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1.
Clin Chem ; 69(7): 711-717, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-37086467

RESUMEN

BACKGROUND: Large ß-globin gene cluster deletions (hereditary persistence of fetal hemoglobin [Hb] or ß-, δß-, γδß-, and ϵγδß-thalassemia), are associated with widely disparate phenotypes, including variable degrees of microcytic anemia and Hb F levels. When present, increased Hb A2 is used as a surrogate marker for ß-thalassemia. Notably, ϵγδß-thalassemias lack the essential regulatory locus control region (LCR) and cause severe transient perinatal anemia but normal newborn screen (NBS) results and Hb A2 levels. Herein, we report a novel deletion of the ϵ, Aγ, Gγ, and ψß loci with intact LCR, δ-, and ß-regions in 2 women and newborn twins. METHODS: Capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), DNA sequencing, multiplex ligation-dependent probe amplification (MLPA), gap-polymerase chain reaction (gap-PCR), and long-read sequencing (LRS) were performed. RESULTS: NBS showed an Hb A > Hb F pattern for both twins. At 20 months, Hb A2 was increased similarly to that in the mother and an unrelated woman. Unexplained microcytosis was absent and the twins lacked severe neonatal anemia. MLPA, LRS, and gap-PCR confirmed a 32 599 base pair deletion of ϵ (HBE1) through ψß (HBBP1) loci. CONCLUSIONS: This deletion represents a hemoglobinopathy category with a distinct phenotype that has not been previously described, an ϵγ-thalassemia. Both the NBS Hb A > F pattern and the subsequent increased Hb A2 without microcytosis are unusual. A similar deletion should be considered when this pattern is encountered and appropriate test methods selected for detection. Knowledge of the clinical impact of this new category will improve genetic counselling, with distinction from the severe transient anemia associated with ϵγδß-thalassemia.


Asunto(s)
Hemoglobinopatías , Talasemia , Talasemia beta , Humanos , Femenino , Talasemia/genética , Talasemia beta/diagnóstico , Talasemia beta/genética , Hemoglobina Fetal/genética , Reacción en Cadena de la Polimerasa Multiplex
2.
Hemoglobin ; 44(3): 174-178, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32552204

RESUMEN

Hb Bronovo [α103(G10)His→Leu, HBA2: c.311A>T] is an α-globin variant that interferes with and decreases binding efficiency to α hemoglobin (Hb) stabilizing protein (AHSP), a chaperone molecule. The histidine residue at position 103 is integral to the AHSP hydrogen bond formation where disruption results in an increased quantity of cytotoxic free α-globin chains, thereby creating a similar pathophysiology as ß-thalassemia (ß-thal). We report a family with Hb Bronovo, including a homozygous proband, which resulted from maternal uniparental disomy (UPD). Although not detected by routine studies in previous reports, the variant protein is visible by intact mass spectrometry (MS).


Asunto(s)
Alelos , Hemoglobinas Anormales/genética , Homocigoto , Mutación , Globinas alfa/genética , Talasemia alfa/diagnóstico , Talasemia alfa/genética , Sustitución de Aminoácidos , Preescolar , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Patrón de Herencia , Masculino , Herencia Materna , Linaje
3.
Am J Hematol ; 2018 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-29790589

RESUMEN

Hereditary erythrocytosis is associated with high oxygen affinity hemoglobin variants (HOAs), 2,3-bisphosphoglycerate deficiency and abnormalities in EPOR and the oxygen-sensing pathway proteins PHD, HIF2α, and VHL. Our laboratory has 40 years of experience with hemoglobin disorder testing and we have characterized HOAs using varied protein and molecular techniques including functional assessment by p50 analysis. In addition, we have more recently commenced adding the assessment of clinically relevant regions of the VHL, BPGM, EPOR, EGLN1 (PHD2), and EPAS1 (HIF2A) genes in a more comprehensive hereditary erythrocytosis panel of tests. Review of our experience confirms a wide spectrum of alterations associated with erythrocytosis which we have correlated with phenotypic and clinical features. Through generic hemoglobinopathy testing we have identified 762 patients with 81 distinct HOA Hb variants (61 ß, 20 α), including 12 that were first identified by our laboratory. Of the 1192 cases received for an evaluation specific for hereditary erythrocytosis, approximately 12% had reportable alterations: 85 pathogenic/likely pathogenic mutations and 58 variants of unknown significance. Many have not been previously reported. Correlation with clinical and phenotypic data supports an algorithmic approach to guide economical evaluation; although, testing is expanded if the suspected causes are negative or of uncertain significance. Clinical features are similar and range from asymptomatic to recurrent headaches, fatigue, restless legs, chest pain, exertional dyspnea and thrombotic episodes. Many patients were chronically phlebotomized with reported relief of symptoms. This article is protected by copyright. All rights reserved.

4.
Clin Exp Rheumatol ; 33(5): 655-63, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26446265

RESUMEN

OBJECTIVES: The purpose of this study was to investigate whether serum interferon (IFN)-regulated chemokine and distinct cytokine response profiles are associated with clinical improvement in patients with refractory inflammatory myopathy treated with rituximab. METHODS: In a randomised, placebo-phase trial Rituximab in Myositis Trial (RIM), 200 refractory adult and paediatric myositis subjects received rituximab. Following rituximab, clinical response and disease activity were assessed. Serum samples and clinical data were collected at baseline and several time-points after rituximab treatment. Multiplexed sandwich immunoassays quantified serum levels of IFN-regulated chemokines and other pro-inflammatory cytokines. Composite IFN-regulated chemokine and Th1, Th2, Th17 and regulatory cytokine scores were computed. RESULTS: Baseline IFN-regulated chemokine, Th1, Th2, Th17 and regulatory cytokine scores correlated with baseline physician global VAS, whereas the baseline Th1, Th2 and Th17 cytokine scores correlated with baseline muscle VAS. We also found baseline IFN-regulated chemokine scores correlated with specific non-muscular targets such as baseline cutaneous (r=0.29; p=0.002) and pulmonary (r=0.18; p=0.02) VAS scores. Among all cytokine/chemokines examined, the baseline score of IFN-regulated chemokines demonstrated the best correlation with changes in muscle VAS at 8 (r=-0.19; p=0.01) and 16 weeks (r=-0.17; p=0.03) following rituximab and physician global VAS at 16 weeks (r=-0.16; p=0.04). In vitro experiments showed increased levels of IL-8 (p=0.04), MCP-1 (p=0.04), IL-6 (p=0.03), IL-1ß (p=0.04), IL-13 (p=0.04), IL-10 (p=0.02), IL-2 (p=0.04) and IFN-γ (p=0.02) in supernatants of TLR-3 stimulated PBMCs from non-responder compared to patients responders to rituximab. CONCLUSIONS: IFN-regulated chemokines before treatment is associated with improvement in disease activity measures in refractory myositis patients treated with rituximab.


Asunto(s)
Antiinflamatorios/uso terapéutico , Quimiocinas/sangre , Interferón-alfa/farmacología , Miositis/tratamiento farmacológico , Rituximab/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Biomarcadores/sangre , Células Cultivadas , Quimiocinas/inmunología , Femenino , Humanos , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Miositis/sangre , Miositis/diagnóstico , Miositis/inmunología , Valor Predictivo de las Pruebas , Inducción de Remisión , Índice de Severidad de la Enfermedad , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Adulto Joven
5.
BMC Musculoskelet Disord ; 16: 257, 2015 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-26382217

RESUMEN

BACKGROUND: To examine the longitudinal utility of a biomarker signature in conjunction with myositis autoantibodies (autoAbs) as predictors of disease improvement in refractory myositis patients treated with rituximab. METHODS: In the RIM Trial, all subjects received rituximab on 2 consecutive weeks. Using start of treatment as baseline, serum samples (n = 177) were analyzed at baseline and after rituximab with multiplexed sandwich immunoassays to quantify type-1 IFN-regulated and other pro-inflammatory chemokines and cytokines. Biomarker scores were generated for the following pathways: type-1 IFN-inducible (IFNCK), innate, Th1, Th2, Th17 and regulatory cytokines. Myositis autoAbs (anti-synthetase n = 28, TIF-γ n = 19, Mi-2 n = 25, SRP n = 21, MJ n = 18, non-MAA n = 24, unidentified autoantibody n = 9, and no autoantibodies n = 33) determined by immunoprecipitation at baseline, were correlated with outcome measures. Kruskal-Wallis rank sum tests were used for comparisons. RESULTS: The mean (SD) values for muscle disease and physician global disease activity VAS scores (0-100 mm) were 46 (22) and 49 (19). IFNCK scores (median values) were higher at baseline in subjects with anti-synthetase (43), TIF1-γ (31) and Mi-2 (30) compared with other autoAb groups (p < 0.001). At 16 weeks after rituximab, anti-synthetase and Mi-2 autoAb positive subjects and non-MAA had a greater improvement in IFNCK scores (- 6.7, - 6.1 and -7.2, p < .001). Both IFNCK high scores (>30) and autoAb group (Mi-2, non-MAA, and undefined autoantibody) demonstrated the greatest clinical improvement based on muscle VAS (muscle-interaction p = 0.075). CONCLUSION: Biomarker signatures in conjunction with autoAbs help predict response to rituximab in refractory myositis. Biomarker and clinical responses are greatest at 16 weeks after rituximab.


Asunto(s)
Antiinflamatorios/uso terapéutico , Dermatomiositis/tratamiento farmacológico , Polimiositis/tratamiento farmacológico , Rituximab/uso terapéutico , Autoanticuerpos/sangre , Biomarcadores/sangre , Quimiocinas/sangre , Citocinas/sangre , Dermatomiositis/sangre , Dermatomiositis/diagnóstico , Dermatomiositis/inmunología , Método Doble Ciego , Humanos , Polimiositis/sangre , Polimiositis/diagnóstico , Polimiositis/inmunología , Inducción de Remisión , Índice de Severidad de la Enfermedad , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Factores de Tiempo , Resultado del Tratamiento
6.
Arthritis Rheum ; 64(12): 4078-86, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22886447

RESUMEN

OBJECTIVE: Muscle enzyme levels are insensitive markers of disease activity in juvenile and adult dermatomyositis (DM), especially during the active treatment phase. To improve our ability to monitor DM disease activity longitudinally, especially in the presence of immunomodulating agents, we prospectively evaluated whether interferon (IFN)-dependent peripheral blood gene and chemokine signatures could serve as sensitive and responsive biomarkers for change in disease activity in adult and juvenile DM. METHODS: Peripheral blood and clinical data were collected from 51 patients with juvenile or adult DM prospectively over 2 study visits. We performed disease activity measurements and calculated whole-blood type I IFN gene and chemokine scores. We also measured serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). RESULTS: Changes in juvenile and adult DM global disease activity correlated positively and significantly with changes in the type I IFN gene score before adjustment for medication use (r = 0.33, P = 0.023) and with changes in the IFN chemokine score before and after adjustment for medication use (r = 0.53, P < 0.001 and r = 0.50, P < 0.001, respectively). Changes in muscle and extramuscular visual analog scale (VAS) scores correlated positively with changes in IFN gene and chemokine scores (P = 0.002, P < 0.001, P = 0.095, P < 0.001). Serum levels of IL-6, IL-8, and tumor necrosis factor α (TNFα) correlated positively with changes in global, muscle, and extramuscular VAS scores (P < 0.05). CONCLUSION: Our findings suggest that changes in type I IFN gene and chemokine scores as well as in levels of IL-6, IL-8, and TNFα may serve as sensitive and responsive longitudinal biomarkers of change in disease activity in juvenile and adult DM, even in the presence of immunomodulating agents.


Asunto(s)
Quimiocinas/sangre , Dermatomiositis/sangre , Progresión de la Enfermedad , Interferón Tipo I/sangre , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Niño , Preescolar , Dermatomiositis/diagnóstico , Femenino , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Sensibilidad y Especificidad , Factor de Necrosis Tumoral alfa/sangre , Regulación hacia Arriba , Adulto Joven
7.
Am J Perinatol ; 29(2): 71-8, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22105432

RESUMEN

Hirschsprung's disease (HD) presents with severe constipation due to absent ganglion cells in the distal rectum. We sought to determine whether maternal chimeric cells are present in aganglionic bowel. We hypothesize that chimeric cells are part of the unfavorable microenvironment that leads to the destruction of enteric neurons in HD. Intestinal biopsies and resections from seven male patients with HD were compared with four male patients with chronic constipation and six with bowel atresia. Fluorescence in situ hybridization was used to identify chimeric cells based on male/female (XX/XY) differences. The location and immunophenotype of chimeric cells were also studied. Chimeric cells were present more often in the small intestine and rectum, compared with the appendix and colon. Patients with HD had a greater number of chimeric cells per 10× magnification field than patients with chronic constipation or congenital atresia. Chimeric cells were predominantly in the submucosa and outer longitudinal muscle layer in HD. Immunophenotyping identified over 40% of chimeric cells as inflammatory. Chimeric cells are present in greater numbers in aganglionic bowel than in other disorders. Clustering of chimeric cells in areas of absent ganglia lends support to the proposed role of maternal microchimerism in allo-autoimmune responses.


Asunto(s)
Quimerismo , Predisposición Genética a la Enfermedad , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/patología , Mucosa Intestinal/patología , Intestino Grueso/patología , Diferenciación Celular , Cromosomas Humanos X , Cromosomas Humanos Y , Estreñimiento/patología , Femenino , Pruebas Genéticas , Humanos , Inmunohistoquímica , Hibridación in Situ , Recién Nacido , Atresia Intestinal/patología , Masculino , Embarazo , Análisis de Secuencia de ADN
8.
J Mol Diagn ; 23(12): 1732-1740, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34839893

RESUMEN

Complex insertion-deletion (indel) events in the globin genes manifest in widely variable clinical phenotypes. Many are incompletely characterized because of a historic lack of efficient methods. A more complete assessment enables improved prediction of clinical impact, which guides emerging therapeutic choices. Current methods have limited capacity for breakpoint assignment and accurate assessment of mutation extent, especially in cases containing duplications or multiple deletions and insertions. Technology, such as long-read sequencing, holds promise for significant impact in the characterization of indel events because of read lengths that span large regions, resulting in improved resolution. Four known complex ß-globin gene cluster indel types were assessed using single-molecule, real-time sequencing technology and showed high correlation with previous reports, including the Caribbean locus control deletion (g.5,305,478_5,310,336del), a large ß-gene duplication containing the Hb S mutation (g.4,640,335_5,290,171dup with g.5,248,232T>A, c.20A>T; variant allele fraction, 64%), and two nested variants (double deletions with intervening inversion): the Indian Gγ(Aγδß)0-thalassemia (g.5,246,804-5,254,275del, g.5,254,276_5,269,600inv, and g.5,269,601_5,270,442del) and the Turkish/Macedonian (δß)0 thalassemia (g.5,235,064_5,236,652del, g.5,236,653_5,244,280inv, and g.5,244,281_5,255,766del). Our data confirm long-read sequencing as an efficient and accurate method to identify these clinically significant complex events. Limitations include high-complexity sample preparation requirements, which hinder routine use in clinical laboratories. Continued improvements in sample and data workflow processes are needed to accommodate volumes in a tertiary clinical laboratory.


Asunto(s)
Análisis de Secuencia de ADN/métodos , Talasemia/genética , Globinas beta/genética , Anemia de Células Falciformes/genética , Femenino , Duplicación de Gen , Heterocigoto , Humanos , India , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Familia de Multigenes , Globinas beta/análisis
9.
ACR Open Rheumatol ; 1(2): 83-89, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31777784

RESUMEN

OBJECTIVE: Our aim was to identify cytokines and chemokines in patients with adult dermatomyositis (DM) and juvenile dermatomyositis (JDM) that predict changes in disease activity. METHODS: Multiplexed immunoassays (Meso Scale Discovery) enabled simultaneous measurement of interferon (IFN)-regulated chemokines and other pro- and anti-inflammatory cytokines specific to differentiation of specific T-cell and innate pathways. Cytokine scores were computed for IFNCK (IP-10, MCP-1), Th1 (IFNÉ£, TNFα, and IL2), Th2 (IL4, IL10, IL12, and IL 13), Th17 (IL6, IL17, IL1ß), macrophage (MIP-1α, MIP-1ß, IL8), and regulatory (IL10, TNFα) factors. Spearman correlation and mixed models were used to examine whether cytokines at a previous visit predict change in disease activity at the next visit. RESULTS: The study included 36 patients (16 DM and 20 JDM) with at least two visits (87 patient intervals between two visits). Mean age (SD) at inclusion was 56.9 (18.4) years for DM and 10.8 (6.6) years in JDM, 67% of patients were female, 89% Caucasian. The mean (SD) physician global, muscle and extra-muscular disease activity Visual Analog Scale scores at inclusion were 41 (26), 36 (30), and 34 (21) mm, respectively. The change in IFN score from one visit to the next was associated with the change in physician global (P = 0.010) and extramuscular (P < 0.001) disease activity scores. Preliminary results revealed significant correlations of previous IFNCK score and IL-6 with subsequent disease activity measures, but after adjustment for multiple visits per patient, these associations did not reach statistical significance. CONCLUSION: There is a potential relationship between IFNCK and other cytokine scores seen in adult and juvenile DM with future disease states.

10.
J Rheumatol ; 44(1): 117-124, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27803134

RESUMEN

OBJECTIVE: To identify shared and differential molecular pathways in blood and affected muscle between adult dermatomyositis (DM) and juvenile DM, and their association with clinical disease activity measures. METHODS: Gene expression of transcription factors and cytokines involved in differentiation and effector function of T cell subsets, regulatory T cells and follicular Th cells, were analyzed in the blood from 21 newly diagnosed adult and 26 juvenile DM subjects and in 15 muscle specimens (7 adult and 8 juvenile DM) using a custom RT2 Profiler PCR Array. Disease activity was determined and measured by established disease activity tools. RESULTS: The most prominent finding was the higher blood expression of Th17-related cytokines [retinoic acid-related orphan receptor-γ, interferon regulatory factor 4, interleukin (IL)-23A, IL-6, IL-17F, and IL-21] in juvenile DM at baseline. In contrast, adult patients with DM showed increased blood levels of STAT3 and BCL6 compared with juvenile DM. In muscle, GATA3, IL-13, and STAT5B were found at higher levels in juvenile patients with DM compared with adult DM. Among 25 patients (11 adult and 14 juvenile DM) who had blood samples at baseline and at 6 months, increased expression of IL-1ß, STAT3, STAT6, STAT5B, and BCL6 was associated with an improvement in global extramuscular disease activity. CONCLUSION: We observed differences in gene expression profiling in blood and muscle between new-onset adult and juvenile DM. Cytokine expression in the blood of juvenile patients with new-onset DM was dominated by Th17-related cytokines compared with adult patients with DM. This may reflect the activation of different Th pathways between muscle and blood.


Asunto(s)
Citocinas/genética , Dermatomiositis/genética , Músculo Esquelético/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/metabolismo , Adolescente , Adulto , Anciano , Niño , Preescolar , Citocinas/metabolismo , Dermatomiositis/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad
11.
J Inflamm (Lond) ; 12: 29, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25918482

RESUMEN

OBJECTIVE: Recently adipokines have been implicated in the regulation of immune and inflammatory responses in autoimmune disease. To investigate the role of adipokines in adult and pediatric patients with newly diagnosed dermatomyositis (DM), we analyzed peripheral blood and skeletal muscle gene expression of four adipokines: visfatin, leptin, adiponectin and resistin. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected for 21 adult DM, 26 juvenile DM, 5 non-disease adult controls, and 6 non-disease pediatric controls at two time points: baseline and 6 months. Muscle biopsies from 5 adult DM patients and 5 non-disease adult controls were collected at baseline. Similarly, muscle biopsies from 7 juvenile DM patients and 5 non-disease pediatric controls were collected at baseline. The gene expression levels of leptin, adiponectin, resistin, visfatin and related inflammatory cytokines, IL-6, TNF- α, and housekeeping genes GAPDH, B2M, and ACTB were generated using a custom RT(2) Profiler PCR Array. RESULTS: Visfatin gene expression levels in peripheral blood were significantly higher in newly diagnosed adult DM cases compared to non-disease controls (P = 0.004) and these levels correlated with baseline clinical parameters such as age (r = 0.34, P = 0.020), male sex (r = -0.35, P = 0.017), prednisone use (r = -0.42, P = 0.006), and DMARD use (r = 0.35, P = 0.025). No significant association was found between change in visfatin gene expression levels and change in disease activity measures. While visfatin gene expression was significantly up-regulated in muscle tissue of juvenile DM patients (P = 0.028), in adult DM patients only a trend towards significance was observed (P = 0.08). Also, muscle gene expression levels of resistin were significantly elevated in both adult and juvenile DM patients compared respectively to non-disease adult and pediatric controls. Furthermore, an association between peripheral blood resistin gene expression and DM disease activity, including global, muscle, and extra-skeletal disease activity was also observed. CONCLUSION: Peripheral blood visfatin gene expression and muscle resistin gene expression are significantly increased in newly diagnosed adult DM patients. Further longitudinal studies should explore the possibility of using gene expression levels of adipokines such as visfatin and resistin as novel clinical diagnostic biomarkers in DM.

12.
J Rheumatol ; 40(7): 1200-11, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23678152

RESUMEN

OBJECTIVE: To determine the clinical characteristics and subsets of peripheral blood lymphocytes (PBL), which correlate with decreased disease activity in patients with juvenile dermatomyositis (JDM). METHODS: Peripheral blood mononuclear cells from 24 patients with JDM were collected at Mayo Clinic Rochester between 2007 and 2011. These were analyzed using fluorescence-activated cell sorting and flow cytometry. Clinical disease activity was determined by visual analog scales (VAS) collected in 2 consecutive visits and correlated with PBL subsets. RESULTS: The change in CD3+CD69+ T cells correlated with the change in global VAS scores. The change in HLA-DR- CD11c+ myeloid dendritic cells also correlated with the change in extramuscular VAS scores. There were trends toward decreased levels of HLA-DR- CD11c+ cells with decreased muscle and global VAS scores, but these did not reach significance. The change in HLA-DR- CD123+ plasmacytoid dendritic cells negatively correlated with the change in muscle VAS scores. Although not statistically significant, decreased levels of CD3-CD16- CD56+ natural killer (NK) cells and HLA-DR- CD86+ myeloid dendritic cells, and increased levels of CD16+CD56- NK cells, correlated with decreased VAS scores. CONCLUSION: Changes in CD3+CD69+ T cells, HLA-DR- CD11c+ myeloid dendritic cells, and HLA-DR- CD123+ plasmacytoid dendritic cells are associated with improved clinical course in JDM and could be used as markers for disease activity, but findings need to be verified in a larger, independent cohort. Lack of significant differences among most of our PBL subsets suggests that lymphocyte phenotyping may be difficult to definitively correlate with disease activity in JDM.


Asunto(s)
Células Dendríticas/inmunología , Dermatomiositis/inmunología , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Adolescente , Niño , Preescolar , Dermatomiositis/sangre , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Masculino , Índice de Severidad de la Enfermedad , Adulto Joven
13.
SAGE Open Med ; 1: 2050312113514404, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-26770692

RESUMEN

OBJECTIVE: We investigated ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, member 13) messenger RNA levels as a biomarker of disease features in systemic lupus erythematosus. METHODS: We measured and compared messenger RNA (mRNA) levels of ADAMTS13 in peripheral blood cells in patients with systemic lupus erythematosus and healthy control subjects by whole-genome microarray. We retrospectively analyzed the correlations of ADAMTS13 mRNA expression with clinical features, laboratory parameters, therapeutic features, and disease activity (according to the Systemic Lupus Erythematosus Disease Activity Index). We also examined the association of three single nucleotide polymorphisms (rs4962145, rs2285467, and rs685523) of the ADAMTS13 gene with patient characteristics. RESULTS: In 309 patients, the median ADAMTS13 mRNA expression levels were significantly higher in blood cells of systemic lupus erythematosus patients than in 23 healthy controls (p = .03). Notably, ADAMTS13 mRNA expression levels were significantly higher in systemic lupus erythematosus patients with a history of stroke (p = .02) or transient ischemic attack (p = .02). Among the three single nucleotide polymorphisms analyzed, rs2285467 was significantly associated with stroke (p = .03) and anticardiolipin antibodies (p = .04). CONCLUSIONS: Increased expression of ADAMTS13 mRNA in blood cells is associated with the presence of ischemic cerebrovascular disease in systemic lupus erythematosus patients and suggests a potential role for ADAMTS13 in the pathogenesis of ischemic cerebrovascular disease in these patients.

14.
J Rheumatol ; 40(3): 294-302, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23322463

RESUMEN

OBJECTIVE: To investigate B cell survival cytokine messenger RNA (mRNA) levels as biomarkers of idiopathic inflammatory myopathies (IIM). METHODS: We measured and compared mRNA levels of B cell survival cytokines by quantitative real-time polymerase chain reaction in 98 patients with IIM, 38 patients with systemic lupus erythematosus, and 21 healthy controls. The cytokines were B cell-activating factor belonging to the tumor necrosis factor family (BAFF); ΔBAFF; and a proliferation-inducing ligand (APRIL); and their receptors BAFF-R, transmembrane activator and calcium modulator and cyclophilin ligand interactor, and B cell maturation antigen (BCMA). We also identified autoantibodies, including anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-topoisomerase 1, anti-hystidyl-tRNA synthetase, anti-ribosomal P, and anti-chromatin. Clinical disease activity was assessed by the International Myositis Assessment and Clinical Studies core set tool. We examined correlation of mRNA with disease activity, medication use, and autoantibodies. RESULTS: We found a positive correlation of BAFF and ΔBAFF expression with 3 disease activity measures, with ΔBAFF having a stronger correlation. Similarly, anti-SSA/Ro-52 and/or anti-SSA/Ro-60 had a strong positive correlation with mRNA levels of BAFF and ΔBAFF, and with relative ratios of BAFF/APRIL and BCMA/BAFF-R. CONCLUSION: These findings highlight the potential importance of BAFF, ΔBAFF, and BAFF-R in the pathogenesis of IIM, and suggest an important role in the assessment of disease activity.


Asunto(s)
Autoanticuerpos/metabolismo , Factor Activador de Células B/metabolismo , Miositis/metabolismo , Adolescente , Adulto , Anciano , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Factor Activador de Células B/genética , Receptor del Factor Activador de Células B/genética , Receptor del Factor Activador de Células B/metabolismo , Antígeno de Maduración de Linfocitos B/genética , Antígeno de Maduración de Linfocitos B/metabolismo , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miositis/genética , Miositis/inmunología , Índice de Severidad de la Enfermedad , Proteína Activadora Transmembrana y Interactiva del CAML/genética , Proteína Activadora Transmembrana y Interactiva del CAML/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo
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