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1.
Artigo em Inglês | MEDLINE | ID: mdl-32004407

RESUMO

We appreciate the comments by Dr. Abeles [1] about our recent publication on anti-nuclear antibody (ANA, referred to as anti-cellular antibody (ACA) in our publication and in this response) negative sera in systemic lupus erythematosus (SLE) that utilized biobanked serum samples from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort [2]. We concur with many of the comments and concerns, although we prefer to think that the issues raised are not so much "debatable" as requiring further study.

2.
Environ Int ; 136: 105472, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31991236

RESUMO

BACKGROUND: Air pollution has many adverse health effects, but the combined or synergistic effects of multiple ambient air pollutants on anti-nuclear antibodies (ANA, a serologic marker of systemic autoimmune rheumatic disease, SARDs) have never been assessed. OBJECTIVE: To flexibly model ANA and individual and joint associations of long-term exposures to nitrogen dioxide (NO2), ozone (O3), and fine particles matter (PM2.5) using a Bayesian Kernel machine regression (BKMR) approach and to compare the results to those from individual logistic regressions. METHODS: Serum ANA positivity was determined for randomly selected CARTaGENE general population subjects in Quebec, Canada. CARTaGENE is a public research platform created for investigating the associations of environmental, genomic, and lifestyle factors on chronic diseases. Ambient NO2, O3, and PM2.5 estimates, derived from ground-measurement and chemical-transport-model simulated concentrations, were assigned to subjects based on residential postal codes at the time of blood collection. Our models adjusted for age, sex, French Canadian origin, smoking, and family income. RESULTS: Concentrations of NO2, O3, and PM2.5 were closely correlated in space. In the 5485 CARTaGENE subjects studied, we did not see clear associations between NO2, PM2.5 or O3 and ANA positivity, with either the BKMR or logistic models. CONCLUSIONS: BKMR did not uncover associations between ANA positivity and individual levels or combined exposures of NO2, O3, and PM2.5; neither did simpler logistic models. Additional studies (in younger populations, in distinct race/ethnicity groups, and/or in jurisdictions with high air pollution levels) would be helpful to reinforce current findings.

3.
Arthritis Res Ther ; 22(1): 5, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915059

RESUMO

OBJECTIVE: To describe successful therapeutic strategies in statin-induced anti-HMGCR myopathy. METHODS: Retrospective data from a cohort of 55 patients with statin-induced anti-HMGCR myopathy, sequentially stratified by the presence of proximal weakness, early remission, and corticosteroid and IVIG use at treatment induction, were analyzed for optimal successful induction and maintenance of remission strategies. RESULTS: A total of 14 patients achieved remission with a corticosteroid-free induction strategy (25%). In 41 patients treated with corticosteroids, only 4 patients (10%) failed an initial triple steroid/IVIG/steroid-sparing immunosuppressant (SSI) induction strategy. Delay in treatment initiation was independently associated with lower odds of successful maintenance with immunosuppressant monotherapy (OR 0.92, 95% CI 0.85 to 0.97, P = 0.015). While 22 patients (40%) presented with normal strength, only 9 had normal strength at initiation of treatment. CONCLUSION: While corticosteroid-free treatment of anti-HMGCR myopathy is now a safe option in selected cases, initial triple steroid/IVIG/SSI was very efficacious in induction. Delays in treatment initiation and, as a corollary, delays in achieving remission decrease the odds of achieving successful maintenance with an SSI alone. Avoiding such delays, most notably in patients with normal strength, may reset the natural history of anti-HMGCR myopathy from a refractory entity to a treatable disease.

4.
Autoimmun Rev ; : 102463, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31927088

RESUMO

The discovery of autoantibodies to ribosomal proteins (anti-RibP) dates back more than fifty years when antibodies to ribosomes were identified in systemic lupus erythematosus (SLE) sera. Over the years, anti-RibP autoantibodies have been the subject of extensive study and became known as a highly specific biomarker for the diagnosis of SLE and were associated with neuropsychiatric SLE (NPSLE), lupus nephritis (LN) and hepatitis (LH). As demonstrated by studies on cultured human cells and of murine models, there is evidence to suggest that anti-RibP may have a pathogenic role in LN and NPSLE. Despite a wealth of evidence, in comparison to other SLE autoantibodies such as anti-Sm and anti-dsDNA, anti-RibP has not been included in classification criteria for SLE. A significant challenge is the variability of assays used to detect anti-RibP, including the antigens and diagnostic platforms employed. This may account for the marked variation in frequencies (10-47%) in SLE and its association with clinical and demographic features reported in SLE cohorts. We performed a systematic literature review and meta-analysis to help clarify its prevalence, various clinical and serological associations in SLE based on the different RibP antigens and assay platforms used.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31628718

RESUMO

BACKGROUND: Screening for Cognitive Impairment (CI) in Systemic Lupus Erythematosus (SLE) conventionally relies on the American College of Rheumatology (ACR) Neuropsychological Battery (NB), which is not universally available. To develop a more accessible screening approach, we assessed validity of the Automated Neuropsychological Assessment Metrics (ANAM). Using the ACR-NB as the gold standard for CI classification, the objectives were to (a) measure overall discriminative validity of the ANAM for CI vs. non-CI, (b) identify ANAM subtests and scores that best differentiate CI from non-CI patients, and (c) derive an ANAM composite indices and cut-offs. METHODS: 211 consecutive adult, female/male SLE patients were administered the ANAM and NB. (a) For overall discriminative validity of the ANAM, we compared CI vs non-CI patients on 4 scores. (b) Six ANAM models using different scores were developed and the most discriminatory subtests were selected using logistic regression analyses. The Area Under the receiver operating characteristics Curve (AUC) was calculated to establish ANAM validity against NB. (c) ANAM composite indices and cut-offs were derived for the best model(s), and sensitivities/specificities calculated. RESULTS: Patients with non-CI performed better on most ANAM subtests, supporting ANAM's discriminative validity. CI could be accurately identified by selected ANAM subtests with top models demonstrating excellent AUCs of 81% and 84%. Derived composite indices and cut-offs demonstrated sensitivity of 78-80% and specificity of 70%. CONCLUSION: This study provides support for ANAM's discriminative validity for CI and utility for cognitive screening in adult SLE. Derived composite indices and cut-offs enhance clinical applicability.

10.
Nucleic Acids Res ; 47(17): 9368-9385, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31400113

RESUMO

Cellular non-membranous RNA-granules, P-bodies (RNA processing bodies, PB) and stress granules (SG), are important components of the innate immune response to virus invasion. Mechanisms governing how a virus modulates PB formation remain elusive. Here, we report the important roles of GW182 and DDX6, but not Dicer, Ago2 and DCP1A, in PB formation, and that Kaposi's sarcoma-associated herpesvirus (KSHV) lytic infection reduces PB formation through several specific interactions with viral RNA-binding protein ORF57. The wild-type ORF57, but not its N-terminal dysfunctional mutant, inhibits PB formation by interacting with the N-terminal GW-domain of GW182 and the N-terminal domain of Ago2, two major components of PB. KSHV ORF57 also induces nuclear Ago2 speckles. Homologous HSV-1 ICP27, but not EBV EB2, shares this conserved inhibitory function with KSHV ORF57. By using time-lapse confocal microscopy of HeLa cells co-expressing GFP-tagged GW182, we demonstrated that viral ORF57 inhibits primarily the scaffolding of GW182 at the initial stage of PB formation. Consistently, KSHV-infected iSLK/Bac16 cells with reduced GW182 expression produced far fewer PB and SG, but 100-fold higher titer of infectious KSHV virions when compared to cells with normal GW182 expression. Altogether, our data provide the first evidence that a DNA virus evades host innate immunity by encoding an RNA-binding protein that promotes its replication by blocking PB formation.


Assuntos
Autoantígenos/genética , RNA Helicases DEAD-box/genética , Herpesvirus Humano 8/genética , Proteínas Proto-Oncogênicas/genética , Proteínas de Ligação a RNA/genética , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Argonauta/genética , Regulação Viral da Expressão Gênica/genética , Células HeLa , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8/patogenicidade , Interações Hospedeiro-Patógeno/genética , Humanos , RNA Viral/genética , Replicação Viral/genética
11.
Clin Epigenetics ; 11(1): 110, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366403

RESUMO

OBJECTIVE: To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk. METHODS: With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. An independent set of T cells from RA patients was used to "validate" the differentially methylated sites. RESULTS: We measured DNA methylation in 137 subjects, of whom 63 were ACPA-positive, 66 were ACPA-negative, and 8 had self-reported RA. We identified 1303 DMRs of relevance, of which one third (402) had underlying genetic effects. These DMRs were enriched in intergenic CpG islands (CGI) and CGI shore regions. Furthermore, the genes associated with these DMRs were enriched in pathways related to Epstein-Barr virus infection and immune response. In addition, 80 (38%) of 208 RA-specific DMRs were replicated in T cells from RA samples. CONCLUSIONS: Sequencing-based high-resolution methylome mapping revealed biologically relevant DNA methylation changes in asymptomatic individuals positive for ACPA that overlap with those seen in RA. Pathway analyses suggested roles for viral infections, which may represent the effect of environmental triggers upstream of disease onset.

12.
Rheumatology (Oxford) ; 58(10): 1784-1793, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323671

RESUMO

OBJECTIVE: Detection of antinuclear antibodies and specific autoantibodies is important in the diagnosis and classification of SSc. Several proteins of the Th/To complex, including Rpp25, Rpp38 and hPop1 are the target of autoantibodies in SSc patients. However, very little is known about the epitope distribution of this autoantigen. Consequently, we screened Rpp25, Rpp38 and hPop1 for B cell epitopes and evaluated their clinical relevance. METHODS: Serum pools with (n = 2) and without (n = 1) anti-Th/To autoantibodies were generated and used for epitope discovery. Identified biomarker candidate sequences were then utilized to synthesize synthetic, biotinylated, soluble peptides. The peptides were tested to determine reactivity with sera from SSc cohorts (n = 202) and controls (n = 159) using a chemiluminescence immunoassay. Additionally, samples were also tested for antibodies to full-length recombinant Rpp25 antibodies by chemiluminescence immunoassay. RESULTS: Several immunodominant regions were found on the three proteins. The strongest reactivity was observed with an Rpp38 peptide (aa 229-243). Autoantibodies to the Rpp38 peptide were detected in 8/149 (5.4%) limited cutaneous SSc patients, but not in any of 159 controls (P = 0.003 by two-sided Fisher's exact probability test). Although reactivity to the novel antigenic peptide was correlated with the binding to Rpp25 (rho = 0.44; P < 0.0001), subsets of patient sera either reacted strongly with Rpp25 or with the novel Rpp38-derived peptide. CONCLUSION: A novel Rpp38 epitope holds promise to increase the sensitivity in the detection of anti-Th/To autoantibodies, thus enhancing the serological diagnosis of SSc.

13.
Monoclon Antib Immunodiagn Immunother ; 38(4): 162-170, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31260385

RESUMO

Kinesin-like protein KIF20B, originally named M-phase phosphoprotein 1 (MPP1), is a plus-end-directed kinesin-related protein that exhibits in vitro microtubule-binding and -bundling properties as well as microtubule-stimulated ATPase activity. It has been characterized as a slow molecular motor that moves toward the plus-end of microtubules. Human autoantibodies directed against KIF20B have been described in up to 25% of patients with idiopathic ataxia and less commonly in other neuropathies and autoinflammatory conditions. One of the limitations of research into the structure and function of KIF20B has been a reliable monoclonal antibody that can be used in a variety of applications. To establish a reference standard for anti-KIF20B immunoassays and facilitate studies on the role of KIF20B in developmental cell biology, we developed an IgG1 monoclonal antibody, 10C7, which reacts with the cognate KIF20B protein in Western immunoblots and in addressable laser bead immunoassays. In HEp2 cells, leptomeningeal pericytes, and transfected HEK293T cells, indirect immunofluorescence studies showed that reactivity was mainly localized to a proportion of interphase nuclei, but during metaphase, it was redistributed throughout the cytoplasm and perichromatin mass. Later in telophase/anaphase, KIF20B was localized to the stem body and midzone of the midbody. 10C7 also showed remarkable staining of a subset of cells in the cerebellum, ovary, and testis tissues. KIF20B was shown to have extensive coiled-coil domains. The monoclonal antibody, 10C7, will be of value to diagnostic laboratory scientists interested in having a reliable reference standard for anti-KIF20B immunoassays as well as cell, molecular, and developmental biology researchers.


Assuntos
Anticorpos Monoclonais/imunologia , Mapeamento de Epitopos , Hibridomas/imunologia , Cinesina/antagonistas & inibidores , Cinesina/imunologia , Neoplasias Laríngeas/metabolismo , Proteínas Recombinantes/imunologia , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/farmacologia , Formação de Anticorpos , Humanos , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/imunologia , Células Tumorais Cultivadas
14.
Respir Med ; 153: 85-90, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31176275

RESUMO

INTRODUCTION: A proportion of patients with idiopathic pulmonary fibrosis (IPF) have autoantibodies directed against intracellular targets. This study aimed to determine the relationship between serologic status, lung function decline and survival. METHODS: IPF patients assessed for antinuclear antibody (ANA) and related antigen-specific serology detected by addressable laser bead immunoassay (ALBIA) were included. Demographics, serial pulmonary function tests and survival were compared between patients with and without autoantibodies. Linear mixed models were used to estimate changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time. Cox-proportional hazards models were used to compare survival, adjusted for a composite score including age, sex and baseline lung function. RESULTS: Of 61 included patients, the mean baseline age was 70 years (SD = 9), 77% were male, and 87% were Caucasian. Either ANA or antigen-specific serology by ALBIA was positive in 25 (41%) during follow-up. ANA was detected in 23 (38%), and specific autoantibodies by ALBIA in 6 (10%). There was no difference in age, sex, race, smoking status, anti-fibrotic use or baseline FVC or DLCO in patients with and without autoantibodies. There was no association between autoantibody status and survival (HR = 1.18, 95% CI 0.61, 2.29), rate of decline in FVC or DLCO (difference in FVC = 4.2 mL/year, p = 0.82; difference in DLCO = 4.6*10-4 mL/min/mmHg/year, p = 0.20). CONCLUSION: These data suggest that autoantibodies are common in IPF and that patients with a subset of autoantibodies, but without features of autoimmunity, demonstrate similar disease behaviour to those without autoantibodies.

15.
Life Sci Alliance ; 2(3)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31221625

RESUMO

STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disorder characterized by blood vessel occlusions, acral necrosis, myositis, rashes, and pulmonary inflammation that are the result of activating mutations in the STimulator of Interferon Genes (STING). We generated a transgenic line that recapitulates many of the phenotypic aspects of SAVI by targeting the expression of the human STING-N154S-mutant protein to the murine hematopoietic compartment. hSTING-N154S mice demonstrated failure to gain weight, lymphopenia, progressive paw swelling accompanied by inflammatory infiltrates, severe myositis, and ear and tail necrosis. However, no significant lung inflammation was observed. X-ray microscopy imaging revealed vasculopathy characterized by arteriole occlusions and venous thromboses. Type I interferons and proinflammatory mediators were elevated in hSTING-N154S sera. Importantly, the phenotype was prevented in hSTING-N154S mice lacking the type I interferon receptor gene (Ifnar1). This model, based on a mutant human STING protein, may shed light on the pathophysiological mechanisms operative in SAVI.


Assuntos
Células Sanguíneas/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Proteínas de Membrana/genética , Mutação , Receptor de Interferon alfa e beta/genética , Doenças Vasculares/genética , Animais , Biomarcadores , Citocinas , Modelos Animais de Doenças , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Linfopenia/genética , Linfopenia/metabolismo , Linfopenia/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Imagem Molecular , Especificidade de Órgãos , Fenótipo , Receptor de Interferon alfa e beta/metabolismo , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia
16.
Front Immunol ; 10: 881, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068947

RESUMO

Due to a missense mutation in the Foxp3 gene, scurfy mice are deficient in functional regulatory T cells (Treg). The consequent loss of peripheral tolerance manifests itself by fatal autoimmune mediated multi-organ disease. Previous studies have outlined the systemic inflammatory disease and demonstrated production of anti-nuclear antibodies (ANA) in scurfy mice. However, specific autoantibody targets remained to be defined. ANA are immunological markers for several connective tissue diseases (CTD) and target a large number of intracellular molecules. Therefore, we examined scurfy sera for the presence of different ANA specificities and further assessed the organ involvement in these animals. Indirect immunofluorescence was used as a screen for ANA in the sera of scurfy mice and dilutions of 1/100 were considered positive. Addressable laser bead immunoassays (ALBIA) were used to detect specific autoantibody targets. Subsequent histological tissue evaluation was verified by hematoxylin and eosin (H&E) staining. In our study, we observed that nearly all scurfy mice produced ANA. The most prevalent pattern in scurfy sera was nuclear coarse speckled, also known as the AC-5 pattern according to the International Consensus on ANA Patterns. U1-ribonucleoprotein (U1RNP) was found to be the most common target antigen recognized by autoantibodies in scurfy mice. Additionally, scurfy mice exhibited a mild myositis with histological characteristics similar to polymyositis/dermatomyositis. Myopathy-specific autoantibody profile revealed significantly increased levels of anti-SMN (survival of motor neuron) as well as anti-Gemin3 antibodies in scurfy sera. Overall, we demonstrate that the impaired peripheral tolerance in the absence of regulatory T cells in scurfy mice is associated with features of mixed connective tissue disease (MCTD). This includes, along with our previous findings, very high titers of anti-U1RNP antibodies and an inflammatory myopathy.

18.
Clin Chem Lab Med ; 57(11): 1754-1763, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31005948

RESUMO

Background International autoantibody standards, traditionally based on material obtained from plasmapheresis of single subjects, represent individual immune response and may not comprehend the heterogeneity of the general population. The anti-DFS70 autoantibody yields a characteristic dense fine speckled (DFS) nuclear pattern on indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA) and speaks against autoimmunity. We propose a novel strategy for developing autoantibody reference standards, based on stepwise pooling of serum samples from hundreds of individuals with anti-DFS70 antibodies. Methods Within a 2-year period, serum samples were selected from routine HEp-2 IFA according to the following criteria: DFS HEp-2 IFA pattern at titer ≥1:640; anti-DFS70 reactivity in three analyte-specific tests (Western blot [WB], enzyme-linked immunosorbent assay [ELISA] and chemiluminescent immunoassay [CLIA]). Aliquots of individual samples were combined into progressively larger pools with stepwise validation of intermediary pools as for individual samples. Validated intermediary pools were merged into a final pool for lyophilization. Results A total of 741 validated samples yielded a 750 mL final pool that was lyophilized into thousands of 200 µL-aliquots. Reconstituted aliquots yielded the expected anti-DFS70 reactivity in ELISA, CLIA and WB, as well as high-titer DFS HEp-2 IFA pattern. The appropriate anti-DFS70 reactivity of the lyophilized pool was confirmed by seven international expert centers, using HEp-2 IFA, ELISA, WB and immunoprecipitation. Conclusions This proof-of-concept study provides an innovative and efficient strategy to build serum reference standards for autoantibody testing. The anti-DFS70 standard will integrate the panel of standards of Autoantibody Standardization Committee (ASC, www.autoab.org), contributing to education for proper assay validation and interpretation of the DFS pattern and other HEp-2 IFA patterns.

19.
Front Immunol ; 10: 662, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001269

RESUMO

Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is present worldwide. Autoantibodies, in particular anti-mitochondrial antibodies (AMA) detected by indirect immunofluorescence assays or newer solid phase immunoassays can detect most, but not all individuals with PBC. Detection of antibodies to the anti-nuclear antigens sp100 and gp210 can identify additional PBC patients, but some seronegative patients remain, often resulting in delayed diagnosis and treatment. Antibodies to kelch-like 12 (KLHL12) and hexokinase 1 (HK-1) were recently identified as new biomarkers for PBC and notably identify patients who are negative for conventional autoantibodies. To become globally adopted, it is important to validate these new biomarkers in different geographic areas. In the present study we evaluated the prevalence of anti-KLHL12 (measured by a KLHL12-derived peptide referred to as KL-p) and anti-HK-1 antibodies by ELISA at five sites within Europe and North America and demonstrated the presence of these antibodies in patients with PBC in all geographies.

20.
Open Forum Infect Dis ; 6(4): ofz114, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30949544

RESUMO

The relationship between pulmonary tuberculosis and auto-antibodies remains undefined. In a study of 75 patients with pulmonary tuberculosis and 75 controls, the prevalence of auto-antibodies was assessed in a reference laboratory using a comprehensive panel with standardized methodology. No significant relationship was found between auto-antibody prevalence and pulmonary tuberculosis.

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