Browsing by Author "Fritzler, Marvin J."
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Item Open Access Anti-centromere autoantibody profiles in scleroderma(1994) LeBlond, Denise Eve; Fritzler, Marvin J.Item Open Access Antiphospholipase A2 Receptor Autoantibodies: A Comparison of Three Different Immunoassays for the Diagnosis of Idiopathic Membranous Nephropathy(2014-04-09) Behnert, Astrid; Schiffer, Mario; Müller-Deile, Janina; Beck, Laurence H.; Mahler, Michael; Fritzler, Marvin J.Background. The recent identification of circulating autoantibodies directed towards the M-type phospholipase A2 receptor (PLA2R) has been a major advancement in the serological diagnosis of idiopathic membranous nephropathy (IMN), a common cause of nephrotic syndrome in adults. The goal of this study was to compare the performance characteristics of two commercial assays as well as the first addressable laser bead immunoassay (ALBIA) developed for the detection of anti-PLA2R antibodies. Methods. Serum samples of 157 IMN patients and 142 controls were studied. Samples were tested by a cell based immunofluorescence assay (CBA-IFA, Euroimmun, Germany), by ELISA (Euroimmun), and by a novel ALBIA employing an in vivo expressed recombinant human PLA2R. Results. Overall, the three assays showed significant qualitative and quantitative correlation. As revealed by receiver operating characteristic analysis, the ALBIA correlated better with the CBA-IFA than the ELISA (). The clinical sensitivities/specificities for IMN were 60.0% (51.0–68.5%)/98.6% (95.0–99.8%) and 56.2% (47.2–64.8%)/100.0% (97.4–100.0%) for ALBIA and CBA-IFA, respectively. Conclusion. The ALBIA represents a promising assay for the detection of anti-PLA2R antibodies showing similar performance to the CBA-IFA and the advantage of ease of use and suitability for high throughput, rapid turnaround times, and multiplexing.Item Open Access Autoantibody reactivity with histone 5(1990) Pauls, John David; Fritzler, Marvin J.The mechanisms responsible for the induction of the autoimmune state in juvenile rheumatoid arthritis (JRA), systemic lupus erythematosus (SLE) and drug-induced lupus (DIL) are poorly understood. One of the features of autoimmunity is the presence of antibodies that react with a variety of self-antigens including nuclear DNA and histone. In keeping with the concept that the autoimmune state is driven by autoantigens, it was hypothesized that autoantibodies from these three patient populations would not bind to the non-mammalian histone H5. The specificity of JRA sera for histone subclasses was examined by immunoblotting. Antibodies to Hl alone were found in 4 of 21 pauciarticular-onset JRA sera, 4 of 19 polyarticular-onset JRA sera, and 2 of 11 systemic-onset JRA sera. Antibodies to H5 alone were found in 1 of 21 pauciarticular JRA sera, 1 of 19 polyarticular JRA sera, and 3 of 11 systemic JRA sera. Antibodies to both Hl and H5 were found in 4 of 21 pauciarticular JRA sera, 4 of 19 polyarticular sera, and 1 of 11 systemic JRA sera. Only two sera reacted with the core histones. No reactivity to histones was observed in 30 sera from age-matched children with non-rheumatic disease. The presence of antibodies to H5 in some JRA patients, in conjunction with sequence similarity analysis, suggests that the immune response in these patients is directed to determinants that are not shared by sequences of mammalian proteins. In an analysis of other patient sera, 79/98 patients with SLE, 3/3 patients with hydralazine-induced lupus (HIL), and 4/4 patients with procainamide-induced lupus (PIL) bound to H5. Proteolytic digestion of H5 and subsequent immunoblotting of the resulting peptides with 9 SLE and 7 DIL sera, revealed binding to an antigenic determinant in the carboxyl terminus. Furthermore, while some H5 antibodies also bind to HI, adsorption and immunoblotting studies identified a population of antibodies that bind specifically to H5. As an approach to determining the linear epitopes on H5, a new solid-phase multi-pin peptide synthesis protocol was used. None of 8 SLE, 3 HIL or 2 PIL sera showed statistically significant reactivity with hexamers in the carboxy-terminus. Of interest, the peptides with the most reactivity were in the globular domain of H5. These observations suggest that the majority of H5 carboxy-terminal determinants observed in immunoblotting experiments are conformational epitopes. Furthermore, since no binding was found to the globular domain by immunoblotting, the linear epitopes in this domain may be unexposed in the native protein. These findings provide new insight into the epitopes on a non-mammalian protein (H5) and give additional information about the origin of autoantibodies in SLE, PIL and HIL.Item Open Access Characterization of a novel endorsomal autoantigen(2006) Stinton, Laura Margaret; Fritzler, Marvin J.Item Open Access Characterization of GW/P Body Components in Astrocyte and Astrocytoma Cells(2013-09-09) Moser, Joanna Joy; Fritzler, Marvin J.GW/P bodies (GWB) are cytoplasmic foci that contain GW182 and Ago2 that bind micro RNA (miRNA) within the RNA-induced silencing complex (RISC) to silence and degrade messenger RNA (mRNA). Clinical studies indicate that 33% of patients with GWB autoantibodies have a motor/sensory neuropathy and/or ataxia. Preliminary data show that GWB are highly expressed in the central nervous system, particularly in astrocytes. Characterizing the protein and RNA components of GWB is key to elucidating their function in astrocyte and astrocytoma cells. First, a detailed immunoprecipiation (IP)-Western blot (WB) protocol was developed to addresses challenges in isolating low abundance protein GW182 and GWB-associated proteins. This protocol provides a biochemical approach for detecting GW182 and associated proteins in biological samples facilitating the elucidation of the diverse functions of GWB. Second, astrocytoma GWB exhibit complex heterogeneity with combinations of LSm4 and XRN1 as well as Ago2 and Dicer, key proteins involved in mRNA degradation and RNA interference respectively. GWB subsets contained the mRNA transport and stabilization proteins SYNCRIP, hnRNPA1 and FMRP, not previously described as part of the GWB complex. Astrocytoma GWB-IP suggested that Dicer, hDcp, LSm4, XRN1, SYNCRIP and FMRP form a multiprotein complex and are involved in a number of regulatory mRNA pathways. Third, GWB/RISC mRNA and miRNA components were profiled by microarray analysis of astrocytoma cells and astrocytes. MiRNAs were highly enriched in astrocyte RISC compared to astrocytoma RISC, astrocytoma and astrocyte cells each contained unique RISC miRNA profiles as compared to their respective cellular miRNA profiles, miR-195, 10b, 29b, 19b, 34a and 455-3p levels were increased and the miR-181b level was decreased in astrocytoma RISC as compared to astrocyte RISC, and the RISC contained decreased levels of mRNAs in astrocyte and astrocytoma cells. Biological pathway analysis of RISC mRNA suggests that ultimately GWB play a pivotal role in malignancy. In future, it is important to move beyond characterizing the GWB components of resting cells, but determine the functional response of GWB when subjected to physiologically relevant stimuli. Clinically, there is much to learn about other GWB autoantigens, other diseases associated with GWB autoantibodies and the genetic basis for GWB autoimmunity.Item Open Access Characterization of GWBs in breast cancer(2005) Luft, LeeAnne Moriah; Fritzler, Marvin J.Item Open Access Clinical and serological evaluation of a novel CENP-A peptide based ELISA(BioMed Central, 2010-05-20) Mahler, Michael; Maes, Liesbeth; Blockmans, Daniel; Westhovens, Rene; Bossuyt, Xavier; Riemekasten, Gabriela; Schneider, Sandra; Hiepe, Falk; Swart, Andreas; Gürtler, Irmgard; Egerer, Karl; Fooke, Margrit; Fritzler, Marvin J.Item Open Access Clinical Phenotypes of Patients with Anti-DFS70/LEDGF Antibodies in a Routine ANA Referral Cohort(2013-02-07) Miyara, Makoto; Albesa, Roger; Charuel, Jean-Luc; El Amri, Mohamed; Fritzler, Marvin J.; Ghillani-Dalbin, Pascale; Amoura, Zahir; Musset, Lucile; Mahler, MichaelObjective. To analyze the clinical value of anti-DFS70 antibodies in a cohort of patients undergoing routine antinuclear antibodies (ANAs) testing. Methods. Sera with a dense fine speckled (DFS) indirect immunofluorescence (IIF) pattern from 100 consecutive patients and 100 patients with other IIF patterns were tested for anti-DFS70 antibodies by a novel chemiluminescence immunoassay (CIA) and for ANA by ANA Screen ELISA (both INOVA). Results. Among the 100 patients with a DFS IIF pattern, 91% were anti-DFS70 positive by CIA compared to 3% in the comparator group . The CIA and IIF titers of anti-DFS antibodies were highly correlated (rho = 0.89). ANA by ELISA was positive in 35% of patients with the DFS IIF pattern as compared to 67% of patients with other patterns . Only 12.0% of patients with DFS pattern and 13.4% with DFS pattern and anti-DFS70 antibodies detected by CIA had systemic autoimmune rheumatic disease (SARD). Only 5/91 (5.5%) patients with anti-DFS70 antibodies had SARD and their sera were negative on the ANA Screen ELISA. Conclusion. Although anti-DFS70 antibodies cannot exclude the presence of SARD, the likelihood is significantly lower than in patients with other IIF patterns and should be included in test algorithms for ANA testing.Item Open Access Current Concepts and Future Directions for the Assessment of Autoantibodies to Cellular Antigens Referred to as Anti-Nuclear Antibodies(2014-04-27) Mahler, Michael; Meroni, Pier-Luigi; Bossuyt, Xavier; Fritzler, Marvin J.The detection of autoantibodies that target intracellular antigens, commonly termed anti-nuclear antibodies (ANA), is a serological hallmark in the diagnosis of systemic autoimmune rheumatic diseases (SARD). Different methods are available for detection of ANA and all bearing their own advantages and limitations. Most laboratories use the indirect immunofluorescence (IIF) assay based on HEp-2 cell substrates. Due to the subjectivity of this diagnostic platform, automated digital reading systems have been developed during the last decade. In addition, solid phase immunoassays using well characterized antigens have gained widespread adoption in high throughput laboratories due to their ease of use and open automation. Despite all the advances in the field of ANA detection and its contribution to the diagnosis of SARD, significant challenges persist. This review provides a comprehensive overview of the current status on ANA testing including automated IIF reading systems and solid phase assays and suggests an approach to interpretation of results and discusses meeting the problems of assay standardization and other persistent challenges.Item Open Access Early endosome antigen 1: characterization and implications for neurological disease(2003) Selak, Sanja; Fritzler, Marvin J.Item Open Access GW182 is a novel protein that localizes to a unique cytoplasmic compartment(2003) Eystathioy, Theophany; Fritzler, Marvin J.Item Open Access Histone domains binding autoimmune sera(1986) Gohill, Jitendra; Fritzler, Marvin J.Item Open Access Identification and characterization of a major golgi complex autoantigen(1994) Griffith, Kevin John; Fritzler, Marvin J.Item Open Access Immunoproliferative effects of nucleosomes(1991) Freigang, Dolores Diane; Fritzler, Marvin J.Item Open Access Myositis with prominent B-cell aggregates causing shrinking lung syndrome in systemic lupus erythematosus: a case report(2022-02-16) Roy, Flavie; Korathanakhun, Pat; Karamchandani, Jason; Dubé, Bruno-Pierre; Landon-Cardinal, Océane; Routhier, Nathalie; Peyronnard, Caroline; Massie, Rami; Leclair, Valérie; Meyer, Alain; Bourré-Tessier, Josiane; Satoh, Minoru; Fritzler, Marvin J.; Senécal, Jean-Luc; Hudson, Marie; O’Ferrall, Erin K.; Troyanov, Yves; Ellezam, Benjamin; Makhzoum, Jean-PaulAbstract Background Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and diaphragmatic weakness in a dyspneic patient. Chest wall dysfunction secondary to pleuritis is the most commonly proposed cause. In this case report, we highlight a new potential mechanism of SLS in SLE, namely diaphragmatic weakness associated with myositis with CD20 positive B-cell aggregates. Case presentation A 51-year-old Caucasian woman was diagnosed with SLE and secondary Sjögren’s syndrome based on a history of pleuritis, constrictive pericarditis, polyarthritis, photosensitivity, alopecia, oral ulcers, xerophthalmia and xerostomia. Serologies were significant for positive antinuclear antibodies, anti-SSA, lupus anticoagulant and anti-cardiolopin. Blood work revealed a low C3 and C4, lymphopenia and thrombocytopenia. She was treated with with low-dose prednisone and remained in remission with oral hydroxychloroquine. Seven years later, she developed mild proximal muscle weakness and exertional dyspnea. Pulmonary function testing revealed a restrictive pattern with small lung volumes. Pulmonary imaging showed elevation of the right hemidiaphragm without evidence of interstitial lung disease. Diaphragmatic ultrasound was suggestive of profound diaphragmatic weakness and dysfunction. Based on these findings, a diagnosis of SLS was made. Her proximal muscle weakness was investigated, and creatine kinase (CK) levels were normal. Electromyography revealed fibrillation potentials in the biceps, iliopsoas, cervical and thoracic paraspinal muscles, and complex repetitive discharges in cervical paraspinal muscles. Biceps muscle biopsy revealed dense endomysial lymphocytic aggregates rich in CD20 positive B cells, perimysial fragmentation with plasma cell-rich perivascular infiltrates, diffuse sarcolemmal upregulation of class I MHC, perifascicular upregulation of class II MHC, and focal sarcolemmal deposition of C5b-9. Treatment with prednisone 15 mg/day and oral mycophenolate mofetil 2 g/day was initiated. Shortness of breath and proximal muscle weakness improved significantly. Conclusion Diaphragmatic weakness was the inaugural manifestation of myositis in this patient with SLE. The spectrum of myologic manifestations of myositis with prominent CD20 positive B-cell aggregates in SLE now includes normal CK levels and diaphragmatic involvement, in association with SLS.Item Open Access Repression of GW/P body components and the RNAi microprocessor impacts primary ciliogenesis in human astrocytes(BioMed Central, 2011-08-31) Moser, Joanna J.; Fritzler, Marvin J.; Rattner, Jerome B.Item Open Access Studying Hypercoagulability in Hip Fracture Patients as Determined by Thrombelastography(2020-06-29) You, Daniel Zheng; Schneider, Prism Steorra; Salo, Paul T.; Fritzler, Marvin J.; Korley, Robert E. C.; Skeith, LeslieHip fractures are the most devastating manifestation of osteoporosis with high venous thromboembolic (VTE) rates reported following surgery. Currently, there is no guideline consensus on the optimal duration of pharmacologic thromboprophylaxis or medication choice. Furthermore, some patients develop VTE despite being on anticoagulation. Thrombelastography (TEG) is a whole-blood viscoelastic hemostatic assay that has the potential to identify hypercoagulable patients at risk for developing VTE. The purpose of this study was to understand the utility of TEG analysis to quantify hypercoagulability and ensuing VTE risk in patients with hip fracture. Serial TEG analysis was performed in a cohort of patients with hip fracture every 24-hours from admission until post-operative day (POD) five, then at two and six weeks post-operatively. Hypercoagulability was quantified using a TEG maximal amplitude (MA) threshold over 65 mm. Multivariable logistic regression evaluated associations between elevated MA values and patient and surgical factors. In total, 121 patients (88 female) with a median age of 81 (range = 53 – 96) were recruited. Although admission TEG analysis revealed normal coagulation status (MA<65mm), patients transitioned to a hypercoagulable state by POD 3. Hypercoagulability peaked two weeks post-operatively. Furthermore, most patients remained hypercoagulable six weeks post-operatively, despite discontinuing anticoagulation one to two weeks prior. On admission, female sex and the presence of chronic kidney disease were associated with hypercoagulability (MA>65mm). Post-operatively, reduced mobility and treatment with arthroplasty were associated with hypercoagulability (MA>65mm). Results from this study support further investigation into individualized extended thromboprophylaxis regimens in patients with hip fracture. Additionally, TEG-identified patient and surgical factors associated with hypercoagulability should be given further consideration to mitigate VTE risk and in the development of future hip fracture specific VTE risk prediction models.Item Open Access Systematic review: cystic fibrosis in the SARS-CoV-2/COVID-19 pandemic(2021-05-20) Mathew, Hannah R.; Choi, May Y.; Parkins, Michael D.; Fritzler, Marvin J.Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the development of life-threatening COVID-19 are believed to disproportionately affect certain at-risk populations. However, it is not clear whether individuals with cystic fibrosis (CF) are at a higher risk of COVID-19 or its adverse consequences. Recurrent respiratory viral infections are often associated with perturbation and pulmonary exacerbations of CF as evidenced by the significant morbidity observed in CF individuals during the 2009 H1N1 pandemic. The primary goal of this review was to systematically survey published accounts of COVID-19 in CF and determine if individuals with CF are disproportionally affected by SARS-CoV-2 and development of COVID-19. Methods We conducted a systematic literature search using EMBASE and Medline between April 28 and December 10, 2020. Six evaluable studies reporting on a total of 339 individuals with CF who developed COVID-19 were included in this study. Results We found that although individuals with CF generally experience acute exacerbations of lung disease from infectious agents, COVID-19 incidence estimates in CF appear to be lower than in the general population. However, there are reports of subsets of CF, such as those who had organ transplants, that may experience a more severe COVID-19 course. Potential protective mechanisms in the CF population include pre-pandemic social isolation practices, infection prevention and control knowledge, altered expression of angiotensin-converting enzyme, and the use of certain medications. Conclusions Although individuals with CF are at risk of acute exacerbations often precipitated by respiratory tract viral infections, published evidence to date indicated that individuals with CF do not experience higher risks of contracting SARS-CoV-2 infection. However, there is evidence that some subsets within the CF population, including those post-transplantation, may experience a more severe clinical course. As SARS-CoV-2 variants are identified and the pandemic goes through additional waves of disease outbreaks, ongoing monitoring of the risk of COVID-19 in individuals with CF is required.Item Open Access The antinuclear antibody HEp-2 indirect immunofluorescence assay: a survey of laboratory performance, pattern recognition and interpretation(2021-02-27) Tebo, Anne E.; Schmidt, Robert L.; Kadkhoda, Kamran; Peterson, Lisa K.; Chan, Edward K. L.; Fritzler, Marvin J.; Wener, Mark H.Abstract Background To evaluate the interpretation and reporting of antinuclear antibodies (ANA) by indirect immunofluorescence assay (IFA) using HEp-2 substrates based on common practice and guidance by the International Consensus on ANA patterns (ICAP). Method Participants included two groups [16 clinical laboratories (CL) and 8 in vitro diagnostic manufacturers (IVD)] recruited via an email sent to the Association of Medical Laboratory Immunologists (AMLI) membership. Twelve (n = 12) pre-qualified specimens were distributed to participants for testing, interpretation and reporting HEp-2 IFA. Results obtained were analyzed for accuracy with the intended and consensus response for three main categorical patterns (nuclear, cytoplasmic and mitotic), common patterns and ICAP report nomenclatures. The distributions of antibody titers of specimens were also compared. Results Laboratories differed in the categorical patterns reported; 8 reporting all patterns, 3 reporting only nuclear patterns and 5 reporting nuclear patterns with various combinations of other patterns. For all participants, accuracy with the intended response for the categorical nuclear pattern was excellent at 99% [95% confidence interval (CI): 97–100%] compared to 78% [95% CI 67–88%] for the cytoplasmic, and 93% [95% CI 86%–100%] for mitotic patterns. The accuracy was 13% greater for the common nomenclature [87%, 95% CI 82–90%] compared to the ICAP nomenclature [74%, 95% CI 68–79%] for all participants. Participants reporting all three main categories demonstrated better performances compared to those reporting 2 or less categorical patterns. The average accuracies varied between participant groups, however, with the lowest and most variable performances for cytoplasmic pattern specimens. The reported titers for all specimens varied, with the least variability for nuclear patterns and most titer variability associated with cytoplasmic patterns. Conclusions Our study demonstrated significant accuracy for all participants in identifying the categorical nuclear staining as well as traditional pattern assignments for nuclear patterns. However, there was less consistency in reporting cytoplasmic and mitotic patterns, with implications for assigning competencies and training for clinical laboratory personnel.Item Embargo The Characterization of a centromeric antigen that reacts with human autoimmune serum(1984) Ayer, Linda Marie Marney; Fritzler, Marvin J.