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Drug hypersensitivity reactions (DHRs) to platinum-based compounds (PCs) are on the rise, and their personalized and safe management is essential to enable first-line treatment for these cancer patients. This study aimed to evaluate the usefulness of the basophil activation test by flow cytometry (BAT-FC) and the newly developed sIgE-microarray and BAT-microarray in diagnosing IgE-mediated hypersensitivity reactions to PCs. A total of 24 patients with DHRs to PCs (20 oxaliplatin and four carboplatin) were evaluated: thirteen patients were diagnosed as allergic with positive skin tests (STs) or drug provocation tests (DPTs), six patients were diagnosed as non-allergic with negative STs and DPTs, and five patients were classified as suspected allergic because DPTs could not be performed. In addition, four carboplatin-tolerant patients were included as controls. The BAT-FC was positive in 2 of 13 allergic patients, with a sensitivity of 15.4% and specificity of 100%. However, the sIgE- and BAT-microarray were positive in 11 of 13 DHR patients, giving a sensitivity of over 84.6% and a specificity of 90%. Except for one patient, all samples from the non-allergic and control groups were negative for sIgE- and BAT-microarray. Our experience indicated that the sIgE- and BAT-microarray could be helpful in the endophenotyping of IgE-mediated hypersensitivity reactions to PCs and may provide an advance in decision making for drug provocation testing.
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Hipersensibilidad a las Drogas , Hipersensibilidad Inmediata , Poliquetos , Fármacos Sensibilizantes a Radiaciones , Tionas , Humanos , Animales , Prueba de Desgranulación de los Basófilos , Compuestos de Platino , Carboplatino/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Antineoplásicos Alquilantes , Inmunoglobulina ERESUMEN
BACKGROUND: In frontotemporal dementia (FTD) spectrum, younger patients may correspond to fusopathy cases, and cognitive decline could be rapidly progressive. We present a clinical and neuropathological description of a patient. CASE PRESENTATION: A 37-year-old man, without a family history of neurodegenerative diseases, was brought by his family to consult for dysarthria and behavioural change. Initial exploration showed spastic dysarthria and disinhibition. He progressively worsened with a pseudobulbar syndrome, right-lateralized pyramidal signs, left hemispheric corticobasal syndrome and, finally, lower motor neuron signs in his right arm. He died four years after the initiation of the syndrome from bronchopneumonia. Laboratory tests (including blood and cerebrospinal fluid (CSF)) were normal. Magnetic resonance imaging (MRI) and fluorodeoxyglucose-containing positron emission tomography (PET-18F-FDG) showed left fronto-insular atrophy and hypometabolism. Subsequently, 123I-ioflupane (DaT-SCAN®) single-photon emission computed tomography (SPECT) was pathologic, manifesting bilaterally decreased activity with greater affection on the left side. Only a third electromyogram (EMG) detected denervation in the last year of evolution. No mutations were found in genes such as Tau, progranulin, C9orf72, FUS, TDP-43, CHMP2B, or VCP. In necropsy, severe frontotemporal atrophy with basophilic neuronal cytoplasmic and intranuclear inclusions, negative for tau and TAR DNA binding protein 43 (TDP-43), but positive for fused in sarcoma (FUS) consistent with specifically basophilic inclusions body disease (BIBD) type was found. CONCLUSIONS: In patients affected by FTD, particularly the youngest, with rapidly progressive decline and early motor affection, fusopathy must be suspected. These cases can include motor signs described in the FTD spectrum. Lower motor neuron affection in EMG could be detected late.
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Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Masculino , Humanos , Adulto , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/genética , Degeneración Lobar Frontotemporal/genética , Cognición , Atrofia , Proteínas de Unión al ADN/genéticaRESUMEN
BACKGROUND: The precise mechanism of action of dimethyl fumarate (DMF) treatment in MS remains unknown. OBJECTIVE: To identify the changes in the blood lymphocyte profile of MS patients predicting no evidence of disease activity (NEDA) status after DMF treatment. METHODS: We studied blood lymphocyte subsets of 64 MS patients treated with DMF at baseline and after 6 months of treatment by flow cytometry. NEDA (41 patients) or ongoing disease activity (ODA, 23 patients) were monitored after a year of follow-up. RESULTS: During treatment, all patients experienced an increase in the naive T cells and a decrease in effector memory ones. However, only NEDA patients showed a significant reduction in central memory CD4+ and CD8+ T cells, memory B cells, CD4+ T cells producing interferon (IFN)-gamma, CD8+ T cells producing tumor necrosis factor-alpha (TNF-alpha), and IFN-gamma and B cells producing TNF-alpha. Additionally, they had an increase in regulatory CD56bright cells not observed in ODA group. After treatment, there was a negative correlation between CD56bright cells and CD8+ T cells producing IFN-gamma and TNF-alpha. CONCLUSION: A pro-tolerogenic shift in the blood leukocyte profile associates with an optimal response to DMF in MS.
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Subgrupos de Linfocitos B/inmunología , Dimetilfumarato/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Subgrupos de Linfocitos B/efectos de los fármacos , Femenino , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Inflamación/inmunología , Masculino , Subgrupos de Linfocitos T/efectos de los fármacos , Adulto JovenRESUMEN
A 60-year-old man presented to a Neurology Clinic specialized in cognitive disorders to evaluate memory complaints. A comprehensive neuropsychological examination detected an isolated and severe hippocampal memory deficit. Laboratory tests, brain magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) tests, including Alzheimer's disease (AD) biomarkers, did not show remarkable results. Due to family history of cognitive impairment, we extended the study to non-Alzheimer monogenic mutations (Next Generation Sequencing) detecting a pathogenic variant of the progranulin (PGRN) gene (c.1414-1âGâ>âT) which has been previously associated with the same phenotype. These results should be considered in patients with an Alzheimer-like presentation, negative AD biomarkers' results, and family history of dementia.
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The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. In particular, previous work showed that A1 overexpression results in more dopaminergic neurons in the olfactory bulb. Prompted by those intriguing results, in this study, we investigated the effects of A1 overexpression on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). We found that A1 overexpression increases the number of dopaminergic substantia nigra pars compacta (SNpc) neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice did not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild-type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, our work shows that A1 regulates the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system.
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Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/patología , Sustancia Negra/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Sistema Nervioso Periférico/metabolismo , Sistema Nervioso Periférico/patología , Ratones Endogámicos C57BL , MamíferosRESUMEN
Background: The "Triana Test" is a novel story recall test based on emotional material with demonstrated accuracy in diagnosing mild cognitive impairment patients. Objective: This study aims to obtain normative data for the "Triana Test". Methods: A normative study was conducted at a university hospital in Spain. Partners of patients were systematically recruited if eligible (age ≥50, no memory complaints, and a total TMA-93 score at or above the 10th percentile). The "Triana Test" was administered and scored. For developing the normative data, a regression-based method was followed. Results: The final sample included 362 participants (median ageâ=â66, rangeâ=â50-88; 64.9% females). A model including age and educational level better predicted the total scores. Combinations of these variables resulted in different 10th percentile scores. Conclusions: Norms for using the "Triana Test" are now available. The provided cutoffs for the 10th percentile will aid in the diagnosis of prodromal Alzheimer's disease.
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BACKGROUND: TMA-93 examines relational binding using images. Biomarker validation has demonstrated that it is discriminative for diagnosing early AD. The effect of cognitive reserve on TMA-93 performance remains unexplored and could improve the interpretative framework for using the test. OBJECTIVE: To study the effect of cognitive reserve on TMA-93 performance and to provide new norms for the test that include its measurement. METHODS: Cognitively unimpaired people aged 55 and over were systematically recruited for this cross-sectional normative study in southern Spain. Age, sex, and scores on the Cognitive Reserve Questionnaire (CRQ; maximum score: 25 points) were collected, and the TMA-93 was administered (maximum score: 30 points). Percentile-based reference data that captured combinations of socio-demographics variables with significant effect on TMA-93 performance were calculated. RESULTS: 902 participants (62.5% female; age: medianâ=â68, IQRâ=â61-75, rangeâ=â55-90) were included. CRQ total scores were globally low (medianâ=â8, IQRâ=â5-13, rangeâ=â0-24). Cognitive reserve, including modifiable items as reading activity and intellectual gaming activity, and age mainly supported the TMA-93 total score variance. Sex seemed to have some influence in the elderly. TMA-93 total scores medians began to drop from 70-75 years old. Higher total score on the CRQ and, possibly, female sex determined a gentler slope. New norms based on these variables showed wide variations in scores for the 5th and 10th percentiles. CONCLUSION: Visual relational binding ability depends on cognitive reserve, including modifiable items. The age-related binding deficit is buffered by higher cognitive reserve and, at older ages, by female sex.
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Disfunción Cognitiva , Reserva Cognitiva , Anciano , Humanos , Femenino , Masculino , Pruebas Neuropsicológicas , Estudios Transversales , Lectura , Encuestas y Cuestionarios , Disfunción Cognitiva/diagnósticoRESUMEN
Vaccines against SARS-CoV-2 have been shown to be safe and effective but their protective efficacy against infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe coronavirus disease 2019 (COVID-19), we report a spatiotemporal description of SARS-CoV-2 infection and replication through the brain. SARS-CoV-2 brain replication occurs primarily in neurons, leading to neuronal loss, signs of glial activation and vascular damage in mice infected with SARS-CoV-2. One or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. These findings further support the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19.
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COVID-19 , SARS-CoV-2 , Ratones , Animales , Humanos , Ratones Transgénicos , Vacunas contra la COVID-19 , EncéfaloRESUMEN
BACKGROUND: Rituximab is extensively used for multiple sclerosis (MS) treatment. However, the best dosage remains to be established. It has been proposed that retreatment could be guided by B lymphocyte (BL) percentages. OBJECTIVE: To establish the best BL value for retreatment with rituximab in MS and to confirm the safety and efficacy of this approach. METHODS: A prospective study was done with an exploratory cohort and a confirmatory cohort of MS patients treated with rituximab between 2017 and 2021. The first one comprised 10 MS patients with BL assessed every 3 months after rituximab infusion and retreatment done when BL values were ≥0.5%. The confirmatory cohort included 41 MS patients (41.5% women, 87.8% with secondary progressive MS, median age = 46.3 (interquartile range: 41.3-52.1) years, disease duration = 14.1 (9-19.6) years, EDSS score = 5.5 (4.0-6.5)). The confirmatory cohort was treated with rituximab following the pattern established in the exploratory cohort. RESULTS: In the exploratory cohort, ≥0.2% BL was established as the best value for retreatment because in most cases, a substantial increase of BL counts was preceded by initial values of 0.2-0.3%. In the confirmatory cohort, rituximab reduced the annualized relapse rate (ARR 0.56 vs. 0.125, p < 0.001), proportion of patients with appearance of new/enlarged T2 lesions (63.4% vs. 12.2%, p < 0.001), gadolinium-enhancing lesions (39% vs. 0%, p < 0.001), and confirmed disability progression (55% vs. 27.5%, p = 0.037). There were 22 patients (53.7%) who achieved NEDA-3. No patients had severe infections, and 10.7% cases had reduced IgG levels. CONCLUSION: Rituximab treatment guided by BL showed high effectiveness and a good safety profile for MS patients after one year of treatment.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Femenino , Humanos , Persona de Mediana Edad , Masculino , Rituximab/efectos adversos , Factores Inmunológicos/efectos adversos , Estudios Prospectivos , Esclerosis Múltiple/inducido químicamente , Linfocitos B , Esclerosis Múltiple Recurrente-Remitente/inducido químicamenteRESUMEN
BACKGROUND: TMA-93 examines relational binding using images. The test has been proven to be discriminative for diagnosing early Alzheimer's disease by biomarkers. Norms for this test are available, but the elderly, at high risk for Alzheimer's disease, have not yet been widely represented. OBJECTIVE: To extend normative data on the TMA-93 for people aged 75 and over. METHODS: An extension of the Spanish TMA-93 normative study was undertaken. Only cognitively unimpaired people aged 75 and over were included. Age, gender, and educational attainment were registered as socio-demographic variables. Using histograms analysis, median comparisons, and linear regression analysis, we selected variables that demonstrated influence on TMA-93 total scores and provided percentile-base reference data according to combinations of those variables. RESULTS: We included 431 new participants, resulting in a total sample of 657 individuals (median ageâ=â78, interquartile rangeâ=â76-81, rangeâ=â75-93). Percentile-base reference data stratified by a combination of age ranges (75-79, nâ=â428; and ≥80 years, nâ=â229), and educational attainment (<âfirst grade, nâ=â253; first grade, nâ=â209; >âfirst grade, nâ=â195) revealed that participants achieved a minimum TMA-93 total score of 26/30 at the 50th-percentile regardless of stratum. At the 10th-percentile, a maximum of 24/30 was achieved in the more educated stratum contrasting with a minimum of 19/30 in the less educated stratum. CONCLUSION: Although mitigated by lower levels of education, performance on the TMA-93 is widely preserved in cognitively unimpaired people aged 75 and over. The test could facilitate the screening of elderly patients with memory complaints.
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Enfermedad de Alzheimer , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Escolaridad , Humanos , Modelos Lineales , Tamizaje Masivo , Pruebas Neuropsicológicas , Valores de ReferenciaRESUMEN
Objective: To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS). Methods: Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula. Results: More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels. Conclusion: Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Humanos , Inflamación , Imagen por Resonancia Magnética , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Estudios ProspectivosRESUMEN
Clinically isolated syndrome patients (CIS) with oligoclonal IgG bands (OCGB) are at high risk for clinically definite multiple sclerosis (MS). However, the outcome for individual patients is unpredictable and the search for reliable blood markers predicting early conversion to multiple sclerosis (MS) has clinical relevance. CD5+ B cells (CD5+Bc) are involved in some autoimmune diseases. This study investigated whether high blood CD5+Bc percentage can predict CIS conversion to MS. Fifty-five consecutive CIS showing OCGB were prospectively studied. Every patient underwent a brain MRI study and a flow cytometry analysis of CD5+Bc percentage. Conversion to MS was studied during follow-up. The CD5+Bc percentage was assessed in 40 controls and a cut-off value of 3.5% (mean+2 SD) was calculated. A blood CD5+Bc percentage above this value predicted earlier conversion to MS in the whole group (hazard ratio [HR]: 3.40; 95% confidence interval [CI]: 1.69-6.68; p=0.0005) and in CIS patients fulfilling three or more Barkhof-Tintoré criteria plus OCGB, who showed higher risk for MS (HR: 3.79; 95% CI: 1.86-15.32; p=0.0018). Multivariate analysis also showed a predictive value for high blood CD5+Bc count (HR: 4.3; 95% CI: 1.9-9.5; p<0.0001). It was concluded that high percentages of CD5+Bc independently associate with increased risk of early conversion to MS in CIS patients with OCGB and Barkhof-Tintoré criteria.
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Linfocitos B/inmunología , Antígenos CD5/sangre , Enfermedades Desmielinizantes/inmunología , Esclerosis Múltiple/inmunología , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Distribución de Chi-Cuadrado , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/patología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/patología , Bandas Oligoclonales/sangre , Bandas Oligoclonales/líquido cefalorraquídeo , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , España , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Serum neurofilament light chains (sNfL) are biomarkers of disease activity in multiple sclerosis (MS), but their value to predict response to treatment, and their association with patient immunological profile, need to be further explored. We studied 80 relapsing-remitting MS patients initiating dimethyl fumarate (DMF) treatment. sNfL levels were explored at baseline and at 3, 6 and 12 months by single molecule array. Blood lymphocyte subsets were measured at baseline and at 6 months by flow cytometry. Patients were followed a year and classified as NEDA (no evidence of disease activity) or ODA (ongoing disease activity). NEDA patients had lower sNfL levels at baseline (p = 0.0001), and after three (p = 0.004) and six (p = 0.03) months of DMF treatment. Consequently, low baseline sNfL values (≤ 12 pg/ml) increased the probability of NEDA (OR 5.8; CI 1.82-15.6; p = 0.002, after correcting by disease activity in the previous year), and associated with significant reductions of central memory CD4+ T lymphocytes, interferon-gamma+ CD8+ T lymphocytes, Natural Killer T cells, and memory B cells upon DMF treatment, being the highest differences in memory B cells (p < 0.0001). This shows that low baseline sNfL values identify MS patients with higher probability of optimal response to DMF and of a reduction in effector immune cells.
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Dimetilfumarato/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/dietoterapia , Proteínas de Neurofilamentos/sangre , Adulto , Linfocitos B/inmunología , Biomarcadores/sangre , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/inmunología , Estudios Prospectivos , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
Objective: To explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment. Methods: Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases. Results: Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058). Conclusions: A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.â.
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Alemtuzumab/efectos adversos , Autoinmunidad/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Inmunosupresores/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Linfocitos B/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.
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Inmunosenescencia/inmunología , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Bandas Oligoclonales/inmunología , Activinas/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/sangre , Linfocitos B/inmunología , Antígeno B7-H1/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Linfocitos T/inmunología , Adulto JovenRESUMEN
OBJECTIVE: To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS). METHODS: In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. p Values were corrected using the Bonferroni test. RESULTS: Ocrelizumab reduced the numbers of naive and memory B cells (p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) (p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20+ T-cell numbers (p < 0.0001) and percentages (p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4+ (p = 0.002) and CD8+ (p = 0.002) T cells and relative decreases of CD4+ (p = 0.03) and CD8+ (p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels (p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd- patients with baseline sNfL >10 pg/mL. CONCLUSIONS: In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Factores Inmunológicos/uso terapéutico , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Femenino , Humanos , Factores Inmunológicos/farmacología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
We described previously that multiple sclerosis (MS) patients with oligoclonal IgM against myelin lipids (M+) develop an aggressive disease. Our aim was to assess possible mechanisms regulating the production of these antibodies. We studied B cell subsets in 180 patients with MS, and 69 with other neurological diseases. M+ MS patients showed a moderate increase of CD5(+) B-cell percentage in peripheral blood and a considerable augment of these cells in cerebrospinal fluid (CSF) that correlated with intrathecal IgM production. The appearance of CD5(+) B cells into the central nervous system (CNS) was related to increased CXCL13 and TNF-alpha levels in CSF. Moreover, the presence of oligoclonal IgM associated with a SNP at position -376 of the TNF-alpha promoter. These results help to elucidate the B lymphocytes responsible for intrathecal IgM secretion in MS and the origin of this abnormal B-cell response in patients with aggressive MS.
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Inmunoglobulina M/inmunología , Esclerosis Múltiple/inmunología , Bandas Oligoclonales/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Antígenos CD19/metabolismo , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Células Sanguíneas/citología , Células Sanguíneas/inmunología , Células Sanguíneas/metabolismo , Antígenos CD5/metabolismo , Líquido Cefalorraquídeo/citología , Líquido Cefalorraquídeo/inmunología , Líquido Cefalorraquídeo/metabolismo , Quimiocina CXCL13/líquido cefalorraquídeo , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina M/biosíntesis , Inmunoglobulina M/líquido cefalorraquídeo , Interleucina-5/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Lípidos/inmunología , Masculino , Glicoproteínas de Membrana/metabolismo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico , Vaina de Mielina/inmunología , Bandas Oligoclonales/biosíntesis , Bandas Oligoclonales/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Recurrencia , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
BACKGROUND: The significance of discrepant findings between histology (BMB) and flow cytometry (FC) in bone marrow (BM) examination at diffuse large B-cell lymphoma (DLBCL) diagnosis is uncertain. METHODS: We performed a 5-year retrospective single-center study of patients diagnosed by DLBCL not otherwise specified (n = 82), divided into three groups according to BM infiltration at diagnosis: BMB-/FC- (75.6%), BMB+/FC+ (13.4%), and BMB-/FC+ (11%). RESULTS: Median infiltration by FC analysis of the BMB-/FC+ group was 0.8% and if we considered BM infiltration as positive in all cases, 4/9 would be upstaged. Median follow was 33 months. Event-free survival (EFS) after 18 months was 82, 23, and 27% for BMB-/FC-, BMB-/FC+, and BMB+/FC+, respectively (p < .001). After 18 months of observation, OS was 87, 46, and 55% for BMB-/FC-, BMB-/FC+, and BMB+/FC+, respectively (p = .001). In multivariate analysis (BM infiltration vs. cell-of-origin according to Hans algorithm and standard IPI), BM infiltration was independently associated with EFS (HR: 1.94, 95% CI: 1.3-2.9) and overall survival (HR: 1.69, 95% CI: 1.1-2.7). CONCLUSION: In summary, minimal BM infiltration, detected by FC but not by BMB, has same prognostic implications than overt BM infiltration and should be considered as extranodal involvement regardless the infiltration quantity.
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Células de la Médula Ósea/patología , Citometría de Flujo , Infiltración Leucémica/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Infiltración Leucémica/epidemiología , Infiltración Leucémica/patología , Linfoma de Células B Grandes Difuso/epidemiología , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. OBJECTIVE: To identify factors associated with lymphopenia in DMF-treated patients and explore changes in blood lymphocyte subsets associated with DMF-induced lymphopenia. METHODS: Prospective longitudinal study including 106 patients initiating DMF treatment followed for a median time of 24.67â¯months. Blood lymphocyte subsets were studied in 64 patients by flow cytometry at baseline and 6â¯months after. RESULTS: Mean absolute lymphocyte counts (ALCs) decreased by 29% during the first year of DMF-treatment. Patients developing lymphopenia showed a faster decline within the three first months. A reduction of ALCs higher than 38% at this time was associated to subsequent development of grade 2-3 lymphopenia (ORâ¯=â¯5.93, 95% CI: 1.9-18.6, pâ¯=â¯0.002). All patients showed a significant decrease in different T and B lymphocyte subsets upon DMF therapy. In addition, lymphopenic patients experienced a selective decrease in natural killer T (NKT) cell percentages (pâ¯=â¯0.01), and a high drop in NKT total counts (pâ¯<â¯0.0001). CONCLUSIONS: Patients who experience a drop in ALCs by >38% at three months of DMF-treatment are about 6-times more likely to develop significant lymphopenia. This decrease is clearly associated with a considerable loss of NKT cells.
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Dimetilfumarato/efectos adversos , Inmunosupresores/efectos adversos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Linfopenia/sangre , Linfopenia/inducido químicamente , Adulto , Femenino , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Estudios Longitudinales , Recuento de Linfocitos/métodos , Linfopenia/diagnóstico , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Objectives: Teriflunomide, a disease-modifying treatment approved for multiple sclerosis (MS), inhibits reversibly dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine biosynthesis and down-regulates proliferation of activated lymphocytes. We aimed to study the impact of this drug in the lymphocyte profiles of MS patients. Methods: Fifty-five patients with relapsing-remitting MS who initiated teriflunomide treatment were included in the study. We studied peripheral blood mononuclear cells obtained before and 6 months after treatment initiation and explored effector, memory, and regulatory cells by flow cytometry. Wilcoxon matched pair tests were used to assess differences between basal and 6 months after treatment results. P-values were corrected with Bonferroni test. Results: When explored T and B cell subsets, we observed a decrease in the percentages of terminally differentiated CD4+ T cells (P = 0.001) and plasmablasts (P < 0.0001) after 6 months of treatment. These results were confirmed with the total cell number. When studied immunomodulatory cells, we observed a clear increase of monocytes expressing programmed death-ligand 1 (PD-L1) (P = 0.005), which correlated negatively with all effector CD8+ T cell subsets. We also observed an increase in the percentage of CD8+ T cells (P = 0.028) and monocytes (P = 0.04) producing IL-10. Conclusions: Teriflunomide induces a specific reduction in effector T and B cells that have shown to play a role in MS course and an increase in immunomodulatory cells. Particularly, this drug induces the expression of PD-L1, a molecule involved in tolerance to autoantigens, which can contribute to inhibit the abnormal immune response taking place in MS.