RESUMEN
The correlation between immune responses and protection from SARS-CoV-2 infections and its duration remains unclear. We performed a sanitary surveillance at the European Institute of Oncology (IEO) in Milan over a 17 months period. Pre-vaccination, in 1,493 participants, we scored 266 infections (17.8%) and 8 possible reinfections (3%). Post-vaccination, we identified 30 infections in 2,029 vaccinated individuals (1.5%). We report that the probability of infection post-vaccination is i) significantly lower compared to natural infection, ii) associated with a significantly shorter median duration of infection than that of first infection and reinfection, iii) anticorrelated with circulating antibody levels.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Vacunas contra la COVID-19/administración & dosificación , COVID-19/inmunología , Inmunoglobulina G/sangre , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/sangre , COVID-19/prevención & control , COVID-19/virología , Femenino , Humanos , Inmunoglobulina G/inmunología , Masculino , Vacunación Masiva , Persona de Mediana Edad , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Factores de Tiempo , Adulto JovenRESUMEN
AIMS: Positive direct antiglobulin tests (DATs) are valuable in identifying the aetiology of autoimmune haemolysis and in guiding therapeutic intervention. However, in HIV-positive individuals with background polyclonal gammopathy, a positive DAT in the absence of haemolysis is common. In this setting, IgG quantification and subtyping may be of value, as this is possible with the recently introduced gel cards. There is paucity of literature evaluating the diagnostic usefulness of IgG subtyping and quantification in HIV-positive individuals who are investigated for autoimmune haemolytic anaemia (AIHA). This study evaluated the usefulness of IgG quantification and subtyping in the diagnostic work-up of AIHA in patients with a positive DAT, with and without HIV infection. METHODS: This retrospective, cross-sectional study included patients investigated for AIHA in a quaternary care hospital. Those with a positive DAT had their IgG subtyped and quantified using the ID-Card DAT IgG1/IgG3 and IgG-dilution cards (Bio-Rad, Cressier, Switzerland). RESULTS: Ninety patients admitted from December 2019 to March 2020 were investigated for AIHA. Forty-four (49%) patients had a positive DAT of whom 26 (59%) had evidence of haemolysis, and 16 (36%) were HIV positive. Concurrent HIV and haemolysis were present in eight patients, two of whom had IgG1 although none had an IgG antibody titre >1:30. None of the HIV-positive patients without features of haemolysis had IgG1/IgG3 or IgG antibody titres >1:30. CONCLUSION: In our clinical setting, IgG quantification and subtyping were found to be of limited value in the diagnostic characterisation of AIHA in HIV-positive patients with false-positive DAT.
Asunto(s)
Anemia Hemolítica Autoinmune/diagnóstico , Anticuerpos Antiidiotipos/sangre , Prueba de Coombs , Infecciones por VIH/diagnóstico , Inmunoglobulina G/sangre , Adulto , Anemia Hemolítica Autoinmune/sangre , Anemia Hemolítica Autoinmune/epidemiología , Anemia Hemolítica Autoinmune/inmunología , Biomarcadores/sangre , Estudios Transversales , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Atopic dermatitis (AD) is one of the most common chronic inflammatory dermatoses characterized by persistent itching and recurrent eczematous lesions. While the primary events and key drivers of AD are topics of ongoing debate, cutaneous inflammation due to inappropriate IgE (auto)antibody-related immune reactions is frequently considered. Highly conserved and immunogenic heat shock protein 90 (Hsp90), a key intra- and extracellular chaperone, can activate the immune response driving the generation of circulating anti-Hsp90 autoantibodies that are found to be elevated in several autoimmune disorders. Here, for the first time, we observed that serum levels of Hsp90 and anti-Hsp90 IgE autoantibodies are significantly elevated (p < 0.0001) in AD patients (n = 29) when compared to age- and gender-matched healthy controls (n = 70). We revealed a positive correlation (0.378, p = 0.042) between serum levels of Hsp90 and the severity of AD assessed by Scoring Atopic Dermatitis (SCORAD). In addition, seropositivity for anti-Hsp90 IgE has been found in 48.27% of AD patients and in 2.85% of healthy controls. Although further studies on a larger group of patients are needed to confirm presented data, our results suggest that extracellular Hsp90 and autoantibodies to Hsp90 deserve attention in the study of the mechanisms that promote the development and/or maintenance of atopic dermatitis.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Autoanticuerpos/sangre , Dermatitis Atópica/sangre , Proteínas HSP90 de Choque Térmico/sangre , Adolescente , Adulto , Anticuerpos Antiidiotipos/inmunología , Niño , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Dermatitis Atópica/patología , Femenino , Proteínas HSP90 de Choque Térmico/inmunología , Humanos , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Emicizumab is a humanized bispecific monoclonal antibody that bridges activated factor IX (FIXa) and factor X (FX) to mimic the function of factor VIII (FVIII). It suppresses the bleeding tendency in hemophilia A patients with or without FVIII inhibitors. A case of an adult FVIII inhibitor-positive hemophilia A patient in whom treatment with emicizumab was discontinued owing to the repeated bleeding events and prolonged activated partial thromboplastin time. OBJECTIVE: To analyze the mechanisms of decreased efficacy of emicizumab. METHODS: Residual plasma samples were used to measure the following: emicizumab concentration in plasma, measured by enzyme-linked immunosorbent assay; titer of anti-drug antibody (ADA) against emicizumab, measured by electrochemiluminescence; and neutralizing activity against emicizumab, measured by Bethesda method modified by using emicizumab-spiked FVIII-deficient plasma. RESULTS: At week 31, emicizumab concentration was 15.0 µg/ml, and ADAs were measured as positive. Emicizumab concentration continued to decrease until emicizumab discontinuation point at week 49, and after week 50, emicizumab concentrations were below the limitation of quantification. The ADA titer increased transiently from week 31, even past the emicizumab discontinuation point at week 49. The ADA titer then gradually decreased until the last sampling point at week 93. Neutralizing activity against emicizumab was detected after emicizumab discontinuation. Epitope analysis showed that the ADAs recognize the anti-FIXa and anti-FX Fab arms of emicizumab, but not the Fc region. CONCLUSION: The appearance of ADAs with emicizumab-neutralizing activity and potential to accelerate emicizumab clearance decreased the efficacy of emicizumab.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Anticuerpos Biespecíficos , Anticuerpos Monoclonales Humanizados , Hemofilia A , Adulto , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Factor VIII , Hemofilia A/diagnóstico , Hemofilia A/tratamiento farmacológico , HumanosRESUMEN
BACKGROUND: Anti-SARS-CoV-2 antibodies have been used in the study of the immune response in infected patients. However, differences in sensitivity and specificity have been reported, depending on the method of analysis. The aim of the present study was to evaluate the diagnostic accuracy of an algorithm in which a high-throughput automated assay for total antibodies was used for screening and two semi-automated IgG-specific methods were used to confirm the results, and also to correlate the analytical results with the clinical data and the time elapsed since infection. METHODS: We studied 306 patients, some hospitalized and some outpatients, belonging to a population with a high prevalence of COVID-19. One-hundred and ten patients were classified as SARS-CoV-2 negative and 196 as positive by polymerase chain reaction. RESULTS: The algorithm and automated assay alone had a specificity and a positive predictive value of 100%, although the sensitivity and negative predictive value of the algorithm was higher. Both methods showed a good sensitivity from day 11 of the onset of symptoms in asymptomatic and symptomatic patients. The absorbance of the total antibodies was significantly higher in severely symptomatic than in asymptomatic or mildly symptomatic patients, which suggests the antibody level was higher. We found 15 patients who did not present seroconversion at 12 days from the onset of symptoms or the first polymerase chain reaction test. CONCLUSION: This study highlights the proper functioning of algorithms in the diagnosis of the immune response to COVID-19, which can help to define testing strategies against this disease.
Asunto(s)
Algoritmos , Anticuerpos Antivirales/sangre , Prueba Serológica para COVID-19/métodos , COVID-19/diagnóstico , Adulto , Anciano , Anticuerpos Antiidiotipos/sangre , COVID-19/epidemiología , Femenino , Humanos , Inmunoensayo/métodos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Estudios Retrospectivos , SARS-CoV-2/inmunología , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. METHODS: In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. RESULTS: IFX trough concentrations ranged from 0 to > 40 µg/mL and were 3-fold lower in children with IBD compared to children with JIA (p = 0.0002) or uveitis (p = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA (p = 0.0002) or uveitis (p = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity (p = 0.004), male gender (p = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) (p = 0.001), reduced serum albumin concentrations (p = 0.0005), and increased disease activity in JIA (p = 0.009) and IBD (p ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. CONCLUSIONS: Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.
Asunto(s)
Artritis Juvenil , Enfermedades Autoinmunes , Monitoreo de Drogas , Enfermedades Inflamatorias del Intestino , Infliximab , Uveítis , Adolescente , Anticuerpos Antiidiotipos/sangre , Artritis Juvenil/sangre , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/epidemiología , Estudios Transversales , Relación Dosis-Respuesta Inmunológica , Monitoreo de Drogas/métodos , Monitoreo de Drogas/normas , Monitoreo de Drogas/estadística & datos numéricos , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/administración & dosificación , Infliximab/inmunología , Infliximab/farmacocinética , Masculino , Tasa de Depuración Metabólica/fisiología , Pediatría/métodos , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/inmunología , Inhibidores del Factor de Necrosis Tumoral/farmacocinética , Estados Unidos/epidemiología , Uveítis/sangre , Uveítis/diagnóstico , Uveítis/tratamiento farmacológicoRESUMEN
INTRODUCTION: Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown. METHODS: Using competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients. RESULTS: Repertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels. CONCLUSIONS: Differences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.
Asunto(s)
Autoanticuerpos , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , alfa-Sinucleína/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antiidiotipos/sangre , Anticuerpos Antiidiotipos/líquido cefalorraquídeo , Anticuerpos Antiidiotipos/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/inmunología , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/sangre , Atrofia de Múltiples Sistemas/líquido cefalorraquídeo , Atrofia de Múltiples Sistemas/inmunología , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/inmunologíaRESUMEN
BACKGROUND: Anti-tumor necrosis factor (TNF) drugs have improved the prognosis for juvenile idiopathic arthritis (JIA) significantly. However, evidence for individual treatment decisions based on serum anti-TNF drug levels and the presence of anti-drug antibodies (ADAbs) in children is scarce. We aimed to assess if anti-TNF drug levels and/or ADAbs influenced physician's treatment decisions in children with JIA. METHODS: Patients' records in our center were retrospectively screened for measurements of anti-TNF drug levels and ADAbs in children with JIA using etanercept, adalimumab or infliximab. Clinical characteristics and disease activity were retrieved from patient charts. RESULTS: We analyzed 142 measurements of anti-TNF drug levels in 65 children with JIA. Of these, ninety-seven (68.3%) were trough concentrations. N = 14/97 (14.4%) of these showed trough concentrations within the therapeutic drug range known for adults with RA and IBD. ADAbs against adalimumab were detected in seven patients and against infliximab in one patient. Seven (87,5%) of these ADAb-positive patients had non-detectable drug levels. A flowchart was made on decisions including rational dose escalation, stopping treatment in the presence of ADAbs and undetectable drug levels, showing that 45% of measurements influenced treatment decisions, which concerned 65% of patients (n = 42/65). CONCLUSIONS: In the majority of patients, measurement of anti-TNF drug levels led to changes in treatment. A wide variation of anti-TNF drug levels was found possibly due to differences in drug clearance in different age groups. There is need for determination of therapeutic drug ranges and pharmacokinetic curves for anti-TNF and other biologics in children with JIA.
Asunto(s)
Adalimumab , Anticuerpos Antiidiotipos/sangre , Artritis Juvenil , Monitoreo de Drogas/métodos , Etanercept , Infliximab , Inhibidores del Factor de Necrosis Tumoral , Adalimumab/inmunología , Adalimumab/uso terapéutico , Anticuerpos Monoclonales/inmunología , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/inmunología , Niño , Toma de Decisiones Clínicas , Relación Dosis-Respuesta Inmunológica , Etanercept/inmunología , Etanercept/uso terapéutico , Femenino , Humanos , Infliximab/inmunología , Infliximab/uso terapéutico , Masculino , Administración del Tratamiento Farmacológico , Selección de Paciente , Inhibidores del Factor de Necrosis Tumoral/inmunología , Inhibidores del Factor de Necrosis Tumoral/uso terapéuticoRESUMEN
INTRODUCTION: While children of all ages may be affected by Guillain-Barre-Syndrome (GBS), there are no reports of Dengue Fever (DF) as the preceding or concurrent infection in this age group. In addition, the presence of anti-GM1 IgM antibody, commonly seen in Multifocal Motor Neuropathy, is rarely encountered in both axonal and demyelinating variants of GBS. Moreover, only few neuromuscular ultrasound findings of the axonal variant in children were reported in the literature. CASE: Here we present a nine-year-old female who developed the classic signs, symptoms and neurophysiologic findings of axonal type of GBS during DF. She had elevated anti-GM1 IgM antibody atypical of this variant and diffusely enlarged nerves via neuromuscular ultrasound. CONCLUSION: In a pediatric patient with DF and acute flaccid paralysis, GBS should always be one of the considerations. Although rare, anti-ganglioside GM1 IgM antibody can still be found in axonal variant of GBS.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Autoanticuerpos/sangre , Axones/patología , Dengue/sangre , Gangliósido G(M1)/sangre , Síndrome de Guillain-Barré/sangre , Niño , Dengue/complicaciones , Dengue/diagnóstico por imagen , Femenino , Síndrome de Guillain-Barré/complicaciones , Síndrome de Guillain-Barré/diagnóstico por imagen , HumanosRESUMEN
Aim: Development and qualification of an easy-to-use ELISA for detection of IgM anti-drug antibodies (ADA) and its use in a clinical Phase I trial. Results & methodology: During the assay development two positive control (PC) approaches, the preparation of a chemically conjugated and a recombinant PC, were pursued. With both PCs, the assay was developed and successfully qualified considering the regulatory guidelines. For a case study, the IgM ADA isotyping assay with the recombinant PC was selected. Different courses and intensities of immune response regarding IgM signals were demonstrated. Conclusion: The easy-to-use ELISA allowed IgM-ADA detection in clinical samples. Conjugated and recombinant IgM PCs were comparable regarding assay sensitivity, precision and suitability.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Terapia Biológica/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , HumanosRESUMEN
OBJECTIVE: microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE. METHODS: We determined the miR-152-3p expression profiles in CD4+ T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4+ T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88). RESULTS: The obtained findings revealed that miR-152-3p was highly-expressed in CD4+ T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4+ T cells and but also to restrain their cellular inflammation, which were also validated in vivo. CONCLUSION: Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4+ T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.
Asunto(s)
Lupus Eritematoso Sistémico/genética , MicroARNs , Adolescente , Adulto , Anciano , Animales , Anticuerpos Antiidiotipos/sangre , Anticuerpos Antinucleares/sangre , Artralgia/genética , Artralgia/inmunología , Niño , Citocinas/inmunología , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/inmunología , Desmetilación , Eritema/genética , Eritema/inmunología , Cara , Femenino , Humanos , Inflamación/genética , Inflamación/inmunología , Leucocitos Mononucleares/inmunología , Lupus Eritematoso Sistémico/inmunología , Masculino , Ratones Endogámicos MRL lpr , Persona de Mediana Edad , Factor 88 de Diferenciación Mieloide/inmunología , Receptores Toll-Like/inmunología , Adulto JovenRESUMEN
Hemolytic uremic syndrome (HUS), a cause of pediatric acute kidney injury (AKI), has a spectrum of extra-renal manifestations. While neurological and gastrointestinal system involvement is common, cardiac involvement is rare. This is more so with pericardial involvement, though it has been reported in a handful of HUS cases associated with shiga toxin-producing Escherichia coli (STEC HUS). However, this complication has scarcely been reported in atypical HUS (aHUS) where there is alternate complement abnormality or DKGE (diacylglycerol kinase epsilon) mutation. We describe two children diagnosed with anti-complement factor H (CFH) antibody-associated aHUS who had pericardial involvement. Two boys, one 10-year-old and another 8-year-old, presented with pallor, oliguria and hypertension. They both had microangiopathic haemolytic anemia, thrombocytopenia and AKI suggestive of HUS. Complement workup revealed elevated anti-CFH antibody titres. With a diagnosis of anti-CFH antibody aHUS, they were started on plasmapheresis, pulse methylprednisolone and cyclophosphamide. The first case developed cardiac tamponade during the second week of hospital stay for which he needed pigtail drainage and further immunosuppression with rituximab. He gradually improved and pigtail was removed. The second case presented with pericardial effusion which subsequently resolved during the course of treatment. Thus, our patients developed pericardial effusion, with one of them progressing to life-threatening cardiac tamponade. Therefore, it is prudent that we are aware of this complication while treating children with aHUS.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Síndrome Hemolítico Urémico Atípico/diagnóstico , Factor H de Complemento/inmunología , Derrame Pericárdico/complicaciones , Síndrome Hemolítico Urémico Atípico/inmunología , Niño , Humanos , MasculinoRESUMEN
Amyotrophic Lateral Sclerosis (ALS) patients express significant clinical heterogeneity that often hinders a correct diagnostic definition. Intracellular deposition of TDP-43, a protein involved in RNA metabolism characterizes the pathology. Interestingly, this protein can be detected in serum, wherein cognate naturally-occurring auto-antibodies (anti-TDP-43 NAb) might be also present, albeit they have never been documented before. In this exploratory study, we quantified the levels of both anti-TDP-43 NAb and TDP-43 protein as putative accessible markers for improving the ALS diagnostic process by using ELISA in N = 70 ALS patients (N = 4 carrying TARDBP mutations), N = 40 age-comparable healthy controls (CTRL), N = 20 motor neuron disease mimics (MN-m), N = 20 Alzheimer's disease (AD) and N = 15 frontotemporal lobar degeneration (FTLD) patients. Anti-TDP-43 NAb were found to be significantly increased in ALS patients compared to all the other groups (p < 0.001). On the other hand, the distribution of serum levels of TDP-43 protein was highly variable among the various groups. Levels were increased in ALS patients, albeit the highest values were detected in MN-m patients. NAb and protein serum levels failed to correlate. For the first time, we report that serum anti-TDP-43 NAb are detectable in human serum of both healthy controls and patients affected by a variety of neurodegenerative disorders; furthermore, their levels are increased in ALS patients, representing a potentially interesting trait core marker of this disease. Further studies are needed to clarify the exact role of the NAb. This information might be extremely useful for paving the way toward targeting TDP-43 by immunotherapy in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/inmunología , Anticuerpos Antiidiotipos/sangre , Autoanticuerpos/sangre , Proteínas de Unión al ADN/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Anticuerpos Antiidiotipos/aislamiento & purificación , Autoanticuerpos/aislamiento & purificación , Proteínas de Unión al ADN/genética , Femenino , Demencia Frontotemporal/sangre , Demencia Frontotemporal/genética , Demencia Frontotemporal/inmunología , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/sangre , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/inmunología , Degeneración Lobar Frontotemporal/patología , Humanos , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/inmunología , Cuerpos de Inclusión/patología , Masculino , Persona de Mediana Edad , Enfermedad de la Neurona Motora/sangre , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/inmunología , Enfermedad de la Neurona Motora/patología , Mutación/genéticaRESUMEN
PURPOSE: Oxidative stress and inflammation have been implicated in the development of retinal vein occlusion (RVO). Oxidation-specific epitopes (OSEs) represent products of oxidative stress that can trigger vascular inflammation and thrombosis. Natural occurring antibodies have been shown to bind oxidation-specific epitopes thereby inhibiting their inflammatory potential and promoting their removal. METHODS: This prospective cross-sectional study included 270 patients with RVO and 81 in-hospital control patients. We measured three types of serum levels of oxidation-specific epitope-specific immunoglobulin M and immunoglobulin G antibodies (anti-copper-oxidized LDL [CuOx-LDL], antiphosphocholine [PC], anti-malondialdehyde-modified LDL [MDA-LDL]). History of arterial hypertension, hyperlipidemia, myocardial infarction, diabetes mellitus, stroke, smoking status, and several laboratory parameters were determined to control for potential confounders. RESULTS: Compared with controls, patients with RVO had significantly lower levels of immunoglobulin M and immunoglobulin G antibodies against CuOx-LDL and PC, and significantly lower levels of immunoglobulin G but not immunoglobulin M antibodies against MDA-LDL. The association between RVO patients and lower levels of these antibodies prevailed upon multivariable adjustment. CONCLUSION: These prospective data show that antibodies against oxidation-specific epitope are lower in patients with RVO compared with control patients and support the concept that oxidative stress and inflammation play key roles in the development and subsequent complications in RVO.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Epítopos/sangre , Inmunoglobulina M/sangre , Lipoproteínas LDL/sangre , Estrés Oxidativo/inmunología , Oclusión de la Vena Retiniana/sangre , Anciano , Anticuerpos Antiidiotipos/inmunología , Biomarcadores/sangre , Estudios Transversales , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Epítopos/inmunología , Femenino , Angiografía con Fluoresceína/métodos , Estudios de Seguimiento , Fondo de Ojo , Humanos , Inmunoglobulina M/inmunología , Lipoproteínas LDL/inmunología , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Estudios Prospectivos , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/inmunología , Tomografía de Coherencia Óptica/métodosRESUMEN
OBJECTIVES: To assess whether the presence of arthritis autoantibodies alongside IgG ACPA predicts clinically suspect arthralgia in ACPA-positive subjects without RA. METHODS: In the population-based Lifelines cohort (n = 40 136), 308 IgG ACPA-positive individuals without RA were present. Serum levels of IgA ACPA, IgA and IgM RF, and IgG anti-carbamylated antibodies were measured at baseline. Individuals were divided based on the Connective tissue disease Screening Questionnaire after 2 years follow-up. Antibodies to Porphyromonas gingivalis were determined at baseline and related to presence of periodontitis and joint complaints at 2 years follow-up. RESULTS: Of 308 subjects 53.6% were also seropositive for IgA ACPA, 42.2% for IgM RF, 23.7% for IgA RF and 13.6% for anti-carbamylated antibodies. We defined 75 persons with clinically suspect arthralgia at risk for RA based on CTD Screening Questionnaire at follow-up. Significantly more seropositivity for IgM RF and higher levels of IgG ACPA, IgA ACPA and IgM RF were found in clinically suspect arthralgia compared with no-clinically suspect arthralgia. In multivariate logistic regression correcting for age, gender and never smoking, positivity for three or more extra autoantibodies was significantly associated with clinically suspect arthralgia. Although levels of anti-P. gingivalis were not different between groups, they were significantly correlated to levels of both RFs, and both ACPAs in clinically suspect arthralgia. CONCLUSIONS: ACPA-positive individuals without RA who develop clinically suspect arthralgia have more and higher levels of other arthritis autoantibodies at baseline. Levels of anti-P. gingivalis are not related to self-reported periodontitis or clinically suspect arthralgia, but are correlated to arthritis autoantibodies in clinically suspect arthralgia.
Asunto(s)
Anticuerpos Antiproteína Citrulinada/sangre , Anticuerpos Antiidiotipos/sangre , Artritis/inmunología , Vigilancia de la Población , Factor Reumatoide/sangre , Adulto , Artritis/sangre , Artritis/epidemiología , Artritis Reumatoide , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Estudios ProspectivosRESUMEN
Mycoplasma genitalium is a sexually transmitted bacterial pathogen that infects men and women. Antigenic variation of MgpB and MgpC, the immunodominant adherence proteins of M. genitalium, is thought to contribute to immune evasion and chronic infection. We investigated the evolution of mgpB and mgpC sequences in men with non-gonococcal urethritis persistently infected with M. genitalium, including two men with anti-M. genitalium antibodies at enrollment and two that developed antibodies during follow-up. Each of the four patients was persistently infected with a different strain type and each patient produced antibodies targeting MgpB and MgpC. Amino acid sequence evolution in the variable regions of MgpB and MgpC occurred in all four patients with changes observed in single and multiple variable regions over time. Using the available crystal structure of MgpC of the G37 type strain we found that predicted conformational B cell epitopes localize predominantly to the variable region of MgpC, amino acids that changed during patient infection lie in these epitopes, and variant amino acids are in close proximity to the conserved sialic acid binding pocket. These findings support the hypothesis that sequence variation functions to avoid specific antibodies thereby contributing to persistence in the genital tract.
Asunto(s)
Adhesinas Bacterianas/genética , Infecciones por Mycoplasma/genética , Mycoplasma genitalium/genética , Uretritis/genética , Secuencia de Aminoácidos/genética , Animales , Anticuerpos Antiidiotipos/sangre , Anticuerpos Antiidiotipos/inmunología , Linfocitos B/inmunología , Linfocitos B/microbiología , Chlorocebus aethiops , Doxiciclina/farmacología , Evolución Molecular , Humanos , Infecciones por Mycoplasma/sangre , Infecciones por Mycoplasma/inmunología , Infecciones por Mycoplasma/microbiología , Mycoplasma genitalium/inmunología , Mycoplasma genitalium/patogenicidad , Reacción en Cadena de la Polimerasa , Uretritis/sangre , Uretritis/inmunología , Uretritis/microbiología , Células VeroRESUMEN
Monoclonal antibodies (mAbs) are a crucial asset for human health and modern medicine, however, the repeated administration of mAbs can be highly immunogenic. Drug immunogenicity manifests in the generation of anti-drug antibodies (ADAs), and some mAbs show immunogenicity in up to 70% of patients. ADAs can alter a drug's pharmacokinetic and pharmacodynamic properties, reducing drug efficacy. In more severe cases, ADAs can neutralize the drug's therapeutic effects or cause severe adverse events to the patient. While some contributing factors to ADA formation are known, the molecular mechanisms of how therapeutic mAbs elicit ADAs are not completely clear. Accurate ADA detection is necessary to provide clinicians with sufficient information for patient monitoring and clinical intervention. However, ADA assays present unique challenges because both the analyte and antigen are antibodies, so most assays are cumbersome, costly, time consuming, and lack standardization. This review will discuss aspects related to ADA formation following mAb drug administration. First, we will provide an overview of the prevalence of ADA formation and the available diagnostic tools for their detection. Next, we will review studies that support possible molecular mechanisms causing the formation of ADA. Finally, we will summarize recent approaches used to decrease the propensity of mAbs to induce ADAs.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Neutralizantes/inmunología , Formación de Anticuerpos , Anticuerpos Antiidiotipos/sangre , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Neutralizantes/sangre , Especificidad de Anticuerpos , Epítopos , Humanos , Inmunoensayo , Factores de RiesgoRESUMEN
PURPOSE: To study the correlations of the recurrence of gastric cancer in patients after radical surgery with serum gastrointestinal hormones, serum anti-Helicobacter pylori (anti-HP) immunoglobulin G (IgG) antibody and vascular endothelial growth factors (VEGFs). METHODS: According to whether gastric cancer recurred within five years after surgery, the patients were divided into recurrence group (RE group, gastric cancer recurred within five years after surgery, n=78) and non-recurrence group (NR group, gastric cancer did not recur within five years after surgery, n=69). Differences in lymph node metastasis, gastrointestinal hormones, VEGFs, anti-HP IgG antibody and the tumor-node-metastasis (TNM) stage between RE group and NR group were detected and compared, so as to analyze the correlations of these factors with the recurrence of gastric cancer in patients after radical surgery. RESULTS: The levels of gastrin (GAS) and motilin (MTL) after meals in RE group and NR group were slightly higher than those before meals. The levels of GAS and MTL in RE group were higher than those in NR group in the two periods (p<0.05). Besides, compared with NR group, RE group had lower pepsinogen (PG) I, PG II and PG I/II ratio (PGR), but a higher positive value of anti-HP IgG antibody (p<0.05) and higher levels of VEGF-A, VEGF-C and VEGF-D (p<0.05). Moreover, there were markedly more cases of gastric cancer in stage III, remarkably few cases of gastric cancer in stage I and obviously more cases of lymph node metastasis in RE group than those in NR group (p<0.05). Multivariate analysis showed that gastrointestinal hormones, lymph node metastasis, VEGFs, the TNM stage of gastric cancer and anti-HP IgG antibody were all risk factors for the recurrence of gastric cancer after radical surgery (p<0.05). CONCLUSIONS: The recurrence of gastric cancer in patients after radical surgery is related to the TNM stage of gastric cancer, gastrointestinal hormones, VEGFs, lymph node metastasis, anti-HP IgG antibody and other factors.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Hormonas Gastrointestinales/sangre , Infecciones por Helicobacter/sangre , Inmunoglobulina G/sangre , Recurrencia Local de Neoplasia/sangre , Neoplasias Gástricas/sangre , Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Anticuerpos Antibacterianos/sangre , Femenino , Helicobacter pylori/patogenicidad , Humanos , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Factores de Riesgo , Neoplasias Gástricas/patologíaRESUMEN
Inotersen (TEGSEDI™) is a 2'-O-(2-methoxyethyl)-modified antisense oligonucleotide, intended for treating hereditary transthyretin (TTR) amyloidosis with polyneuropathy. The potential immunogenicity (IM) response to inotersen was evaluated in chronic nonclinical safety studies and the pivotal phase 2/3 clinical study. The evaluation was designed to assess the characteristics of antidrug antibodies (ADAs) and their effects on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety in animals and humans. No immunogenic response was observed after long-term treatment with inotersen in mice. In monkeys, the incidence rate of IM to inotersen appeared to be dose dependent, with 28.6%-50.0% of animals developing ADAs after 36 weeks of treatment. This was characterized as late onset (median onset of 185 days) with low titers (median titer of 8, or 400 if minimum required dilution of 50 is included). The overall incidence rate of patients who developed ADAs was 30% after 65 weeks of treatment with median onset of 203 days and median peak titer of 300. IM had minimal effect on plasma peak (Cmax) and total exposure (i.e. area under curve, AUC) of inotersen, but showed elevated plasma trough levels in both IM-positive animals and humans. However, ADAs had no effect on tissue exposure, TTR messenger RNA, or plasma TTR levels in the long-term monkey study. Similarly, IM showed no effect on plasma TTR levels in clinical studies. Thus, ADAs antibodies were binding antibodies, but not neutralizing antibodies. Finally, no association was observed between IM and toxicity findings (eg, platelet, complement activation, and histopathology findings) in the inotersen 9-month monkey study. In humans, no difference was observed in hematology, including platelets, kidney function tests, or incidence of adverse events between IM-positive and -negative patients. Overall, IM showed no effect on toxicity or safety of inotersen evaluated in both monkeys and humans. ClinicalTrials.gov Identifier: NCT01737398.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/tratamiento farmacológico , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos/administración & dosificación , Oligorribonucleótidos/administración & dosificación , Prealbúmina/genética , Animales , Anticuerpos Antiidiotipos/sangre , Anticuerpos Antiidiotipos/inmunología , Plaquetas/inmunología , Enfermedad de Charcot-Marie-Tooth/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Haplorrinos , Humanos , Inmunogenicidad Vacunal/genética , Inmunogenicidad Vacunal/inmunología , Pruebas de Función Renal , Masculino , Ratones , Oligonucleótidos/efectos adversos , Oligonucleótidos Antisentido/efectos adversos , Oligonucleótidos Antisentido/sangre , Oligonucleótidos Antisentido/farmacocinética , Oligorribonucleótidos/efectos adversos , Oligorribonucleótidos/sangre , Oligorribonucleótidos/farmacocinética , Prealbúmina/antagonistas & inhibidores , Prealbúmina/inmunologíaRESUMEN
A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases (n = 270) and a prospective cohort of rheumatoid arthritis (RA) patients (n = 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 µg/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 µg/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 µg/mL. ADA were seldom detected in patients with >1 µg/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.