclerosis , Tumor Necrosis Factor-alpha , Humans , Brain , Claudin-5 , Cytokines , Endothelial Cells , GTP Phosphohydrolases , Ligands , Multiple Sclerosis/genetics , Phosphoric Monoester Hydrolases , Tensins , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/pharmacology , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
3.
Int J Mol Sci ; 21(23)2020 Nov 30.
Article in English | MEDLINE | ID: mdl-33266021

ABSTRACT

There is increasing evidence that deregulation of metals contributes to a vast range of neurodegenerative diseases including multiple sclerosis (MS). MS is a chronic inflammatory disease of the central nervous system (CNS) manifesting disability and neurological symptoms. The precise origin of MS is unknown, but the disease is characterized by focal inflammatory lesions in the CNS associated with an autoimmune reaction against myelin. The treatment of this disease has mainly been based on the prescription of immunosuppressive and immune-modulating agents. However, the rate of progressive disability and early mortality is still worrisome. Metals may represent new diagnostic and predictive markers of severity and disability as well as innovative candidate drug targets for future therapies. In this review, we describe the recent advances in our understanding on the role of metals in brain disorders of neurodegenerative diseases and MS patients.


Subject(s)
Brain/pathology , Metals/metabolism , Multiple Sclerosis/metabolism , Neurodegenerative Diseases/metabolism , Animals , Homeostasis , Humans , Inflammation/pathology
4.
Cytokine ; 126: 154859, 2020 02.
Article in English | MEDLINE | ID: mdl-31629989

ABSTRACT

BACKGROUND: There are many studies presenting data of biologics and several ELISA kits commercially available for monitoring infliximab serum trough levels (s-IFXt) and anti-drug antibodies (ADAb). We propose to compare technical characteristics and results of three different assays on a cohort of 35 patients under infliximab (IFX) and suffering from inflammatory bowel disease (IBD). PATIENTS AND METHODS: s-IFXt and ADAb were systematically measured with three ELISA kits: Lisa-Tracker® Duo infliximab (Theradiag®), Ridascreen® IFX Monitoring (R-Biopharm AG®) and Promonitor® IFX (Progenika Biopharma SA®). RESULTS: The main technical features that differed between kits for measuring s-IFXt were: (i) TNF coating, (ii) immune complexes revelation strategy and/or (iii) interference with other anti-TNFα agents. For kits measuring ADAb, they were revelation steps and unit of results. There was an excellent mathematical correlation of s-IFXt between assays however Bland-Altman analysis denoted (i) s-IFXt were on average 48 to 69% higher in Ridascreen® than in the other two assays, and (ii) elevated s-IFXt were higher with Promonitor® compared to Lisa-Tracker®. As a consequence, there were some substantial discrepancies between assays for classification of s-IFXt into concentration ranges. Despite unstandardized units, pairwise qualitative comparison showed a perfect agreement between the three pairs of ADAb assays. CONCLUSION: Our data show that the evaluated assays are not quantitatively interchangeable due to substantial variations in some results that could lead, for some patients, to divergent therapeutic decisions. We remind to be cautious when comparing study results issued from different kits and recommend using the same assay for the longitudinal follow-up of IBD patients.


Subject(s)
Enzyme-Linked Immunosorbent Assay/methods , Inflammatory Bowel Diseases/drug therapy , Infliximab/immunology , Infliximab/therapeutic use , Adolescent , Adult , Aged , Cohort Studies , Female , Humans , Infliximab/blood , Male , Middle Aged , Tumor Necrosis Factor-alpha
5.
J Transl Med ; 17(1): 51, 2019 02 20.
Article in English | MEDLINE | ID: mdl-30786899

ABSTRACT

BACKGROUND: Inflammation and demyelination are the main processes in multiple sclerosis. Nevertheless, to date, blood biomarkers of inflammation are lacking. TWEAK, a transmembrane protein that belongs to the TNF ligand family, has been previously identified as a potential candidate. METHODS: Twenty-eight patients (9 males, 19 females) were prospectively included after a first clinical episode suggestive of multiple sclerosis and clinically followed during 3 years. Fifty-seven healthy controls were also included. TWEAK serum levels and MRI exams including magnetization transfer imaging were performed at baseline, 6- and 12-month follow-up. RESULTS: TWEAK serum levels were significantly increased in the patient group (mean baseline = 1086 ± 493 pg/mL, mean M6 = 624 ± 302 pg/mL and mean M12 = 578 ± 245 pg/mL) compared to healthy controls (mean = 467 ± 177 pg/mL; respectively p < 0.0001, 0.01 and 0.06). Serum levels of soluble TWEAK were significantly increased during relapses, compared to time periods without any relapse (respectively 935 ± 489 pg/mL and 611 ± 292 pg/mL, p = 0.0005). Moreover, patients presenting at least one gadolinium-enhanced CNS lesion at baseline (n = 7) displayed significantly increased serum TWEAK levels in comparison with patients without any gadolinium-enhanced lesion at baseline (n = 21) (respectively 1421 ± 657 pg/mL vs 975 ± 382 pg/mL; p = 0.02). Finally, no correlation was evidenced between TWEAK serum levels and the extent of brain tissue damage assessed by magnetization transfer ratio. CONCLUSIONS: The present study showed that TWEAK serum levels are increased in MS patients, in relation to the disease activity. This simple and reproducible serum test could be used as a marker of ongoing inflammation, contributing in the follow-up and the care of MS patients. Thus, TWEAK is a promising serum marker of the best window to perform brain MRI, optimizing the disease control in patients.


Subject(s)
Cytokine TWEAK/blood , Inflammation/blood , Multiple Sclerosis/blood , Nervous System/pathology , Adult , Female , Gadolinium/chemistry , Humans , Magnetic Resonance Imaging , Male , Multiple Sclerosis/diagnostic imaging , Nervous System/diagnostic imaging , Recurrence , Solubility
6.
Sci Rep ; 8(1): 5146, 2018 03 23.
Article in English | MEDLINE | ID: mdl-29572472

ABSTRACT

In both multiple sclerosis and its model experimental autoimmune encephalomyelitis (EAE), the extent of resident microglia activation and infiltration of monocyte-derived cells to the CNS is positively correlated to tissue damage. To address the phenotype characterization of different cell subsets, their spatio-temporal distributions and contributions to disease development we induced EAE in Thy1-CFP//LysM-EGFP//CD11c-EYFP reporter mice. We combined high content flow cytometry, immunofluorescence and two-photon imaging in live mice and identified a stepwise program of inflammatory cells accumulation. First on day 10 after induction, EGFP+ neutrophils and monocytes invade the spinal cord parenchyma through the meninges rather than by extravasion. This event occurs just before axonal losses in the white matter. Once in the parenchyma, monocytes mature into EGFP+/EYFP+ monocyte-derived dendritic cells (moDCs) whose density is maximal on day 17 when the axonal degradation and clinical signs stabilize. Meanwhile, microglia is progressively activated in the grey matter and subsequently recruited to plaques to phagocyte axon debris. LysM-EGFP//CD11c-EYFP mice appear as a powerful tool to differentiate moDCs from macrophages and to study the dynamics of immune cell maturation and phenotypic evolution in EAE.


Subject(s)
Dendritic Cells/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Immunity, Innate , Leukocytes/immunology , Microglia/immunology , Spinal Cord/immunology , Animals , Dendritic Cells/pathology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/pathology , Leukocytes/pathology , Mice , Mice, Transgenic , Microglia/pathology , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Spinal Cord/pathology
7.
Front Immunol ; 8: 1534, 2017.
Article in English | MEDLINE | ID: mdl-29201025

ABSTRACT

Observed in many central nervous system diseases, neuroinflammation (NI) proceeds from peripheral immune cell infiltration into the parenchyma, from cytokine secretion and from oxidative stress. Astrocytes and microglia also get activated and proliferate. NI manifestations and consequences depend on its context and on the acute or chronic aspect of the disease. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 pathway has been involved in chronic human inflammatory pathologies such as neurodegenerative, autoimmune, or malignant diseases. New data now describe its regulatory effects in tissues or fluids from patients with neurological diseases. In this mini-review, we aim to highlight the role of TWEAK/Fn14 in modulating NI in multiple sclerosis, neuropsychiatric systemic lupus erythematosus, stroke, or glioma. TWEAK/Fn14 can modulate NI by activating canonical and non-canonical nuclear factor-κB pathways but also by stimulating mitogen-activated protein kinase signaling. These downstream activations are associated with (i) inflammatory cytokine, chemokine and adhesion molecule expression or release, involved in NI propagation, (ii) matrix-metalloproteinase 9 secretion, implicated in blood-brain barrier disruption and tissue remodeling, (iii) astrogliosis and microgliosis, and (iv) migration of tumor cells in glioma. In addition, we report several animal and human studies pointing to TWEAK as an attractive therapeutic target.

8.
Immunol Res ; 64(5-6): 1243-1246, 2016 12.
Article in English | MEDLINE | ID: mdl-27618831

ABSTRACT

We report here the case of a 50-years-old man treated for mixed connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein (U1RNP) antibodies who secondarily developed a granulomatosis with polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of the association between anti-U1RNP and anti-PR3-ANCA antibodies by a systematic retrospective study in ten European hospitals. Overall, out of 11,921 samples analyzed for both auto-antibodies, 18 cases of anti-U1RNP and anti-PR3-ANCA double positivity were found and only one patient presented with both MCTD and GPA symptoms. Our retrospective analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double positivity is infrequent and very rarely associated with both MTCD and GPA. Our observation describes for the first time the coexistence of MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP and ANCA antibodies was rarely reported in the literature. Eleven cases of MCTD and ANCA vasculitis have been reported to date, with only two cases with anti-PR3-ANCA association, and only one vasculitis. The seven other cases reported in the literature presented with an association of MCTD and microscopic polyangiitis which appears to be a more frequent presentation than MTCD associated with GPA.


Subject(s)
Autoantibodies/blood , Granulomatosis with Polyangiitis/epidemiology , Mixed Connective Tissue Disease/epidemiology , Myeloblastin/immunology , Ribonucleoproteins, Small Nuclear/immunology , Asthenia , Europe/epidemiology , Granulomatosis with Polyangiitis/complications , Granulomatosis with Polyangiitis/diagnosis , Hospitals , Humans , IgA Vasculitis , Male , Mass Screening , Middle Aged , Mixed Connective Tissue Disease/complications , Mixed Connective Tissue Disease/diagnosis , Prevalence , Weight Loss
9.
J Transl Med ; 14(1): 185, 2016 06 23.
Article in English | MEDLINE | ID: mdl-27338143

ABSTRACT

BACKGROUND: TNF weakly inducer of apoptosis (TWEAK) is member of the TNF ligand superfamily. Various data support that TWEAK produced by synovial macrophages may contribute to synovitis observed in psoriatic arthritis (PsoA). In PsoA, anti-TNF therapy has been successful in agreement with the key role of TNF in the pathogenesis and the generation by PsoA patients of anti-TNF autoantibodies referred as "beneficial autoimmunity to pro-inflammatory mediators". However, the role of TNF-alpha in the regulation of TWEAK modulation of inflammation during PsoA remains unknown. METHODS: We have studied level course during anti-TNF therapy of serum soluble TWEAK. In the same cohort, we have investigated the generation of TWEAK-binding autoantibodies by PsoA patients before and after anti-TNF therapy. RESULTS: Patients with PsoA had significantly higher serum levels of TWEAK compared with controls [respective means (±SEM) were 645 pg/ml (64) and 467 pg/ml (23); (p = 0.006)] but serum soluble TWEAK levels were not correlated with BASDAI (Spearman's coefficients <0.003, p > 0.05). Our study showed that soluble TWEAK levels were not modulated by etanercept therapy [respective Means (±SEM) were 605 (95) (week 12) and 744 (97) (week 24) pg/ml; (p > 0.23)]. Anti-TWEAK autoantibodies were detected in 9/13 (69.2 %) PsoA patients at inclusion and only in 3/57 (5.3 %) healthy blood donors (p < 0.0001). These circulating antibodies were persistent in PsoA patients and detected at similar levels during etanercept therapy. Moreover we showed that they had a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. CONCLUSION: Our study revealed that during psoriatic arthritis (1) serum TWEAK was up regulated and (2) TWEAK-binding autoantibodies are generated. Both parameters were not influenced by anti-TNF therapy and persisted at high levels during anti-TNF therapy. For the first time we described here TWEAK-binding IgG autoantibodies with a down regulating effect on CCL-2 secretion by endothelial cells stimulated by rh TWEAK in vitro. Finally, our results suggest that TWEAK may be involved in PsoA pathogeny. Trial registration This clinical trial was approved by the local Ethics Committee "Comité de Protection des Personnes Sud-Méditerranée V" with the registration number: 2011-002954-29, and French health minister registration number AFSSAPS A110784-42 obtained the 08/22/2011. This clinical trial is registered in Clinical trial.gov under the number: NCT02164214.


Subject(s)
Arthritis, Psoriatic/drug therapy , Arthritis, Psoriatic/immunology , Autoantibodies/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factors/metabolism , Adult , Aged , Arthritis, Psoriatic/blood , Autoantibodies/blood , Chemokine CCL2/metabolism , Cohort Studies , Cytokine TWEAK , Down-Regulation , Endothelial Cells/metabolism , Female , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Male , Middle Aged , Protein Binding , Tumor Necrosis Factors/blood
10.
Immunol Res ; 64(3): 677-86, 2016 06.
Article in English | MEDLINE | ID: mdl-26744256

ABSTRACT

Anti-signal recognition particle (SRP) antibodies are important serological markers for the diagnosis and the prognosis of idiopathic inflammatory myopathy (IIM), especially to distinguish immune-mediated necrotizing myopathy (IMNM). This study was set up to investigate the phenotype associated with anti-SRP antibodies and to evaluate the methods for detecting these antibodies. Clinical and biological data were retrospectively obtained from 60 adult patients with anti-SRP antibodies detected by a dot immunoassay from 12 centers. Thirty-six (60 %) out of these 60 patients suffered from an IIM, and among them, 21 patients were diagnosed as IMNM. Among patients with a definite IIM, proximal weakness and myalgia were prominent symptoms at the time of diagnosis. Only few patients displayed severe extra-muscular symptoms such as cardiac involvement or severe myositis. Mean creatine kinase levels were high for all patients except for two of them. When testing by indirect immunofluorescence (IIF) on HEp2 cells, the fraction of patients displaying the typical anti-SRP fine speckled staining of the cytoplasm was higher in patients with IIM (30/36) (83 %) than in patients with non-IIM (3/24) (12.5 %) (p < 0.0001). Thirty (91 %) out of 33 patients with a positive immunodot and a characteristic IIF cytoplasmic staining suffered from a clinical definite myositis, whereas only 6 (22 %) out of 27 patients with a positive immunodot but a negative cytoplasmic pattern suffered from a myositis (p < 0.00001). This series highlights the strong heterogeneity of anti-SRP positivity that encompassed IMNM and non-IMNM and supports the necessity of considering both IIF and dot immunoassay to confirm the diagnosis of anti-SRP-associated myositis.


Subject(s)
Autoantibodies/metabolism , Myositis/diagnosis , Adult , Aged , Cell Line, Tumor , Female , Fluorescent Antibody Technique, Indirect , Humans , Immunoblotting , Male , Middle Aged , Myalgia , Myositis/immunology , Necrosis , Retrospective Studies , Signal Recognition Particle/immunology
11.
Immunol Res ; 64(2): 455-60, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26350265

ABSTRACT

Autoantibodies are a common feature of rheumatoid arthritis (RA), and their detection is used as a diagnostic tool in medical practice. Rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) detection in patients' sera are now included in 2010 ACR/EULAR criteria for RA diagnosis. In this study, we evaluated a new vimentin-derived ACPA ELISA, the anti-cyclic citrullinated peptide high sensitive (CCP hs) test, and we compared its performance with the RF IgM and anti-CCP3 tests on a French multicenter cohort of 84 RA patients, 107 non-RA patients and 100 healthy controls. Sensitivities for RA diagnosis were 71.4, 84.5 and 64.3 % and specificities were 88.4, 86.9 and 87.3 % for CCP hs, CCP3 and RF IgM, respectively. There was a moderate correlation between CCP hs and CCP3 titers (Pearson's r = 0.43; p < 0.0001). These results support the contention that anti-CCP hs antibodies are new reliable ACPA with high specificity for RA.


Subject(s)
Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/immunology , Autoantibodies/immunology , Peptides, Cyclic/immunology , Adult , Aged , Autoantibodies/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , ROC Curve , Sensitivity and Specificity
13.
PLoS One ; 8(11): e80433, 2013.
Article in English | MEDLINE | ID: mdl-24303014

ABSTRACT

Antibodies against Saccharomyces cerevisiae (ASCA) and Escherichia coli outer membrane porin C (anti-OmpC) are known to be detectable in the serum of patients with Crohn's disease (CD) but display a very poor sensitivity for the disease especially in forms with isolated colonic involvement. In this study we aimed at evaluating performances of these markers in supernatant of cultured colonic biopsies. Patients with colonic CD (n =  67), ulcerative colitis (UC) (n = 35) and control individuals (n = 37) were prospectively recruited for colonoscopy pinch biopsies and blood sampling. Serum and supernatant of culture tissues were analyzed for ASCA and anti-OmpC. Direct immunofluorescence was also performed on colonic tissues for total IgA detection. We detected for the first time ASCA IgA/IgG and anti-OmpC IgA in cultured colonic tissue supernatants. For both markers, sensitivities for diagnosing CD were better in supernatants (ASCA: 53.7%, anti-OmpC: 28.4%) than in serum (ASCA: 31.3%, anti-OmpC: 22.4%). Combination of results from a panel of these tests gave the greatest sensitivity ever described for CD diagnosis in colonic forms (70.2%). In this study, we described, for the first time, ASCA in supernatant of colonic tissue cultures. This assaying approach in CD diagnosis should be taken into consideration in the future especially in CD forms with isolated colonic involvement.


Subject(s)
Antibodies, Fungal/immunology , Crohn Disease/immunology , Crohn Disease/microbiology , Saccharomyces cerevisiae/immunology , Adolescent , Adult , Aged , Antibodies, Bacterial/blood , Antibodies, Bacterial/immunology , Antibodies, Fungal/blood , Biomarkers/blood , Colitis, Ulcerative/immunology , Colitis, Ulcerative/microbiology , Crohn Disease/diagnosis , Culture Media, Conditioned , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Middle Aged , Porins/immunology , Reproducibility of Results , Sensitivity and Specificity , Tissue Culture Techniques , Young Adult
14.
J Neuroinflammation ; 10: 9, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23320797

ABSTRACT

BACKGROUND: The TNF ligand family member TWEAK exists as membrane and soluble forms and is involved in the regulation of various human inflammatory pathologies, through binding to its main receptor, Fn14. We have shown that the soluble form of TWEAK has a pro-neuroinflammatory effect in an animal model of multiple sclerosis and we further demonstrated that blocking TWEAK activity during the recruitment phase of immune cells across the blood brain barrier (BBB) was protective in this model. It is now well established that endothelial cells in the periphery and astrocytes in the central nervous system (CNS) are targets of TWEAK. Moreover, it has been shown by others that, when injected into mice brains, TWEAK disrupts the architecture of the BBB and induces expression of matrix metalloproteinase-9 (MMP-9) in the brain. Nevertheless, the mechanisms involved in such conditions are complex and remain to be explored, especially because there is a lack of data concerning the TWEAK/Fn14 pathway in microvascular cerebral endothelial cells. METHODS: In this study, we used human cerebral microvascular endothelial cell (HCMEC) cultures as an in vitro model of the BBB to study the effects of soluble TWEAK on the properties and the integrity of the BBB model. RESULTS: We showed that soluble TWEAK induces an inflammatory profile on HCMECs, especially by promoting secretion of cytokines, by modulating production and activation of MMP-9, and by expression of cell adhesion molecules. We also demonstrated that these effects of TWEAK are associated with increased permeability of the HCMEC monolayer in the in vitro BBB model. CONCLUSIONS: Taken together, the data suggest a role for soluble TWEAK in BBB inflammation and in the promotion of BBB interactions with immune cells. These results support the contention that the TWEAK/Fn14 pathway could contribute at least to the endothelial steps of neuroinflammation.


Subject(s)
Blood-Brain Barrier/physiology , Endothelium, Vascular/physiology , Human Umbilical Vein Endothelial Cells/physiology , Models, Neurological , Receptors, Tumor Necrosis Factor/physiology , Tumor Necrosis Factors/physiology , Blood-Brain Barrier/pathology , Cell Line, Tumor , Cell Survival/physiology , Cytokine TWEAK , Endothelium, Vascular/pathology , Human Umbilical Vein Endothelial Cells/pathology , Humans , Signal Transduction/physiology , TWEAK Receptor
15.
Front Immunol ; 4: 489, 2013 Dec 27.
Article in English | MEDLINE | ID: mdl-24409182

ABSTRACT

The TWEAK/Fn14 pathway is now well-known for its involvement in the modulation of inflammation in various human autoimmune/chronic inflammatory diseases (AICID) including lupus, rheumatoid arthritis, and multiple sclerosis. A panel of data is now available concerning TWEAK expression in tissues or biological fluids of patients suffering from AICID, suggesting that it could be a promising biological marker in these diseases. Evidences from several teams support the hypothesis that blocking TWEAK/Fn14 pathway is an attractive new therapeutic lead in such diseases and clinical trials with anti-TWEAK-blocking antibodies are in progress. In this mini-review we discuss the potential use of TWEAK quantification in AICD management in routine practice and highlight the challenge of standardizing data collection to better estimate the clinical utility of such a biological parameter.

16.
Clin Res Hepatol Gastroenterol ; 36(4): e57-9, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22883833

ABSTRACT

In an 8-year-old boy with biochemical hepatic disorders, an histological examination of a liver biopsy showed a severe chronic hepatitis without cirrhosis. The biliary tract was normal and no toxic or infectious etiologies were found. Spontaneous improvement of the clinical status was observed in the following weeks but biochemical abnormalities were persistent and a second episode occurred 3 years after. Immunological studies showed anti-mitochondrial-2 antibodies (AMA-2) confirmed by an immunoblot performed with rat mitochondrial proteins resolved by two-dimensional electrophoresis. We described here the second case in the literature of paediatric autoimmune hepatitis associated with well documented AMA-2.


Subject(s)
Autoantibodies/blood , Hepatitis, Autoimmune/blood , Hepatitis, Autoimmune/immunology , Mitochondrial Proteins/immunology , Biomarkers/blood , Child , Hepatitis, Autoimmune/diagnosis , Humans , Male
17.
Autoimmunity ; 42(1): 63-8, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19127456

ABSTRACT

BACKGROUND: Antibodies for double-stranded DNA (anti-dsDNA) and chromatin represent specific markers of systemic lupus erythematosus (SLE). AIMS: (1) To evaluate the analytical performance of a multiplexed bead assay (BioPlex 2200) for the simultaneous detection of anti-dsDNA and anti-chromatin antibodies, (2) to compare the results for anti-dsDNA with those obtained using Farr assay, and (3) to analyze the clinical relevance of these antibodies when applied to the follow-up of SLE patients with active nephritis. PATIENTS AND METHODS: Hundred and five clinically characterized SLE patients and 96 healthy blood donors sera were analyzed by BioPlex 2200. RESULTS: Prevalence of these antibodies was significantly higher (p < 0.0001) in SLE patients than in controls (68 and 70% for anti-dsDNA and anti-chromatin, vs. 1% for both anti-dsDNA and anti-chromatin, respectively). If you consider a sample positive if either anti-dsDNA and/or anti-chromatin is positive, then the prevalence of these antibodies reached 78% (82/105) in SLE patients. For anti-dsDNA measurements, the kappa coefficient was 0.59 between BioPlex 2200 and Farr assay. Comparison between SLE patients with and without nephritis in a follow-up study showed that patients with active nephritis were associated with an increase of anti-dsDNA and anti-chromatin levels and a reduction of CH50, whereas no variation of antibody levels was observed in SLE patients without nephritis. CONCLUSION: Our results demonstrated a benefit of simultaneously measuring anti-dsDNA and anti-chromatin in SLE patients. The BioPlex 2200 achieved good analytical performances and proved to be a useful method for monitoring and diagnosing SLE.


Subject(s)
Antibodies, Antinuclear/blood , Autoantibodies/blood , Chromatin/immunology , DNA/immunology , Lupus Erythematosus, Systemic/diagnosis , Reagent Kits, Diagnostic , Adult , Autoimmune Diseases/diagnosis , Autoimmune Diseases/immunology , Cell Line , Female , Fluorescent Antibody Technique, Indirect , Humans , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/immunology , Lupus Nephritis/diagnosis , Lupus Nephritis/immunology , Male , Microspheres , Middle Aged , Radioimmunoprecipitation Assay
18.
J Leukoc Biol ; 85(1): 132-5, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18945822

ABSTRACT

The TNF superfamily ligand, TNF-like weak inducer of apoptosis (TWEAK), regulates cellular responses ranging from proliferation to cell death in a manner highly dependent on the cell type and the microenvironmental context. We have shown previously that treatment of experimental autoimmune encephalomyelitis mice after the priming phase with neutralizing anti-TWEAK antibodies results in a reduction in the severity of the disease and leukocyte infiltration. To further characterize TWEAK/fibroblast growth factor-inducible 14-kDa protein (Fn14) involvement during multiple sclerosis (MS), we evaluated in MS patients and controls: TWEAK and Fn14 expression on PBMC and soluble TWEAK concentration in serum and cerebrospinal fluid (CSF). Thirty-six consecutive patients were enrolled, including 11 patients with relapsing-remitting MS, 11 with a clinical isolated syndrome suggestive of MS (CISSMS), and 14 controls with non-MS diseases. Intracellular TWEAK could be observed in lymphocytes and/or monocytes in all groups of patients. None of the 36 patients displayed TWEAK expression at the cell surface of lymphocytes. In contrast, 12 out of the 36 patients were positive for membrane TWEAK expression on their monocytes. Among these patients, eight were from the CISSMS group. Fn14 was not detected in PBMC. The soluble form of TWEAK is detectable in serum and CSF of patients, and TWEAK concentrations were not statistically different between the disease groups. We demonstrated for the first time that TWEAK is expressed at the cell surface of monocytes during MS, especially in the CISSMS group. Our results support the proposal that TWEAK could be a target for antibody therapy in MS.


Subject(s)
Cell Membrane/metabolism , Monocytes/metabolism , Multiple Sclerosis/metabolism , Receptors, Tumor Necrosis Factor/metabolism , Tumor Necrosis Factors/biosynthesis , Adolescent , Adult , Aged , Cytokine TWEAK , Female , Humans , Lymphocytes/metabolism , Male , Middle Aged , TWEAK Receptor , Tumor Necrosis Factors/blood , Tumor Necrosis Factors/cerebrospinal fluid , Young Adult
19.
Ann N Y Acad Sci ; 1109: 245-55, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17785313

ABSTRACT

BioPlex 2200 multiplexed assays system is an automatic method allowing detection of antinuclear antibodies (ANA). The aim of our study was to evaluate the determination of 13 autoantibodies against chromatinic and nonchromatinic nuclear antigens by the BioPlex 2200 system and to compare the results achieved by this method to those obtained with our routinely used immunoassays. One thousand and four serum samples consecutively sent for ANA detection were routinely tested by indirect immunofluorescence (IIF) on HEp2 cells. Among them, 321 were also analyzed by dsDNA enzyme immunoassay (EliA) test and 657 by double immunodiffusion (DID) for extractable nuclear antigen (ENA) antibodies. All the sera were evaluated by the BioPlex 2200 ANA screen kit allowing simultaneous detection of antibodies against the following antigens: dsDNA, chromatin, SSA-52 kDa, SSA-60 kDa, SSB, Sm, Sm/RNP, RNP-A, RNP-68 kDa, Scl70, centromere B, Jo-1, and P ribosomal proteins. The kappa coefficient between BioPlex 2200 and routine tests for detection of ANA on HEp2 cells, anti-dsDNA, and anti-ENA antibodies was, respectively, 0.31, 0.66, and 0.61. The comparison with our routine tests showed numerous discrepancies between IIF ANA screening and BioPlex but a good concordance for detection of anti-dsDNA and anti-ENA specificities. BioPlex 2200 system is a rapid and sensitive method for simultaneous quantitative detection of several autoantibodies. It is perfectly well adapted to determine ANA antigenic specificities of samples found positive using initial IIF screening. The capability of this multiplexed technology to analyze simultaneously 13 ANA autoantibodies leads to the rapid availability of an "autoimmune connective tissue disease serologic profile."


Subject(s)
Antibodies, Antinuclear/blood , Antibodies, Antinuclear/immunology , Mass Screening/methods , Antigens/immunology , Autoantibodies/blood , Autoantibodies/immunology , Humans , Sensitivity and Specificity
20.
J Clin Immunol ; 25(4): 338-45, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16133990

ABSTRACT

Oligoclonal free light chains (FLC) banding has been described in multiple sclerosis (MS) and should be correlated with disease activity. However, discrepancies between studies have been reported because of differences in methods. A new quantitative, rapid, and automated method using nephelometry is now available. Our objective was to investigate the interest of this method for the diagnosis and prognosis of MS. For this purpose, FLC index was determined in paired samples of CSF and serum from consecutive and unselected patients from the same department of neurology. We enrolled 89 patients (33 MS, 15 "possible MS", and 41 controls) and correlated with IgG index, IgG oligoclonal banding, and clinical MS progression criteria. The main results were (1) FLC kappa index was more sensitive but less specific than IgG index for the diagnosis of MS, (2) two MS patients were negative for oligoclonal banding but exhibited a positive kappa index, (3) no relation between FLC kappa indices, MS clinical criteria, and disease progression was found. In conclusion, FLC kappa index should be considered as a useful complementary test for MS diagnosis. Its pronostic interest remains to be determined on a larger cohort of possible MS patients.


Subject(s)
Immunoglobulin Light Chains/cerebrospinal fluid , Multiple Sclerosis/cerebrospinal fluid , Nephelometry and Turbidimetry , Adolescent , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Immunoassay/methods , Immunoglobulin G/blood , Immunoglobulin G/cerebrospinal fluid , Immunoglobulin Light Chains/blood , Immunoglobulin kappa-Chains/blood , Immunoglobulin kappa-Chains/cerebrospinal fluid , Immunoglobulin lambda-Chains/blood , Immunoglobulin lambda-Chains/cerebrospinal fluid , Male , Middle Aged , Multiple Sclerosis/diagnosis , Nephelometry and Turbidimetry/methods , Sensitivity and Specificity
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