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OBJECTIVE: Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations. METHODS: We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders. RESULTS: Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels. INTERPRETATION: Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024.
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Background: Amyotrophic lateral sclerosis (ALS) is a fatal disorder, which imposes a severe emotional burden on patients. Appropriate coping mechanisms may alleviate this burden and facilitate wellbeing, with social support known to be a successful coping strategy. This observational study aimed to determine the interplay of general coping traits of hope for success and fear of failure, coping behavior of social activity, and patients' wellbeing. Methods: In this cross-sectional study, patients with ALS from a clinical-epidemiological registry in Southwestern Germany were interviewed regarding coping traits (achievement-motivated behavior: hope for success and fear of failure), coping behavior of social activity, and psychosocial adjustment, determined using measures of depressiveness, anxiety [both measured by Hospital Anxiety and Depression Scale (HADS)], and quality of life [Anamnestic Comparative Self-Assessment (ACSA)]. Demographics, clinical [ALS Functional Rating Scale revised version (ALSFRS-R)], and survival data were recorded. Results: A total of 868 patients [60.70% male patients, mean age: 64.70 (±10.83) years, mean ALSFRS-R: 37.36 ± 7.07] were interviewed. Anxiety in patients was found to be associated with a high fear of failure. In contrast, a generally positive attitude in patients exemplified in high hopes for success was associated with better wellbeing. Finally, coping behavior of social activity explained up to 65% of the variance of depressiveness among the patients with ALS. Conclusion: In this study, we present evidence that the wellbeing of patients with ALS is not an immediate fatalistic consequence of physical degradation but rather determined by coping traits and behavior, which may be trained to substantially increase the wellbeing of patients with ALS.
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Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case-control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m2). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case-control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.
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Esclerosis Amiotrófica Lateral , Insuficiencia Renal Crónica , Masculino , Humanos , Anciano , Femenino , Pronóstico , Estudios de Casos y Controles , Estudios Prospectivos , Cistatina C , Insuficiencia Renal Crónica/complicaciones , Tasa de Filtración Glomerular , Sistema de Registros , Creatinina , BiomarcadoresRESUMEN
INTRODUCTION: Cost of illness studies are essential to estimate societal costs of chronic inflammatory demyelinating polyneuropathy (CIDP) and identify cost-driving factors. METHODS: In total, 108 patients were recruited from 3 specialized neuroimmunological clinics. Costs were calculated for a 3-month period, including direct and indirect costs. The following outcomes were assessed: inflammatory neuropathy cause and treatment disability scale, Mini-Mental State Examination, Beck Depression Inventory, Charlson comorbidity index, EuroQol-5D, World Health Organization quality of life instrument, and socioeconomic status. Univariate and multivariate analyses were applied to identify cost-driving factors. RESULTS: Total quarterly costs were 11,333. Direct costs contributed to 83% of total costs (9,423), whereas indirect costs accounted for 17% (1,910) of total costs. The cost of intravenous immunoglobulin (IVIg) was the main determinant of total costs (67%). Reduced health-related quality of life and depressive symptoms were identified as independent predictors of higher total costs. DISCUSSION: CIDP is associated with high societal costs, mainly resulting from the cost of IVIg treatment. Muscle Nerve 58: 681-687, 2018.
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Costo de Enfermedad , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/economía , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/epidemiología , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Femenino , Alemania/epidemiología , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Modelos Lineales , Masculino , Persona de Mediana Edad , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/psicología , Calidad de Vida , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: It is a continuous matter of discussion whether immune activation by vaccination in general and Influenza vaccination in particular increases the risk for clinical deterioration of autoimmune diseases. This prospective study investigated the serological and clinical course of autoimmune Myasthenia gravis (MG) after a seasonal influenza vaccination. METHODS: This randomized, placebo-controlled, double-blind study enrolled MG patients with antibodies against acetylcholine-receptors (AChR-ab). They were allocated to receive seasonal influenza vaccine or placebo. The primary endpoint was the relative change of AChR-ab-titer over 12weeks. A relative increase of 20% was set as non-inferiority margin. Secondary endpoints were clinical changes in the modified Quantitative Myasthenia Gravis Score (QMG), increase of anti-influenza-ELISA-antibodies, and changes of treatment. The study is registered with Clinicaltrialsregister.eu, EudraCT number 2006-004374-27. FINDINGS: 62 patients were included. Mean±standard deviation (median) in the vaccine and placebo group were AChR-ab-titer changes of -6.0%±23.3% (-4.0%) and -2.8%±22.0% (-0.5%) and QMG score changes of -0.08±0.27 (0.17) and 0.11±0.31 (0.00), respectively. The difference between groups (Hodges-Lehmann estimate with 95% CI) was - for the AChR-ab-titer change 4·0% [-13.3%, 4.5%] (p=0.28 for testing a difference, p<0.0001 for testing non-inferiority) and for the QMG change 0·00 [-0.17, 0.00] (p=0.79 for testing a difference). The occurrence of 74 adverse events (AE) was comparable between groups. The most common AE was flu-like symptoms. One serious AE (hospitalisation following gastrointestinal haemorrhage) in the verum group was not related to the vaccine. INTERPRETATION: Influenza vaccination in MG is safe. Uprating the potential risk of a severe course of MG exacerbation during influenza infection compared to the 95% CI differences for the endpoints, vaccination is principally indicated in this patient population.
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Anticuerpos Antivirales/inmunología , Progresión de la Enfermedad , Gripe Humana/inmunología , Miastenia Gravis/inmunología , Miastenia Gravis/virología , Receptores Colinérgicos/inmunología , Vacunación , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vacunación/efectos adversosRESUMEN
INTRODUCTION: In cases of exacerbation or crisis, myasthenia gravis (MG) patients can be treated with intravenous immunoglobulin (IVIg), plasmapheresis, or immunoadsorption. However, IVIg efficacy data in maintenance treatment are sparse. METHODS: We prospectively observed 16 index patients with chronic and insufficiently controlled MG under standard immunosuppressant therapy and symptomatic treatment. The IVIg treatment response was measured using changes in quantitative myasthenia gravis (QMG) score and surrogates. Based on these results, a sample size calculation for a future randomized, controlled trial (RCT) was simulated. RESULTS: There was an enduring decline in QMG score and other parameters of about 50% under IVIg maintenance treatment. RCT sample size calculation results in 73 or 33 patients per arm to detect at least a 20% vs. 30% clinical difference in QMG score. CONCLUSION: We recommend using the QMG score as a primary endpoint for an RCT of IVIg maintenance for chronic MG.
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Inmunoglobulinas Intravenosas/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Adulto , Anciano , Determinación de Punto Final , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Stress constitutes a risk factor for diseases where the immune system plays a significant role. Stress is recognized as a possible trigger for flare ups during the course of multiple sclerosis (MS). The disclosure to the patient of the diagnosis of MS, the commencement of immunomodulatory therapy, and the unpredictability and vagaries of disease progression are all sources of stress. Biological stress systems such as the hypothalamic-pituitary-adrenal system and the sympathetic nervous system may influence the pathogenesis and the disease course of MS. The ability to cope with stress may also be impaired, mediated for example by cognitive deficits or loss of abilities and resources as disease progresses or by the high prevalence of concurrent mood disturbances such as depression and chronic fatigue. Psychiatric comorbidities of MS disease or therapy as well as impairments of coping strategies are underrecognized in clinical practice. Treatment plans for depression among MS patients, as the most common psychiatric comorbidity, should be individualized with integrated approaches. Antidepressants are effective for the treatment of depression in MS patients although further clinical research into the neurobiological and psychological bases of depressive disorders in MS patients is clearly needed. In therapy, coping strategies can be enhanced through multidisciplinary assessment of the various challenges and restrictions imposed by the disease and assisting and supporting the patient in addressing these. Exercise, as a form of positive stress (eustress), also has a role in therapy.
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Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Esclerosis Múltiple/psicología , Estrés Fisiológico/efectos de los fármacos , Estrés Psicológico/psicología , Adaptación Psicológica , Afecto/efectos de los fármacos , Antidepresivos/efectos adversos , Cognición/efectos de los fármacos , Comorbilidad , Depresión/diagnóstico , Depresión/epidemiología , Depresión/fisiopatología , Depresión/psicología , Terapia por Ejercicio , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiopatología , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/fisiopatología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/fisiopatología , Factores de Riesgo , Estrés Psicológico/epidemiología , Estrés Psicológico/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Resultado del TratamientoRESUMEN
AIMS: To estimate costs of multiple sclerosis (MS) in a German cohort according to severity of the disease and clinical symptoms. METHODS: 144 patients were recruited from an MS outpatient clinic. Costs were calculated according to current German health-economic guidelines from the perspective of the social health insurance system. Patients were either interviewed or completed a questionnaire. Cost assessment covered a 3-month period. Health outcomes were: Expanded Disability Status Scale, MS Functional Composite, Functional Assessment of MS, fatigue, depression (Beck Depression Inventory II) and patients' socioeconomic status. Multivariate linear regression identified independent cost predictors. RESULTS: Total quarterly costs per patient were EUR 10,329 (95% CI 9,357-11,390). Direct costs were EUR 5,344 for the social health insurance system and EUR 140 for the patient. Drugs represented the major share of direct costs (and 35% of total costs); indirect costs accounted for 47% of total costs. Univariate and multivariate analyses identified age, disability, fatigue and depression as independent predictors for total, indirect or drug costs. CONCLUSION: MS represents a high economic burden, with direct costs exceeding indirect costs. To reduce costs, research should focus on prevention that slows down progression of MS. Rehabilitation and symptomatic treatment may have merits in decreasing indirect costs.
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Costo de Enfermedad , Costos de la Atención en Salud/estadística & datos numéricos , Esclerosis Múltiple/economía , Adulto , Estudios de Cohortes , Femenino , Alemania , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The objective of this study was to address the differences in onset and disease progression between familial and sporadic multiple sclerosis (MS) and the association within sibling pairs. METHODS: Ninety-eight siblings and their controls were included from a database of 763 sporadic MS-patients, randomly pair-matched for age, gender, clinical course, disease duration and treatment. Sixty-eight available siblings completed a prospective six-year follow-up. Outcome parameters included baseline Expanded Disability Status Scale (EDSS), age at onset, mono- or multifocal onset, disease progression and conversion to secondary progression of initially relapsing-remitting MS. For statistical analyses Wilcoxon's signed-rank statistics for categorical differences, t-statistics for continuous variables, McNemar's test for relative frequencies of categories, intra-class correlations for within sibling-pair associations, or Kaplan-Meier analysis for survival analyses were used; all two-sided at the 5% level. RESULTS: Disease onset was slightly earlier (29.01 vs. 29.44 years, p = 0.0492) and multifocal onset significantly more often (p = 0.0052) in familial than in sporadic MS. Notably, a substantial within sibling-pair correlation for disease progression (rho = 0.40; p = 0.0062) as well as a higher risk for siblings than for controls to convert into secondary progression (0.545 vs. 0.227; p = 0.018) could be observed. CONCLUSIONS: Familial MS differs from sporadic cases with respect to age at onset, multifocal involvement as first clinical event, and conversion into secondary progression. The progression rate of one out of two affected siblings may act as a predictor for the other sib.
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Progresión de la Enfermedad , Esclerosis Múltiple/genética , Riesgo , Hermanos , Adulto , Edad de Inicio , Bases de Datos Factuales , Evaluación de la Discapacidad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Midregional Proenkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) are stable fragments of the precursor peptides for enkephalins and substance P, respectively. We measured MR-PENK A and NT-PTA concentrations by sensitive chemiluminescence immunoassays in cerebrospinal fluid (CSF) of 19 neurologically healthy controls (NHC), 28 patients with other neurologic disorders (OND), 70 patients with dementia disorders (38 Alzheimer's disease [AD], 8 dementia with Lewy bodies [DLB], 12 frontotemporal dementia [FTD], and 12 patients with vascular dementia [VD]), and 16 patients with acute neuroinflammation (AN). Median concentrations of NT-PTA were decreased in all patient groups compared to NHC showing significant differences between patients with NHC and AN (p<0.001), OND and AN (p<0.001), FTD and AN (p<0.01) and pAD and AN (p<0.05). Median MR-PENK A levels were lower in patients with OND, dementia disorders (including AD, FTD, DLB and VD) and AN compared to NHC subjects, although this differences did not reach statistical significance (p>0.05). A maximum difference of both proneuropeptide fragments was found between NHC subjects and patients with AN, with a more than 2fold decrease in median NT-PTA and a 1.5fold decrease in median MR-PENK A levels. Concentrations of both proneuropeptide fragments were positively correlated in all patients (r=0.77, p<0.001). Our results indicate alterations of the cerebral PENK A- and PTA-system in both, dementia and acute neuroinflammatory disorders. These neuropeptide systems seem to be highly correlated in healthy and pathological status.
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Demencia/líquido cefalorraquídeo , Encefalitis/líquido cefalorraquídeo , Encefalinas/líquido cefalorraquídeo , Encefalinas/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Precursores de Proteínas/líquido cefalorraquídeo , Precursores de Proteínas/genética , Anciano , Encefalinas/química , Femenino , Humanos , Inmunoensayo/métodos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Precursores de Proteínas/química , Estadística como AsuntoRESUMEN
The inhibitory Fc-gamma receptor FcgammaRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcgammaRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower FcgammaRIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of FcgammaRIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare -386C/-120A FcgammaRIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, FcgammaRIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory FcgammaRIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating FcgammaRIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.
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Linfocitos B/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Receptores de IgG/genética , Adulto , Anciano , Estudios de Casos y Controles , Demografía , Femenino , Humanos , Inmunoglobulinas Intravenosas , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Regiones Promotoras Genéticas/genética , Receptores de IgG/metabolismo , Regulación hacia Arriba/genéticaAsunto(s)
Síndrome de Klinefelter/complicaciones , Síndrome de Klinefelter/fisiopatología , Trastornos Parkinsonianos/complicaciones , Adulto , Progresión de la Enfermedad , Genes Dominantes , Pruebas Genéticas , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/genética , Linaje , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Procalcitonin (PCT) is an established marker for severe systemic bacterial infection and sepsis in blood. Here we measured PCT by immunoassay in CSF and matched serum/plasma samples of controls and patients with different primary dementia disorders and acute neuroinflammation. PCT in CSF was significantly increased in patients with probable Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and acute neuroinflammation (encephalitis, meningitis) compared to non-demented controls. In contrast, PCT levels in matched plasma samples were normal in dementia groups, but elevated in meningitis/encephalitis. Our results indicate a central production of PCT and suggest PCT as a valuable marker candidate for the monitoring of dementia and acute neuroinflammation.
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Calcitonina/líquido cefalorraquídeo , Demencia/líquido cefalorraquídeo , Encefalitis/líquido cefalorraquídeo , Inflamación Neurogénica/líquido cefalorraquídeo , Precursores de Proteínas/líquido cefalorraquídeo , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Calcitonina/sangre , Péptido Relacionado con Gen de Calcitonina , Estudios de Casos y Controles , Demencia/sangre , Encefalitis/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inflamación Neurogénica/sangre , Precursores de Proteínas/sangre , Curva ROCRESUMEN
MRI is routinely used for in vivo detection of multiple sclerosis (MS) lesions. Histopathological correlates of MRI signal alterations are still poorly defined. In the present study, we describe a mouse model of MS presenting with inflammatory brain lesions. During the acute disease phase, two independent lesion patterns were identified by T1- and T2-weighted high-resolution 3D MRI: lesions with reduced signal intensity on both T1- and T2-weighted images (type A) and lesions with slightly reduced signal intensity on T1-weighted images and increased signal intensity on T2-weighted images (type B). Type A lesions were characterized by significantly denser inflammatory cell infiltrates and more myelin loss than type B lesions. Lesion cellularity, myelin loss and immunoglobulin deposition correlated with MRI signal intensities in both lesion types. Gd-DTPA enhancement correlated with Ig deposition and spacially matched to areas with abundant activated microglia cells at the lesion border. Using serial MRI, type A lesions revealed a persistent hypointense pattern reflecting axon and myelin loss. Signal intensity increases on T2-weighted images of type B lesions decreased during lesion evolution, and no significant T1 signal alterations developed. Taken together, MRI of mouse EAE models with brain lesions provide new insights into lesion pathology and evolution and may prove useful for the in vivo assessment of new therapeutic strategies in MS.
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Encéfalo/patología , Encefalomielitis Autoinmune Experimental/patología , Esclerosis Múltiple/patología , Enfermedad Aguda , Traslado Adoptivo , Animales , Astrocitos/patología , Tronco Encefálico/patología , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos , Microglía/patología , Esclerosis Múltiple/inmunología , Vaina de Mielina/patología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
The weakness in myasthenia gravis (MG) is mediated by T helper cell (Th)-dependent autoantibodies against neuromuscular epitopes. So far, analyzing Th phenotypes or antigen specificities has yielded very few clues to pathogenesis. Here we adopt an alternative antigen-independent approach, analyzing T cell receptor (TCR) Vbeta usage/expansions in blood from 118 MG patients. We found major expansions (>or= five standard deviations above the mean of 118 healthy, individually age- and sex-matched controls) in diverse Vbeta in 21 patients (17.6%, p<0.001) among CD4+ T cells, and in 45 patients (38.1%, p<0.001) among CD8+ T cells. In informative probands, the expanded CD4+ cells consistently showed a Th cell phenotype (CD57+CXCR5+) and expressed Th1 cytokines. Furthermore, their expression of markers for activation, lymphocyte trafficking and B cell-activating ability persisted for >or=3 years. Surprisingly, we noted a selective decline in the expansions/their CD57 positivity while the probands' MG was improving. CDR3 spectratyping suggested mono- or oligoclonal origins, which were confirmed by the prevalent TCR Vbeta CDR3 sequences of Th cells cloned from repeat bleeds. Thus, our data provide evidence for persistent clonally expanded CD4+ B helper T cell populations in the blood of MG patients. These unexpected CD4+ expansions might hold valuable clues to MG immunopathogenesis.
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Proliferación Celular , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Miastenia Gravis/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Células Clonales , Femenino , Humanos , Región Variable de Inmunoglobulina/biosíntesis , Región Variable de Inmunoglobulina/genética , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Miastenia Gravis/genética , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Although the cause of MS is still uncertain, many findings point toward an ongoing autoimmune response to myelin antigens. Because of its location on the outer surface of the myelin sheath and its pathogenicity in the experimental autoimmune encephalomyelitis model, myelin oligodendrocyte glycoprotein (MOG) is one of the potential disease-causing self antigens in MS. However, the role of MOG in the pathogenesis of MS has remained controversial. In this study we addressed the occurrence of autoantibodies to native MOG and its implication for demyelination and axonal loss in MS. We applied a high-sensitivity bioassay, which allowed detecting autoantibodies that bind to the extracellular part of native MOG. Antibodies, mostly IgG, were found in sera that bound with high affinity to strictly conformational epitopes of the extracellular domain of MOG. IgG but not IgM antibody titers to native MOG were significantly higher in MS patients compared with different control groups with the highest prevalence in primary progressive MS patients. Serum autoantibodies to native MOG induced death of MOG-expressing target cells in vitro. Serum from MS patients with high anti-MOG antibody titers stained white matter myelin in rat brain and enhanced demyelination and axonal damage when transferred to autoimmune encephalomyelitis animals. Overall these findings suggest a pathogenic antibody response to native MOG in a subgroup of MS patients.
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Autoanticuerpos/inmunología , Esclerosis Múltiple/inmunología , Glicoproteína Asociada a Mielina/inmunología , Animales , Autoanticuerpos/sangre , Glioma/genética , Glioma/metabolismo , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Proteínas de la Mielina , Vaina de Mielina/metabolismo , Glicoproteína Asociada a Mielina/genética , Glicoproteína Asociada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
Substance P (SP) is an excitatory neurotransmitter in the central and peripheral nervous system. Most of its physiological functions are mediated through binding to the neurokinin-1 receptor (NK-1R). Recently, proinflammatory properties of SP have been described. In this study we utilized T cell transfer experimental autoimmune encephalomyelitis (EAE) to investigate the role of SP in CNS autoimmune disease. Treatment with the NK-1R antagonist CP-96,345 dramatically reduced clinical and histological signs of EAE if administered before disease onset. The protective effect of CP96,345 treatment was related to a reduced expression of the adhesion molecules ICAM-1 and VCAM-1 on CNS endothelia. The cellular composition or activation status of splenocytes was not affected by CP-96,345 administration, while the secretion of proinflammatory Th1 cytokines was reduced in treated animals. Th2 cytokines remained largely unaffected by NK-1 receptor antagonist treatment. In summary, our findings suggest that the protective effect of CP96,345 treatment is mediated by stabilization of the blood-brain barrier and suppression of Th1 immunity.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Compuestos de Bifenilo/farmacología , Sistema Nervioso Central/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/prevención & control , Antagonistas del Receptor de Neuroquinina-1 , Sustancia P/inmunología , Traslado Adoptivo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Endotelio Vascular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Inmunohistoquímica , Inflamación/inmunología , Inflamación/patología , Inflamación/prevención & control , Molécula 1 de Adhesión Intercelular/biosíntesis , Molécula 1 de Adhesión Intercelular/efectos de los fármacos , Ratones , Linfocitos T/efectos de los fármacos , Molécula 1 de Adhesión Celular Vascular/biosíntesis , Molécula 1 de Adhesión Celular Vascular/efectos de los fármacosAsunto(s)
Anemia/etiología , Antiparkinsonianos/efectos adversos , Apomorfina/efectos adversos , Hematoma/etiología , Hipocinesia/etiología , Infusiones Parenterales/efectos adversos , Leucocitosis/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Neumonía Neumocócica/complicaciones , Recto del Abdomen , Enfermedad Aguda , Anciano , Antiparkinsonianos/administración & dosificación , Apomorfina/administración & dosificación , Diagnóstico Diferencial , Progresión de la Enfermedad , Quimioterapia Combinada , Hematoma/complicaciones , Hematoma/diagnóstico por imagen , Humanos , Hipocinesia/diagnóstico , Hipocinesia/tratamiento farmacológico , Masculino , Enfermedad de Parkinson/diagnóstico por imagen , Radiografía , Recto del Abdomen/diagnóstico por imagenRESUMEN
MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8(+) T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.