Publications by authors named "Sylvain Dubucquoi"

62 Publications

Acquired Hemophilia A in IgG4-Related Disease: Case Report, Immunopathogenic Study, and Review of the Literature.

Front Immunol 2020 18;11:558811. Epub 2020 Dec 18.

CHU Lille, Département de Médecine Interne et Immunologie Clinique, Lille, France.

We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4 lymphoplasmacytic infiltration; and serum IgG4 levels were markedly elevated, compatible with IgG4-related disease (IgG4-RD). He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4 plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4 plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10 [5.7 10-1.79 10]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10 [2.0 10-6.0 10]), a polyclonal setting in which all IgG4 plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10 at diagnosis and 1.0 10 at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4 plasma cell proliferation.
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http://dx.doi.org/10.3389/fimmu.2020.558811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793697PMC
December 2020

Severe SARS-CoV-2 patients develop a higher specific T-cell response.

Clin Transl Immunology 2020 23;9(12):e1217. Epub 2020 Dec 23.

Institut d'Immunologie CHU de Lille Lille France.

Objectives: Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for studying long-term immunity and vaccine strategies. We quantified IFNγ-secreting T cells reactive against the main viral SARS-CoV-2 antigens using a standardised enzyme-linked immunospot assay (ELISpot).

Methods: Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T-CoV-Spot assay, we assessed T-cell and antibody responses in mild, moderate and severe SARS-CoV-2 patients and in control samples collected before the outbreak.

Results: Specific T cells were assessed in 60 consecutive patients (mild,  = 26; moderate,  = 10; and severe patients,  = 24) during their follow-up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in  = 60 (100%),  = 56 (93.3%),  = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T-CoV-Spot assay showed a specificity of 96.7% (95% CI, 88.5-99.6%) and a specificity of 90.3% (75.2-98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti-S1 and anti-RBD serum antibodies.

Conclusion: IFNγ T-CoV-Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long-lived memory T-cell response after vaccination. Our study demonstrates that SARS-CoV-2 patients developing a severe disease achieve a higher adaptive immune response.
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http://dx.doi.org/10.1002/cti2.1217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757425PMC
December 2020

Extended myositis-specific and -associated antibodies profile in systemic sclerosis: A cross-sectional study.

Joint Bone Spine 2021 01 9;88(1):105048. Epub 2020 Jul 9.

Univ. Lille, U1286 - Infinite - Institute for Translational Research in Inflammation, 59000 Lille, France; Inserm, U1286, 59000 Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), 59000 Lille, France. Electronic address:

Objective: In systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM), auto-antibodies are used in daily practice as potent biomarkers of clinical phenotypes. This study aimed at estimating the prevalence of myositis-specific (MSA) and myositis-associated (MAA) auto-antibodies in a well-characterised SSc patients cohort using two different immunoblot assays, and studying their clinical associations.

Methods: In this cross-sectional study, the sera of 300 consecutive patients were tested at the same time with myositis antibodies Euroimmun® and D-tek® immunoblot assays.

Results: Prevalence of MSA/MAA, MSA and MAA were 17.0%, 8.0% and 9.7%, respectively. When combining results of both tests, anti-PM/Scl 100 were found in 5.0% (95% confidence interval 2.8; 8.1); anti-PM/Scl 75 and anti-TIF1γ in 3.7% (1.8; 6.5); anti-Ku 3.0% (1.4; 5.6); anti-MDA5 in 1.3% (0.4; 3.4); anti-Mi-2 β, anti-NXP2, anti-PL-7 and anti-SRP in 0.7% (0.08; 2.4); anti-EJ and anti-PL-12 in 0.3% (0.01; 1.8) of patients. No reactivity against SAE1, Jo-1 or OJ was observed. Anti-PM/Scl 75 antibodies were associated with interstitial lung disease (80% vs. 42%) and myositis (27% vs. 3%); anti-Ku antibodies were associated with myositis (33% vs. 3%).

Conclusion: In this cross-sectional study of 300 SSc patients, the prevalence of MSA/MAA, MSA and MAA using immunoblot assays were 17.0%, 8.0% and 9.7%, respectively. MAA positivity was associated with ILD and myositis, but this study did not highlight any clinical associations with MSA positivity.
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http://dx.doi.org/10.1016/j.jbspin.2020.06.021DOI Listing
January 2021

Serious Infectious Events and Immunoglobulin Replacement Therapy in Patients With Autoimmune Disease Receiving Rituximab: A Retrospective Cohort Study.

Clin Infect Dis 2021 Mar;72(5):727-737

University of Lille, Institute for Translational Research in Inflammation (INFINITE), Lille, France.

Background: Rituximab (RTX) is widely administered to patients with autoimmune disease (AID). This study aimed to estimate the incidence of serious infectious events (SIEs) after RTX initiation in patients with AID. We also described the characteristics and risk factors of SIEs, and immunoglobulin replacement therapy (IgRT) strategies.

Methods: Patients treated between 2005 and 2016 were included in this retrospective monocentric cohort study. An RTX course was defined as the complete RTX treatment regimen received by a given patient for AID. SIEs and IgRT were right-censored at 24 months after RTX initiation.

Results: Two hundred twenty-one patients were included (corresponding to 276 RTX courses). Reasons for RTX initiation included connective tissue disease (38%), systemic vasculitis (36%), and autoimmune cytopenia (22%). The 1- and 2-year incidences of SIEs were 17.3 (95% confidence interval [CI], 12.0-22.5) and 11.3 (95% CI, 8.1-14.5) per 100 person-years, respectively. Forty-seven SIEs were observed, mostly comprising pneumonias (45%) and bacteremias (21%). When documented, the microorganisms were bacterial (55%) and fungal (12%). Identified risk factors of SIEs were age, history of diabetes, history of cancer, concomitant steroid treatment, and low CD4 lymphocyte count at RTX initiation. IgRT was started in 22 RTX courses (8%).

Conclusions: In patients with AID treated with RTX, the 1- and 2-year incidence of SIE was 17.3 and 11.3 per 100 person-years, respectively. Reports of SIE characteristics, risk factors, and IgRT strategies highlight the need for an appropriate and individualized assessment prior to and following RTX to prevent SIEs, particularly in patients with comorbidities.
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http://dx.doi.org/10.1093/cid/ciaa127DOI Listing
March 2021

[Stability study and external quality assessment scheme implementation for complement components dosage on EDTA plasma].

Ann Biol Clin (Paris) 2019 12;77(6):669-680

CHU Lille, Institut d'immunologie, Lille, France, Université de Lille, U995-LIRIC-Lille Inflammation Research International Center, Lille, France.

Although the use of EDTA-containing collection tubes is known to stabilize the complement analytes and to make the results more reliable, no external quality assessment (EQA) scheme based on EDTA plasma samples is available to date in France. Consequently, a number of clinical laboratories currently participate to EQA program on samples whose matrix is different from their routine practice. The aim of this work was to offer a new external quality assessment scheme, as an inter-laboratory exchange (ILE). The ILE samples come from pooled EDTA plasmas of healthy subjects and are diluted to obtain distinct control levels. The protocol has been validated on CH50, C3, C4 and C1-inhibitor measurements, through: (i) a stability study of post-centrifugation storage of EDTA plasma samples at room temperature, 4̊C and -20̊C; (ii) the demonstration of the linearity of the dilution steps; and (iii) a stability study of the diluted samples. Our results demonstrate a four-weeks stability of the ILE samples prepared and stored according to our protocol. Those results are compatible with the ILE implementation constraints, and the program has been implemented in January 2018. The one-year ILE implementation experience is also presented. The newly implemented ILE will be useful for the accreditation of the complement activity of French laboratories using EDTA plasma samples.
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http://dx.doi.org/10.1684/abc.2019.1501DOI Listing
December 2019

Classical pathway activity C3c, C4 and C1-inhibitor protein reference intervals determination in EDTA plasma.

Biochem Med (Zagreb) 2019 Oct;29(3):030707

Department of Immunology, Lille University Hospital, Lille, France.

Introduction: Reference intervals (RIs) for complement assays in EDTA plasma samples have not previously been published. The objectives of the present study were to validate and/or determine RIs for classical pathway (CP50) activity and C3c, C4 and C1 inhibitor protein (C1INH) assays and to assess the need for age-specific RIs in EDTA plasma.

Materials And Methods: We retrospectively evaluated a cohort of 387 patients attending our university hospital and known to be free of complement-modifying diseases. The need for age partitioning was assessed and RIs were calculated according to the CLSI protocol.

Results: No need for age partitioning was evidenced for CP50 activity, C3c and C4 concentrations and RIs (90% CI) were calculated from the pooled data: 35.4 (33.1-37.2) to 76.3 (73.7-83.6) U/mL for CP50 activity, 0.80 (0.75-0.87) to 1.64 (1.59-1.72) g/L for C3c, and 0.12 (0.10-0.14) to 0.38 (0.36-0.40) g/L for C4. Our results highlight a positive association between age and C1INH concentrations. We derived 3 age partitions (6 months to 30 years, 30-50 and > 50 years) and the related RIs: 0.20 (0.18-0.21) to 0.38 (0.36-0.40) g/L, 0.22 (0.20-0.24) to 0.39 (0.36-0.41) g/L and 0.25 (0.22-0.27) to 0.41 (0.40-0.43) g/L, respectively).

Conclusions: The newly determined RIs for CP50 activity were higher than those provided by the manufacturer for EDTA plasma samples, whereas those for C3c and C4 RIs were similar to the values provided for serum samples. The C1INH concentration and activity were found to be associated with age and age-specific RIs are mandatory for this analyte.
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http://dx.doi.org/10.11613/BM.2019.030707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784422PMC
October 2019

Assessment of T-cell polarization on the basis of surface marker expression: Diagnosis and potential therapeutic implications in lymphocytic variant hypereosinophilic syndrome.

J Allergy Clin Immunol Pract 2020 Mar 13;8(3):1110-1114.e2. Epub 2019 Sep 13.

Institut d'Immunologie, CHU de Lille, Lille, France; Univ. Lille, U995-LIRIC-Lille Inflammation Research International Center, Lille, France; Département de Médecine Interne, CHU de Lille, Lille, France; Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Lille, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.08.049DOI Listing
March 2020

Prevalence and Clinical Associations of Antiphospholipid Antibodies in Systemic Sclerosis: New Data From a French Cross-Sectional Study, Systematic Review, and Meta-Analysis.

Front Immunol 2018 2;9:2457. Epub 2018 Nov 2.

Univ. Lille, U995, Lille Inflammation Research International Center, Lille, France.

Antiphospholipid antibodies (aPL) can be present in the sera of systemic sclerosis (SSc) patients. This study aimed to determine the prevalence of aPL in a cross-sectional study of SSc patients, to assess their clinical associations, to perform a systematic review of published reports and a meta-analysis to estimate the worldwide prevalence of aPL in SSc. Two-hundred and forty-nine SSc patients were consecutively tested once for lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2glycoprotein I (anti-β2GpI) antibodies. Clinical associations with aPL positivity were studied using a logistic regression model. A systematic review of the literature was carried out in PubMed and Embase. Meta-analysis was performed using number of aPL positive (at least one of the three antibodies positive) and negative patients. Meta-regression was used to study potential factors explaining the heterogeneity between studies. In our cross-sectional study, aPL positivity was found in 16 patients (prevalence 6.4%; 95%CI [3.8-10.4]). In multivariate analysis, there was a significant association between aPL positivity and venous thrombosis (VT) (OR 6.25 [1.18-33.00]; = 0.028) and miscarriage (OR 5.43; 95%CI [1.31-22.13]; = 0.017). Twenty-four studies were included in the meta-analysis, representing a total population of 3036 SSc patients. The overall pooled prevalence of aPL in SSc was 14% (9-20) with a high degree of heterogeneity among studies. This study found a prevalence of aPL positivity in our SSc population of 6.4% (3.8-10.4) and an overall worldwide pooled prevalence of 14% (9-20). In our SSc population, aPL positivity was associated with VT and miscarriage. These data provide additional insights into the role of aPL in the vasculopathy observed in SSc.
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http://dx.doi.org/10.3389/fimmu.2018.02457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234954PMC
September 2019

Antiphospholipid Syndrome With Isolated Isotype M Anticardiolipin and/or Anti-B2GPI Antibody Is Associated With Stroke.

Stroke 2018 11;49(11):2770-2772

Service de Médecine Interne, Centre National de Référence Maladies Systémiques et Auto-immunes Rares (C.M.Y., H.M., D.L., E.H., P.-Y.H., M.L.), CHU, F-59000 Lille, France.

Background and Purpose- International classification criteria for antiphospholipid syndrome (APS) include IgM (immunoglobulin M), aCL (anticardiolipin), and aB2GPI (anti-β2-glycoprotein-I) antibodies, but their relevance is still debated. We aimed to assess whether patients with isolated IgM aCL and/or aB2GPI at diagnosis have specific characteristics and outcomes. Methods- We retrospectively included APS patients with isolated IgM antiphospholipid antibodies (isolated-IgM-APS) and compared them to APS patients with IgG and IgM, or IgG alone and/or lupus anticoagulant (nonisolated-IgM-APS). Results- Among the 168 APS patients included, 24 (14.3%) had isolated IgM. Median follow-up was 92.5 months (36-151.5). Isolated-IgM-APS patients were 9.5 years older. At diagnosis, stroke was more frequent in isolated-IgM-APS after adjustment for cardiovascular risk factors (odds ratio, 3.8; 95% CI, 1.3-11.5). IgM isotype remained isolated in 17 of 24 (70.8%) patients over time. Global relapse-free survival did not differ between the two groups. In thrombotic APS, monotherapy with antiplatelet agents was more frequently used in isolated-IgM-APS group with 14 of 20 versus 28 of 134 patients ( P<0.0001), with a higher relapse rate with antiplatelet agent alone compared to vitamin K antagonists, especially for patients presenting with a stroke (hazard ratio, 7.37; 95% CI, 1.19-19.0). Conclusions- Isolated IgM APS patients should not be disregarded because they represent 14.3% of an APS population. They have some characteristics: older age at diagnosis and a strong association with stroke. Clinicians must be aware of this situation because antiplatelet agent do not seem to well prevent relapses compared to vitamin K antagonist.
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http://dx.doi.org/10.1161/STROKEAHA.118.023021DOI Listing
November 2018

C-Reactive protein as a diagnostic tool in differential diagnosis of hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis.

J Allergy Clin Immunol Pract 2019 Apr 11;7(4):1347-1351.e3. Epub 2018 Oct 11.

CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), University of Lille, Lille, France; Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), France; CHU Lille, Institut d'Immunologie, University of Lille, Lille, France; Inserm, CHU Lille, U995 - LIRIC - Lille Inflammation Research International Center, University of Lille, Lille, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.10.002DOI Listing
April 2019

Low endocan levels are predictive of Acute Respiratory Distress Syndrome in severe sepsis and septic shock.

J Crit Care 2018 10 20;47:121-126. Epub 2018 Jun 20.

Univ. Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France; CNRS, UMR 8204, F-59000 Lille, France; INSERM, U1019, F-59000 Lille, France; CHU Lille, Pôle de Réanimation, Hôpital Roger Salengro, F-59000 Lille, France.

Purpose: Endocan is a circulating proteoglycan measured at high blood levels during severe sepsis, with a likely lung anti-inflammatory function. The aim of this study was to assess whether paradoxically low endocan levels at Intensive Care Unit (ICU) admission could predict Acute Respiratory Distress Syndrome (ARDS) within 72 h in severe septic patients.

Materials And Methods: Patients admitted for severe sepsis in the ICU of a French University Hospital were included in a prospective single-center observational study between October 2014 and March 2016.

Results: 72 patients admitted in ICU for severe sepsis were included. Endocan blood values at inclusion were significantly lower in patients who developed an ARDS at 72 h (p < 0.001). For endocan blood values > 5.36 ng/mL, the adjusted OR for development of ARDS at 72 h was of 0.001 (95% CI 0-0.215; p = 0.011). In our cohort, an endocan value < 2.54 ng/mL predicted ARDS at 72 h with a positive predictive value of 1 (Sp = 1 (95% CI 0.94-1)).

Conclusions: In a cohort of severe septic patients, we observed that low blood levels of endocan at ICU admission were predictive of ARDS at 72 h.
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http://dx.doi.org/10.1016/j.jcrc.2018.06.018DOI Listing
October 2018

Whole-Body Distribution and Clinical Association of Telangiectases in Systemic Sclerosis.

JAMA Dermatol 2018 07;154(7):796-805

University Lille, Lille Inflammation Research International Center, Lille, France.

Importance: In systemic sclerosis (SSc), to date, no study has precisely described the total number and fine distribution of telangiectases (TAs), their clinical association with the disease, and the biological mechanisms causing their development.

Objectives: To describe the whole-body distribution of TAs and assess the association between the whole-body TA number and the characteristics of patients with SSc.

Design, Setting, And Participants: A single-center, cross-sectional study was conducted between July 11, 2016, and March 15, 2017, at the National Referral Centre for Rare Systemic and Autoimmune Diseases in France. A population-based sample of 106 adults who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria for SSc were included; 8 patients who had previously received laser treatment for TAs were excluded.

Main Outcomes And Measures: The number of TAs on the whole body (total and those >5 mm) and TA distribution in different areas were recorded. The association with clinical and biological data was studied using univariate and multivariate linear regression.

Results: A total of 106 patients (83 [78.3%] women) were enrolled, including 12 with precapillary pulmonary hypertension (PH). Mean (SD) age was 60.6 (13.5) years. Telangiectasia distribution was 37.2% on the face, 33.2% on the upper limbs, including 26.4% on the hands, 28.1% on the trunk, including 17.1% for the upper part of the trunk, and 1.5% on the lower limbs. In analysis using the multivariate linear regression model, the whole-body TA number was independently associated with male sex (percentage change, 144.4%; 95% CI, 7.5% to 455.9%; P = .03), PH (162.8%; 95% CI, 5.6% to 553.8%; P = .04), history of pulmonary embolism (336.4%; 95% CI, 39.0% to 1270.1%; P = .01), glomerular filtration rate (-1.6%; 95% CI, -3.2% to -0.1% per 1-mL/min/1.73 m2 increase; P = .04), and soluble endoglin level (28.2%; 95% CI, 1.2% to 62.5% per 1-ng/mL increase; P = .04). Receiver operating characteristic analyses assessing the ability of TAs to identify the presence of PH revealed that the area under the curve was significant for the TA number on the whole body (0.77; 95% CI, 0.57 to 0.88), on the hands and face (0.81; 95% CI, 0.57 to 0.91), and on the hands (95% CI, 0.77; 95% CI, 0.57 to 0.89).

Conclusions And Relevance: In the patients in this study with SSc, TAs were predominantly located on the face, hands, and the upper part of the trunk. Telangiectases appeared to be associated with vasculopathy features of SSc, particularly with PH and soluble endoglin levels.
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http://dx.doi.org/10.1001/jamadermatol.2018.0916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128493PMC
July 2018

Immunoglobulin G (IgG) and IgG subclass reference intervals in children, using Optilite® reagents.

Clin Chem Lab Med 2018 07;56(8):1319-1327

CHU Lille, Institut d'Immunologie, Lille, France.

Background: Immunoglobulin G (IgG) and IgG subclass assays are indicated in patients with suspected primary immunodeficiency (PID). Commercially available assays for IgG subclass determination are calibrated against various preparations, and so specific reference values are required for each of them. Using Optilite® reagents from The Binding Site Group Ltd., we sought to determine the pediatric IgG and IgG subclass reference intervals with respect to the ERM-DA470k certified reference material.

Methods: Levels of IgG and IgG subclasses were analyzed in serum samples collected from a large cohort of PID-free children and adolescents. Reference intervals were calculated for previously published age groups (6-12 months, 12-18 months, 18 months-2 years, 2-3 years, 3-4 years, 4-6 years, 6-9 years, 9-12 years and 12-18 years), according to the Clinical and Laboratory Standards Institute's C28-A3c protocol.

Results: A total of 456 serum samples were analyzed. The correlation between the total IgG and the sum of the IgG subclasses was good (r2=0.96). No statistically significant gender-specific differences were observed. Our results for the changes over time in IgG and IgG subclass levels are consistent with previous reports. The differences between our lower/upper reference limits and those in the literature are probably due to variations in calibration.

Conclusions: Our present results provide a reliable basis for the diagnosis of PIDs in childhood and for the accreditation of laboratories using Optilite® immunoturbidimetric reagents for IgG subclass measurement. Laboratory scientists and clinicians should be aware of the need for manufacturer-specific IgG subclass reference intervals.
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http://dx.doi.org/10.1515/cclm-2018-0001DOI Listing
July 2018

Altered B lymphocyte homeostasis and functions in systemic sclerosis.

Autoimmun Rev 2018 Mar 16;17(3):244-255. Epub 2018 Jan 16.

Univ. Lille, U995, Lille Inflammation Research International Center (LIRIC), F-59000 Lille, France; Inserm, U995, F-59000 Lille, France; CHU Lille, Institut d'immunologie, F-59000 Lille, France.

Beyond the production of autoantibodies, B-cells are thought to play a role in systemic sclerosis (SSc) by secreting proinflammatory/profibrotic cytokines. B-cells are a heterogeneous population with different subsets distinguished by their phenotypes and cytokine production. Data about B-cell subsets, cytokine production and intracellular pathways leading to this production are scarce in SSc. The aim of our study was to describe B-cell homeostasis, activation, proliferation, cytokine production in B-cells and serum and B-cell intracellular signaling pathways in SSc. We hypothezided that B-cell homeostasis and cytokine production were altered in SSc and could be explained by serum cytokine as well as by intracellular signaling pathway abnormalities. Forty SSc patients and 20 healthy controls (HC) were prospectively included. B-cell subsets were determined by flow cytometry using CD19, CD21, CD24, CD38, CD27, IgM and IgD. CD25, CD80, CD95, HLA-DR were used to assess B-cell activation. Intracellular production of IL-10 and IL-6 were assessed by flow cytometry after TLR9 and CD40 stimulation. IL-6, IL-10, Ki67, Bcl2 mRNA were quantified in B-cells. Cytokine production was also assessed in sera and supernatants of B-cell culture, using a multiplex approach. Signaling pathways were studied through phosphorylation of mTOR, ERK, STAT3, STAT5 using a flow cytometry approach. We found that SSc patients exhibited an altered peripheral blood B-cell subset distribution, with decreased memory B-cells but increased proportion of naive and CD21CD38 B-cell subsets. We observed an increased expression of activation markers (CD80, CD95, HLA-DR) on some B-cell subsets, mainly the memory B-cells. Secretion of IL-6, BAFF and CXCL13 were increased in SSc sera. There was no correlation between the peripheral blood B-cell subsets and the serum concentrations of these cytokines. After stimulation, we observed a lower proportion of IL-10 and IL-6 producing B-cells in SSc. Finally, we observed a significant decrease of mTOR phosphorylation in SSc patient B-cells. In conclusion, we observed an altered B-cell homeostasis in SSc patients compared to HC. Memory B-cells were both decreased and activated in patients. IL-10 producing B-cells were decreased in SSc. This decrease was associated with an alteration of mTOR phosphorylation in B-cells. Conversely, there was no correlation between serum cytokine profile and B-cell homeostasis alterations.
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http://dx.doi.org/10.1016/j.autrev.2017.10.015DOI Listing
March 2018

Value of the Overall Pneumococcal Polysaccharide Response in the Diagnosis of Primary Humoral Immunodeficiencies.

Front Immunol 2017 20;8:1862. Epub 2017 Dec 20.

CHU Lille, Institut d'Immunologie, Lille, France.

Background: An overall response assay [OVA, based on a 23-valent pneumococcal polysaccharide vaccine (PPV23)] is widely used to screen for anti-pneumococcal antibodies. Given the heterogeneity of response from one polysaccharide (PS) to another, a World Health Organization-standardized serotype-specific enzyme-linked immunosorbent assay (SSA) is considered to be the only reliable method for testing anti-PS antibody responses in individuals with suspected primary immunodeficiencies (PIDs).

Objective: To evaluate the OVA relative to the reference SSA.

Methods: Serum samples of adult patients referred for a suspected PID were collected before and then 4-8 weeks after immunization with PPV23. The anti-pneumococcal response was systematically assessed with an SSA (7-16 serotypes) and interpreted according to the American Academy of Asthma, Allergy and Immunology's current guidelines. We used receiver operating characteristic curves and agreement indices to assess the OVA's diagnostic value in a first cohort. In order to validate these findings, a second (validation) cohort was then prospectively included.

Results: Sixty-two adult patients were included, and 42 (67.7%) were defined as poor responders according to the SSA. Only the post-immunization titer in the OVA was able to correctly identify poor responders; a titer below 110 mg/L gave a positive predictive value of 100% [identifying 24 (57.1%) of the 42 poor responders], and similar levels of diagnostic performance were observed in the validation cohort. The pre-vaccination antibody titer, the post/pre-vaccination antibody titer ratio and a post-vaccination titer above 110 mg/L in the OVA were not predictive of the response in the SSA.

Conclusion: A post-vaccination antibody titer below 110 mg/L in the OVA was constantly associated with a poor PPV23 response using the SSA. In all other cases, SSA is the only reliable method for assessing diagnostic vaccination with PPV23.
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http://dx.doi.org/10.3389/fimmu.2017.01862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742330PMC
December 2017

Proinflammatory B-cell profile in the early phases of MS predicts an active disease.

Neurol Neuroimmunol Neuroinflamm 2018 Mar 22;5(2):e431. Epub 2017 Dec 22.

Université de Lille, CHU Lille, LIRIC-INSERM U 995, FHU Imminent, France.

Objective: To assess whether any alteration of B-cell subset distribution and/or the cytokine production capacities of B cells could be associated with any stage of MS and could be predictive of MS evolution.

Methods: We prospectively enrolled radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), naive patients with relapsing remitting MS (RRMS) of any disease modifying drug, and healthy controls (HCs). Peripheral blood B-cell subset distributions and the interleukin (IL)-6/IL-10-producing B-cell ratio were assessed by flow cytometry to evaluate their proinflammatory and anti-inflammatory functional properties.

Results: Twelve RIS, 46 CIS, 31 RRMS patients, and 36 HCs were enrolled. We observed that a high IL-6/IL-10-producing B-cell ratio in patients with RIS/CIS was associated with the evolution of the disease in the short term (6 months). This imbalance in cytokine production was mainly explained by an alteration of the production of IL-10 by B cells, especially for the transitional B-cell subset. In addition, a significant increase in IgD/CD27 B cells was detected in patients with CIS and RRMS compared with HCs ( = 0.01). Apart from this increase in exhausted B cells, no other variation in B-cell subsets was observed.

Conclusions: The association between a high IL-6/IL-10-producing B-cell ratio and the evolution of patients with RIS/CIS suggest a skew of B cells toward proinflammatory properties that might be implicated in the early phases of MS disease.
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http://dx.doi.org/10.1212/NXI.0000000000000431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745361PMC
March 2018

Endocan is a stable circulating molecule in ICU patients.

Clin Biochem 2017 Oct 18;50(15):870-877. Epub 2017 Apr 18.

Univ. Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France; CNRS, UMR 8204, F-59000 Lille, France; INSERM, U1019, F-59000 Lille, France; CHU Lille, Pôle de Réanimation, Hôpital Roger Salengro, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France.

Background: Endocan is a lung endothelial cell secreted proteoglycan, possessing multiple physiological roles and potential therapeutic and diagnostic utility as biomarker in pneumonia and acute respiratory distress syndrome. Endocan synthesis and secretion can be induced by proinflammatory cytokines such as TNF-α, but can also be subject of proteolytic degradation causing preanalytical variation.

Methods: We investigated the stability of endocan in conventional serum, plasma, anticoagulated whole blood, as well as whole blood and plasma stabilized with protease inhibitors.

Results: Among the recipient tubes for blood collection, those with EDTA gave minimal interference. No dilution effect was observed on recovery tests from 1:2 to 1:16 (v:v). The recovery test in 10 plasma EDTA samples from healthy subjects or septic patients indicated a median recovery of 104.5% [104%-107.5%], and 97% [88.5%; 102.5%], respectively. Patient's plasma endocan remains stable when stored at room temperature till 72h, or following 3 freeze thaw cycles. Finally, no interference was observed with hemolytic, icteric or turbidic plasma samples.

Conclusion: These results are consistent with the view that endocan measured in ICU patients is intact, stable, and accurate. Then, the low endocan level observed in ICU patients who developed ARDS is likely to be reliable.
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http://dx.doi.org/10.1016/j.clinbiochem.2017.04.011DOI Listing
October 2017

Specific Polysaccharide Antibody Deficiency Revealed by Severe Bacterial Infections in Adulthood: A Report on 11 Cases.

Clin Infect Dis 2017 Jul;65(2):328-331

CHU Lille, Institut d'Immunologie.

We report on 11 cases of specific polysaccharide antibody deficiency (SPAD) revealed in adulthood by severe infections with encapsulated bacteria. Given that immunoglobulin replacement therapy can effectively prevent the recurrence of bacterial infections in this context, SPAD should be considered once other antibody deficiencies have been ruled out.
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http://dx.doi.org/10.1093/cid/cix284DOI Listing
July 2017

Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature.

Autoimmun Rev 2017 Apr 13;16(4):377-384. Epub 2017 Feb 13.

Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France; INSERM, U995, F-59000 Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), F-59000 Lille, France; Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET). Electronic address:

Background: As intravenous immunoglobulins (IVIG) exhibit immunomodulatory and antifibrotic properties, they may be a relevant treatment for systemic sclerosis (SSc). The objectives of this work were thus to report on the efficacy and safety of IVIG in a population of SSc patients and to review the available literature.

Methods: 46 patients from 19 French centers were retrospectively recruited. They were included if they had a diagnosis of SSc and received at least 1 IVIG infusion at a dosage >1g/kg/cycle. Relevant data collected at IVIG discontinuation were compared to those collected at IVIG initiation. A comprehensive literature review was performed.

Results: We observed a significant improvement of muscle pain (74% vs. 20%, p<0.0001), muscle weakness (45% vs. 21%, p=0.01), joint pain (44% vs. 19%, p=0.02), CK levels (1069±1552UI vs. 288±449UI, p<0.0001) and CRP levels (13.1±17.6mg/L vs. 9.2±16.6mg/L, p=0.001). We also noted a trend for an improvement of gastro-esophageal reflux disease (68% vs. 53%, p=0.06) and bowel symptoms (42% vs. 27%, p=0.06). Skin and cardiorespiratory involvements remained stable. Finally, corticosteroid daily dose was significantly lower by the end of treatment (13.0±11.6mg/day vs. 8.9±10.4mg/day, p=0.01). Only two severe adverse events were reported (one case of deep vein thrombosis and one case of diffuse edematous syndrome).

Conclusion: Our work suggests that IVIG are a safe therapeutic option that may be effective in improving musculoskeletal involvement, systemic inflammation, digestive tract symptoms and could be corticosteroid sparing.
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http://dx.doi.org/10.1016/j.autrev.2017.02.008DOI Listing
April 2017

B Cell Homeostasis and Functional Properties Are Altered in an Hypochlorous Acid-Induced Murine Model of Systemic Sclerosis.

Front Immunol 2017 7;8:53. Epub 2017 Feb 7.

U995, LIRIC - Lille Inflammation Research International Center, Université de Lille, Lille, France; INSERM, U995, Lille, France; Département de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), Lille, France.

Introduction: During systemic sclerosis (SSc), peripheral B cells display alterations in subset homeostasis and functional properties and are a promising therapeutic target. However, there is only few data regarding whether these anomalies are accurately reproduced in animal models of SSc.

Objective: In this work, we assessed the B cell homeostasis modifications in an experimental model of SSc [hypochlorous acid (HOCl)-induced mouse], both at a phenotypic and functional level, during the course of the disease.

Methods: Balb/c mice underwent daily intradermal injections of HOCl (or phosphate-buffered saline) and were then sacrificed at day 21 (early inflammatory stage) or day 42 (late fibrotic stage). For phenotypic studies, the distribution of the main spleen cell subsets (B cells, T CD4 and CD8 cells, NK cells, macrophages) and splenic B cell subsets (immature, mature naïve, germinal center, antibody-secreting, memory, B1) was assessed by flow cytometry. For functional studies, splenic B cells were immediately MACS-sorted. Production of interleukin (IL)-6, CCL3, IL-10, and transforming growth factor (TGF)-β was assessed by RT-PCR and after 48 h of culture by ELISA. Regulatory B cell (Breg) counts were quantified by flow cytometry.

Results: Phenotypic analyses showed an early expansion of transitional B cells, followed by a late expansion of the mature naive subset and decrease in plasmablasts and memory B cells. These anomalies are similar to those encountered in SSc patients. Functional analyses revealed a B-cell overproduction of pro-inflammatory cytokines (IL-6 and CCL3) and an impairment of their anti-inflammatory capacities (decreased production of IL-10 and TGF-β, reduced levels of Bregs) at the early inflammatory stage; and an overproduction of pro-fibrotic cytokines (TGF-β and IL-6) at the late fibrotic stage. These results approximate the anomalies observed in human SSc.

Conclusion: This work reports the existence of anomalies in B cell homeostasis and functional properties in an animal model of SSc that approximate those displayed by SSc patients. These anomalies vary over the course of the disease, which pleads for their participation in inflammatory and fibrotic events. This makes the HOCl mouse a relevant experimental model for the study of B cells, and therefore, B-cell-targeted therapies in SSc.
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http://dx.doi.org/10.3389/fimmu.2017.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293837PMC
February 2017

Anti-Ephrin Type-B Receptor 2 (EphB2) and Anti-Three Prime Histone mRNA EXonuclease 1 (THEX1) Autoantibodies in Scleroderma and Lupus.

PLoS One 2016 12;11(9):e0160283. Epub 2016 Sep 12.

INSERM UMRs 1097, Parc Scientifique de Luminy, Marseille, France.

In a pilot ProtoArray analysis, we identified 6 proteins out of 9483 recognized by autoantibodies (AAb) from patients with systemic sclerosis (SSc). We further investigated the 6 candidates by ELISA on hundreds of controls and patients, including patients with Systemic Lupus Erythematosus (SLE), known for high sera reactivity and overlapping AAb with SSc. Only 2 of the 6 candidates, Ephrin type-B receptor 2 (EphB2) and Three prime Histone mRNA EXonuclease 1 (THEX1), remained significantly recognized by sera samples from SSc compared to controls (healthy or with rheumatic diseases) with, respectively, 34% versus 14% (P = 2.10-4) and 60% versus 28% (P = 3.10-8). Above all, EphB2 and THEX1 revealed to be mainly recognized by SLE sera samples with respectively 56%, (P = 2.10-10) and 82% (P = 5.10-13). As anti-EphB2 and anti-THEX1 AAb were found in both diseases, an epitope mapping was realized on each protein to refine SSc and SLE diagnosis. A 15-mer peptide from EphB2 allowed to identify 35% of SLE sera samples (N = 48) versus only 5% of any other sera samples (N = 157), including SSc sera samples. AAb titers were significantly higher in SLE sera (P<0.0001) and correlated with disease activity (p<0.02). We could not find an epitope on EphB2 protein for SSc neither on THEX1 for SSc or SLE. We showed that patients with SSc or SLE have AAb against EphB2, a protein involved in angiogenesis, and THEX1, a 3'-5' exoribonuclease involved in histone mRNA degradation. We have further identified a peptide from EphB2 as a specific and sensitive tool for SLE diagnosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160283PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019431PMC
August 2017

Vaginal Mucosal Homeostatic Response May Determine Pregnancy Outcome in Women With Bacterial Vaginosis: A Pilot Study.

Medicine (Baltimore) 2016 Feb;95(5):e2668

From the Faculty of Medicine of Lille, EA7366 Host-Pathogen Translational Research Group, University Lille North of France (EF, KF, EK, TG, RD); CHRU de Lille, Service de Maladies Infectieuses, Hôpital Claude Huriez (EF, KF, RD); University Lille, CHU Lille, IRCL, Structural and Functional Genomics Core Facility (MF, CV, RD); CHU Lille, Institut d'Immunologie-Centre de Biologie Pathologie et Génétique (SD, RD); UDSL, EA 2686, UFR Médecine (SD, RD); Univ Lille Nord de France (SD, BG, RD, DS); CHU Lille, Institut de Microbiologie, Laboratoire de Bactériologie Hygiène, Centre de Biologie Pathologie et Génétique (RD); UDSL, UFR Médecine (RD); CHU Lille, Service de Gestion du Risque Infectieux, des Vigilances et d'Infectiologie (BG); UDSL, EA 2694, UFR Médecine (BG, DS); Hôpital Saint Vincent, Service de Gynécologie-Obstétrique (GB); CHU Lille, Service de Gynécologie-Obstétrique Hôpital Jeanne de Flandre (DS), Lille, France.

Bacterial vaginosis (BV) is considered as a trigger for an inflammatory response that could promote adverse pregnancy outcome (APO). We hypothesized that BV-related inflammation could be counterbalanced by anti-inflammatory and mucosal homeostatic responses that could participate in pregnancy outcomes.A total of 402 vaginal self-samples from pregnant women in their first trimester were screened by Nugent score. In this population, we enrolled 23 pregnant women with BV but without APO, 5 pregnant women with BV and developing APO, 21 pregnant women with intermediate flora, and 28 random control samples from pregnant women without BV or APO.BV without APO in pregnant women was associated with 28-fold interleukin-8, 5-fold interleukin-10, and 40-fold interleukin-22 increases in expression compared to controls. BV associated with APO in pregnant women shared 4-fold increase in tumor necrosis factor, 100-fold decrease in interleukin-10, and no variation in interleukin-22 expressions compared to controls. Next-generation sequencing of vaginal microbiota revealed a shift from obligate anaerobic bacteria dominance in BV without APO pregnant women to Lactobacillus dominance microbiota in BV with APO.Our results show that the anti-inflammatory and mucosal homeostatic responses to BV may determine outcome of pregnancy in the setting of BV possibly through effects on the vaginal microbiota.
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http://dx.doi.org/10.1097/MD.0000000000002668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748914PMC
February 2016

Heterogeneous clinical spectrum of anti-SRP myositis and importance of the methods of detection of anti-SRP autoantibodies: a multicentric study.

Immunol Res 2016 06;64(3):677-86

Department of Immunology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, chemin du grand revoyet, 69495, Pierre-Benite Cedex, France.

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.
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http://dx.doi.org/10.1007/s12026-015-8774-6DOI Listing
June 2016

Antineutrophil Cytoplasmic Antibody-Positive Small-Vessel Vasculitis Associated with Antithyroid Drug Therapy: How Significant Is the Clinical Problem?

Thyroid 2015 Dec 19;25(12):1273-81. Epub 2015 Oct 19.

1 Service of Endocrinology and Metabolic Diseases, CHRU de Lille , Lille, France .

Background: The aim of this review was to delineate the characteristics of antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis associated with antithyroid drugs (ATD). A PubMed search was made for English language articles using the search terms antithyroid drugs AND ANCA OR ANCA-associated vasculitis.

Summary: The literature includes approximately 260 case reports of ANCA-associated small-vessel vasculitis related to ATD, with 75% of these associated with thiouracil derivatives (propylthiouracil [PTU]) and 25% with methyl-mercapto-imidazole derivatives (MMI/TMZ). The prevalence of ANCA-positive cases caused by ATD varied between 4% and 64% with PTU (median 30%), and 0% and 16% with MMI/TMZ (median 6%). Young age and the duration of ATD therapy were the main factors contributing to the emergence of ANCA positivity. Before ATD therapy initiation, the prevalence of ANCA-positive patients was 0-13%. During ATD administration, 20% of patients were found to be positive for ANCA. Only 15% of ANCA-positive patients treated with ATD exhibited clinical evidence of vasculitis, corresponding to 3% of all patients who received ATD. Clinical manifestations of ANCA-associated vasculitis related to ATD were extremely heterogeneous. When vasculitis occurred, ATD withdrawal was usually followed by rapid clinical improvement and a favorable prognosis.

Conclusions: ANCA screening is not systematically recommended for individuals on ATD therapy, particularly given the decreasing use of PTU in favor of TMZ/MMI. Particular attention should be given to the pediatric population with Graves' disease who receive ATD, as well as patients treated with thiouracil derivatives and those on long-term ATD therapy.
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http://dx.doi.org/10.1089/thy.2014.0603DOI Listing
December 2015

Diagnostic performance of a new vimentin-derived ACPA (CCP high sensitive) in patients with rheumatoid arthritis.

Immunol Res 2016 Apr;64(2):455-60

Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, 147, Bd Baille, 13005, Marseille, France.

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.
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http://dx.doi.org/10.1007/s12026-015-8690-9DOI Listing
April 2016

Serological proteome analysis reveals new specific biases in the IgM and IgG autoantibody repertoires in autoimmune polyendocrine syndrome type 1.

Autoimmunity 2015 27;48(8):532-41. Epub 2015 Aug 27.

b UDSL, EA 2686, UFR Médecine , Lille , France .

Objective: Autoimmune polyendocrine syndrome type 1 (APS 1) is caused by mutations in the AIRE gene that induce intrathymic T-cell tolerance breakdown, which results in tissue-specific autoimmune diseases.

Design: To evaluate the effect of a well-defined T-cell repertoire impairment on humoral self-reactive fingerprints, comparative serum self-IgG and self-IgM reactivities were analyzed using both one- and two-dimensional western blotting approaches against a broad spectrum of peripheral tissue antigens.

Methods: Autoantibody patterns of APS 1 patients were compared with those of subjects affected by other autoimmune endocrinopathies (OAE) and healthy controls.

Results: Using a Chi-square test, significant changes in the Ab repertoire were found when intergroup patterns were compared. A singular distortion of both serum self-IgG and self-IgM repertoires was noted in APS 1 patients. The molecular characterization of these antigenic targets was conducted using a proteomic approach. In this context, autoantibodies recognized more significantly either tissue-specific antigens, such as pancreatic amylase, pancreatic triacylglycerol lipase and pancreatic regenerating protein 1α, or widely distributed antigens, such as peroxiredoxin-2, heat shock cognate 71-kDa protein and aldose reductase. As expected, a well-defined self-reactive T-cell repertoire impairment, as described in APS 1 patients, affected the tissue-specific self-IgG repertoire. Interestingly, discriminant IgM reactivities targeting both tissue-specific and more widely expressed antigens were also specifically observed in APS 1 patients. Using recombinant targets, we observed that post translational modifications of these specific antigens impacted upon their recognition.

Conclusions: The data suggest that T-cell-dependent but also T-cell-independent mechanisms are involved in the dynamic evolution of autoimmunity in APS 1.
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http://dx.doi.org/10.3109/08916934.2015.1077230DOI Listing
September 2016