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2.
Front Med (Lausanne) ; 7: 108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32296708

RESUMO

Metabolic profiling studies have recently indicated dysfunctional mitochondria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This includes an impaired function of pyruvate dehydrogenase complex (PDC), possibly driven by serum factor(s), which leads to inadequate adenosine triphosphate generation and excessive lactate accumulation. A reminiscent energy blockade is likely to occur in primary biliary cholangitis (PBC), caused by anti-PDC autoantibodies, as recently proposed. PBC is associated with fatigue and post-exertional malaise, also signifying ME/CFS. We herein have investigated whether ME/CFS patients have autoreactive antibodies that could interfere with mitochondrial function. We found that only 1 of 161 examined ME/CFS patients was positive for anti-PDC, while all PBC patients (15/15) presented significant IgM, IgG, and IgA anti-PDC reactivity, as previously shown. None of fibromyalgia patients (0/14), multiple sclerosis patients (0/29), and healthy blood donors (0/44) controls showed reactivities. Anti-mitochondrial autoantibodies (inner and outer membrane) were negative in ME/CFS cohort. Anti-cardiolipin antibody levels in patients did not differ significantly from healthy blood donors. In conclusion, the impaired mitochondrial/metabolic dysfunction, observed in ME/CFS, cannot be explained by presence of circulating autoantibodies against the tested mitochondrial epitopes.

3.
Acta Neuropathol Commun ; 8(1): 49, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293546

RESUMO

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.

4.
J Neuroimmunol ; 340: 577147, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31951875

RESUMO

To assess if markers of complement activation are associated with disease activity, C1q, C3, C3a and sC5b-9 levels in plasma and cerebrospinal fluid (CSF) were determined in 41 patients with clinically isolated syndrome (CIS) or remitting multiple sclerosis (RRMS), in a prospective longitudinal four-year cohort study. C1q in CSF (CSF-C1q) was significantly higher in patients than in controls. Baseline CSF-C1q and CSF-C3a correlated with several neuroinflammatory markers and neurofilament light chain levels. Baseline CSF-C3a correlated with the number of T2 lesions at baseline and new T2 lesions during follow-up. Baseline CSF-C3a was also significantly higher in patients with (n = 21) than in patients without (n = 20) signs of disease activity according to the NEDA-3 concept during one year of follow-up (p ≤ .01) Study results support that complement activation is involved in MS pathophysiology and that CSF-C3a carries prognostic information.


Assuntos
Ativação do Complemento/fisiologia , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/imunologia , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/imunologia , Adulto , Estudos de Coortes , Proteínas do Sistema Complemento/líquido cefalorraquidiano , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos
6.
J Autoimmun ; 106: 102340, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629628

RESUMO

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. METHODS: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). RESULTS: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03-1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). CONCLUSION: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.

7.
Eur J Pediatr ; 179(1): 133-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31691001

RESUMO

Individuals with celiac disease (CD) are at increased risk of invasive pneumococcal disease (IPD). The aim of this study was to explore whether the complement response to Streptococcus pneumoniae differed according to CD status, and could serve as an explanation for the excess risk of IPD in CD. Twenty-two children with CD and 18 controls, born 1999-2008, were included at Kalmar County Hospital, Sweden. The degree of complement activation was evaluated by comparing levels of activation products C3a and sC5b-9 in plasma incubated for 30 min with Streptococcus pneumoniae and in non-incubated plasma. Complement analyses were performed with enzyme-linked immunosorbent assay (ELISA). Pneumococcal stimulation caused a statistically significant increase in C3a as well as sC5b-9 in both children with CD and controls but there was no difference in response between the groups. After incubation, C3a increased on average 4.6 times and sC5b-9 22 times in both the CD and the control group (p = 0.497 and p = 0.724 respectively).Conclusion: Complement response to Streptococcus pneumoniae seems to be similar in children with and without CD and is thus unlikely to contribute to the increased susceptibility to invasive pneumococcal disease in CD.What is Known:• An excess risk of pneumococcal infections has been demonstrated in individuals with celiac disease.• Infectious complications can depend on hyposplenism but alternative mechanisms are sparsely examined.What is New:• Complement activation in response to Streptococcus pneumoniae was examined in children with and without celiac disease but no differences could be demonstrated.


Assuntos
Doença Celíaca/complicações , Ativação do Complemento , Infecções Pneumocócicas/etiologia , Adolescente , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Celíaca/imunologia , Doença Celíaca/microbiologia , Criança , Complemento C3a/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Suscetibilidade a Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Infecções Pneumocócicas/imunologia , Fatores de Risco
8.
Mult Scler Relat Disord ; 36: 101424, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31586802

RESUMO

BACKGROUND: Fatigue is common in multiple sclerosis and is associated with reduced quality of life. This study aimed to assess the correlation between fatigue scores and data from other self-assessment questionnaires, neuropsychological tests and neuroimaging, as well as data on neuroimmunological markers in cerebrospinal fluid (CSF) and serum/plasma, in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). METHODS: Modified fatigue impact scale (MFIS) scores were determined in 38 patients with newly diagnosed CIS or RRMS at baseline and after one year in a prospective longitudinal cohort study. Non-parametric correlation analyses were used to assess associations between MFIS scores and other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36)), as well as with neuropsychological test performances (e.g. Auditory Consonant Trigram Test (ACTT)), clinical parameters (e.g. disease duration and expanded disability status scale (EDSS)), magnetic resonance imaging (MRI) data (number of T2 lesions in brain MRI and total brain volume) and several neurodegenerative/neuroinflammatory markers in CSF and serum/plasma (IL-1ß, IL-6, CXCL1, CXCL10, CXCL13, CCL-22 in plasma; neurofilament light chain (NFL) in serum; IL-6, CXCL1, CXCL10, CXCL13, CCL22, NFL and chitinase-3-like-1 (CHI3L1) in CSF. CSF and serum/plasma from 21 age- and sex-matched healthy controls were available for comparison. RESULTS: At both baseline and one-year follow-up, fatigue scores correlated significantly with HAD, MSIS-29 and SF-36 scores and ACTT performance (Spearman´s rho 0.45-0.78, all p ≤ 0.01) but not with the other neuropsychological test results, disease duration, EDSS ratings, number of T2 lesions, total brain volume or neurodegenerative/neuroinflammatory markers, including neurofilament light chain levels in CSF and serum. In group comparisons, MFIS scores were similar in patients fulfilling no evidence of disease activity-3 (NEDA-3) (n = 18) and patients not fulfilling NEDA-3 (n = 20) during one year of follow-up (p > 0.01). CONCLUSIONS: In this cohort of patients with newly diagnosed CIS and RRMS, fatigue scores were associated with mood, disease impact on daily life and quality of life as well as with alterations of attentive functions. Study results indicate that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters like EDSS, T2 lesions and NFL levels.


Assuntos
Doenças Desmielinizantes , Autoavaliação Diagnóstica , Fadiga , Esclerose Múltipla Recidivante-Remitente , Proteínas de Neurofilamentos/metabolismo , Receptores Nicotínicos/sangue , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/fisiopatologia , Fadiga/etiologia , Fadiga/metabolismo , Fadiga/fisiopatologia , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/metabolismo , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Índice de Gravidade de Doença
9.
Autoimmunity ; 51(6): 310-318, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30369267

RESUMO

Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman-Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman-Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p = .0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r = 0.65, p = .16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman-Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.


Assuntos
Endocardite/imunologia , Armadilhas Extracelulares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Transtornos Psicóticos/imunologia , Convulsões/imunologia , Adulto , Anticorpos Antifosfolipídeos/sangue , Autoanticorpos/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Endocardite/sangue , Endocardite/complicações , Endocardite/cirurgia , Armadilhas Extracelulares/metabolismo , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Imagem por Ressonância Magnética , Valva Mitral/cirurgia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Transtornos Psicóticos/líquido cefalorraquidiano , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/tratamento farmacológico , Ribonucleoproteínas/imunologia , Convulsões/líquido cefalorraquidiano , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Tomografia Computadorizada por Raios X
10.
Infect Dis (Lond) ; 50(11-12): 853-858, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30298768

RESUMO

BACKGROUND: Immunoglobulin G subclass deficiencies (IgGsd) are associated with recurrent respiratory tract infections. Immunoglobulin substitution therapy may be needed to prevent chronic lung tissue damage but tools for identifying the patients that will benefit from this treatment are still insufficient. Some FcγR polymorphisms seem to predispose for an increased risk for infections. In this study we wanted to evaluate if the FcγR-profile differs between individuals with IgGsd and a control population. METHODS: Single nucleotide polymorphisms (SNPs) of FcγRIIa, FcγRIIIa and FcγRIIc in 36 IgGsd patients and 192 controls with similar sex and geographical distribution were analyzed by TaqMan allelic discrimination assay or Sanger sequencing. RESULTS: In the IgGsd-group, homozygous frequency for FcγRIIa-R/R131 (low-binding capacity isoform) was higher (p = .03) as well as for non-classical FcγRIIc-ORF (p = .03) and classical FcγRIIc-ORF tended (p = .07) to be more common compared to the controls. There was no difference between the groups regarding FcγRIIIa. CONCLUSION: The gene for classical FcγRIIc-ORF tended to be more frequent in individuals with immunoglobulin G subclass deficiency and the genes for non-classical FcγRIIc-ORF as well as low-binding capacity receptor FcγRIIa-R/R131 were more frequent. Further studies on the FcγR polymorphisms may pave way for identifying individuals that will benefit from immunoglobulin substitution.


Assuntos
Deficiência de IgG/genética , Polimorfismo Genético/genética , Receptores de IgG/genética , Infecções Respiratórias/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Homozigoto , Humanos , Masculino , Projetos Piloto , Polimorfismo de Nucleotídeo Único/genética , Infecções Respiratórias/imunologia , Suécia
11.
J Neuroinflammation ; 15(1): 209, 2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-30021640

RESUMO

BACKGROUND: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. METHODS: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI®) were recorded during 4 years of follow-up. RESULTS: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p < 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. CONCLUSIONS: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively.


Assuntos
Encéfalo/diagnóstico por imagem , Esclerose Múltipla , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Adulto , Quimiocinas/sangue , Quimiocinas/líquido cefalorraquidiano , Avaliação da Deficiência , Feminino , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Imagem por Ressonância Magnética , Masculino , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico por imagem , Curva ROC , Estudos Retrospectivos , Adulto Jovem
12.
Brain Behav ; 7(10): e00803, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29075563

RESUMO

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are often associated with other immune-mediated diseases or malignancy. Some studies have reported a high frequency of celiac disease in IIM. The aim of this study was to investigate the prevalence of celiac disease, systemic inflammatory diseases, and malignancy in a cohort of IIM patients, and estimate the incidence of IIM in the county of Östergötland, Sweden. MATERIAL AND METHODS: We reviewed medical records and analyzed sera from 106 patients, fulfilling pathological criteria of inflammatory myopathy, for the presence of IgA antibodies against endomysium and gliadin. Antibody-positive patients were offered further investigation with small bowel biopsy or investigation for the presence of antibodies against antitissue transglutaminase (t-TG). The patients were classified according to Bohan and Peter or Griggs criteria. The presence of celiac disease, systemic inflammatory, and malignant diseases was documented. RESULTS: Four of 88 patients classified as IIM (4.5%) had biopsy-confirmed celiac disease, which is higher than the prevalence in the general population, detected with a similar screening procedure (0.53%). Thirty-three patients (38%) had a systemic inflammatory disease and five (5.7%) a malignancy. The incidence of confirmed IIM in the county of Östergötland was 7.3 per million/year. CONCLUSIONS: The results highlight the high frequency of associated inflammatory and malignant diseases and confirm an increased prevalence of celiac disease in IIM.


Assuntos
Doença Celíaca , Intestino Delgado/patologia , Miosite , Adulto , Idoso , Anticorpos/análise , Biópsia/métodos , Doença Celíaca/epidemiologia , Doença Celíaca/imunologia , Doença Celíaca/patologia , Estudos de Coortes , Feminino , Gliadina/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Músculo Liso/imunologia , Músculo Liso/patologia , Miosite/epidemiologia , Miosite/imunologia , Miosite/patologia , Neoplasias/epidemiologia , Prevalência , Suécia/epidemiologia
13.
Mult Scler ; 23(8): 1137-1147, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27758955

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a neurological disorder that causes significantly reduced ability to work, and the Expanded Disability Status Scale (EDSS) is one of the main predictors for reduced work ability. OBJECTIVES: To investigate how work requirements, flexible work conditions and disease-modifying drugs (DMDs) influence the work ability in relation to different EDSS grades in two MS populations. METHODS: Work ability was studied in two MS populations: one in the southern and one in the northern part of Sweden, both demographically similar. In the latter population, more active work-promoting interventions have been practised and second-generation DMDs have been widely used from the onset of disease for several years. RESULTS: The proportion of MS patients who participated in the workforce or studied was significantly higher in the northern compared with the southern population ( p < 0.001). The employees in the northern population had significantly lower requirements, greater adapted work conditions and were able to work more hours per week. Higher EDSS was associated with lower reduction in number of worked hours per week in the northern population ( p = 0.042). CONCLUSION: Our data indicated that treatment strategy and adjusted work conditions have impact on work ability in MS.


Assuntos
Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Trabalho , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Suécia , Resultado do Tratamento , Adulto Jovem
14.
Acta Neuropathol Commun ; 4(1): 82, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-27503347

RESUMO

Neuromyelitis optica/spectrum disorder (NMO/SD) is a severe, inflammatory disease of the central nervous system (CNS). In the majority of patients, it is associated with the presence of pathogenic serum autoantibodies (the so-called NMO-IgGs) directed against the water channel aquaporin 4 (AQP4), and with the formation of large, astrocyte-destructive lesions in spinal cord and optic nerves. A large number of recent studies using optical coherence tomography (OCT) demonstrated that damage to optic nerves in NMO/SD is also associated with retinal injury, as evidenced by retinal nerve fiber layer (RNFL) thinning and microcystic inner nuclear layer abnormalities. These studies concluded that retinal injury in NMO/SD patients results from secondary neurodegeneration triggered by optic neuritis.However, the eye also contains cells expressing AQP4, i.e., Müller cells and astrocytes in the retina, epithelial cells of the ciliary body, and epithelial cells of the iris, which raised the question whether the eye can also be a primary target in NMO/SD. Here, we addressed this point in experimental NMO/SD (ENMO) induced in Lewis rat by transfer of AQP4268-285-specific T cells and NMO-IgG.We show that these animals show retinitis and subsequent dysfunction/damage of retinal axons and neurons, and that this pathology occurs independently of the action of NMO-IgG. We further show that in the retinae of ENMO animals Müller cell side branches lose AQP4 reactivity, while retinal astrocytes and Müller cell processes in the RNFL/ganglionic cell layers are spared. These changes only occur in the presence of both AQP4268-285-specific T cells and NMO-IgG.Cumulatively, our data show that damage to retinal cells can be a primary event in NMO/SD.


Assuntos
Aquaporina 4/metabolismo , Imunoglobulina G/metabolismo , Neuromielite Óptica/imunologia , Retina/imunologia , Retinite/imunologia , Linfócitos T/metabolismo , Animais , Aquaporina 4/genética , Astrócitos/imunologia , Astrócitos/patologia , Axônios/imunologia , Axônios/patologia , Modelos Animais de Doenças , Neuromielite Óptica/complicações , Neuromielite Óptica/patologia , Ratos Endogâmicos Lew , Retina/patologia , Retinite/etiologia , Retinite/patologia , Linfócitos T/patologia
15.
PLoS One ; 11(3): e0151244, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26990978

RESUMO

Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.


Assuntos
Barreira Hematoencefálica/imunologia , Regulação da Expressão Gênica/imunologia , Interferon Tipo I/imunologia , Neuromielite Óptica/imunologia , Medula Espinal/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Barreira Hematoencefálica/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Linfonodos/imunologia , Linfonodos/patologia , Macrófagos/imunologia , Macrófagos/patologia , Microglia/imunologia , Microglia/patologia , Neuromielite Óptica/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Ratos , Ratos Endogâmicos Lew , Medula Espinal/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
16.
J Rheumatol ; 42(5): 817-25, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25684763

RESUMO

OBJECTIVE: Analysis of antibodies against dsDNA is an important diagnostic tool for systemic lupus erythematosus (SLE), and changes in anti-dsDNA antibody levels are also used to assess disease activity. Herein, 4 assays were compared with regard to SLE specificity, sensitivity, and association with disease activity variables. METHODS: Cross-sectional sera from 178 patients with SLE, of which 11 were followed consecutively, from a regional Swedish SLE register were analyzed for immunoglobulin G (IgG) anti-dsDNA by bead-based multiplex assay (FIDIS; Theradig), fluoroenzyme-immunoassay (EliA; Phadia/Thermo Fisher Scientific), Crithidia luciliae immunofluorescence test (CLIFT; ImmunoConcepts), and line blot (EUROLINE; Euroimmun). All patients with SLE fulfilled the 1982 American College of Rheumatology and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) classification criteria. Healthy individuals (n = 100), patients with rheumatoid arthritis (n = 95), and patients with primary Sjögren syndrome (n = 54) served as controls. RESULTS: CLIFT had the highest SLE specificity (98%) whereas EliA had the highest sensitivity (35%). When cutoff levels for FIDIS, EliA, and EUROLINE were adjusted according to SLICC-12 (i.e., double the reference limit when using ELISA), the specificity and sensitivity of FIDIS was comparable to CLIFT. FIDIS and CLIFT also showed the highest concordance (84%). FIDIS performed best regarding association with disease activity in cross-sectional and consecutive samples. Fisher's exact test revealed striking differences between methods regarding associations with certain disease phenotypes. CONCLUSION: CLIFT remains a good choice for diagnostic purposes, but FIDIS performs equally well when the cutoff is adjusted according to SLICC-12. Based on results from cross-sectional and consecutive analyses, FIDIS can also be recommended to monitor disease activity.


Assuntos
DNA/imunologia , Imunoensaio/métodos , Lúpus Eritematoso Sistêmico/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Adulto Jovem
17.
Mult Scler J Exp Transl Clin ; 1: 2055217315608203, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-28607705

RESUMO

BACKGROUND: Multiple sclerosis (MS) often causes a reduced ability to work. Improved disease control as well as adjustment of working conditions may improve work ability in MS. OBJECTIVES: The objective of this article is to compare the degree of sickness absence in two MS populations that either have or have not received disease-modifying drug (DMD) treatments or active work-promoting measures. METHODS: We investigated the occurrence of sickness absence in MS patients living in Västerbotten County, Sweden, in 2013, in which the majority of MS patients receive DMD treatment. The result was compared with a previous survey in the same area during a period when no DMD was available and no work-promoting measures for MS patients were practiced. RESULTS: The proportion of MS patients active in the labor market or studying increased from 38% to 70% in the contemporary compared with the historic population (p < 0.001). The proportion of MS patients with a full-time disability pension decreased from 27% to 12% (p < 0.001). There was a significant decrease of sickness absence in several individual EDSS grades. CONCLUSIONS: Our data indicate that treatment with DMDs combined with active work-promoting measures lead to improved work ability in MS.

18.
Infect Dis (Lond) ; 47(1): 13-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25378084

RESUMO

BACKGROUND: Primary immune deficiency (PID) due to humoral defects is associated with recurrent respiratory tract infections (RTIs). Reliable clinical warning signs of PID would facilitate early diagnosis and thereby reduce long-term complications. The aim of the present study was to evaluate the accuracy of the warning sign, 'four or more antibiotic-treated RTIs annually for 3 or more consecutive years,' for detecting PID among adults in a primary health-care setting. METHODS: Fifty-three cases with 'four or more antibiotic-treated RTIs annually for 3 or more consecutive years' were selected from a Swedish primary health-care registry of RTIs. In addition, 66 age- and sex-matched controls were selected having a maximum of one antibiotic-treated RTI during the period covered by the study. Levels of immunoglobulin (Ig) IgG, IgA, IgM, IgG subclasses, and IgG antibodies against Haemophilus influenzae and Streptococcus pneumoniae as well as the inflammatory markers, C-reactive protein, interleukin (IL)-6 and IL-8 were determined. RESULTS: IgG subclass deficiencies (IgGsd) were found in 5/53 (9.4%) of the cases and in 7/66 (10.6%) controls. The most frequent deficiency was IgG3sd and this was found in three participants in the case group and seven in the control group. The mean level of IgG3 was lower in the control group (p = 0.02). The mean level of IL-8 was lower in the case group (p = 0.02). CONCLUSION: The results show that physicians working in primary health care cannot solely rely on the frequency of antibiotic-treated RTIs as a warning sign for the detection of common humoral immune deficiencies.


Assuntos
Deficiência de IgG/complicações , Infecções Respiratórias/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Deficiência de IgG/diagnóstico , Deficiência de IgG/epidemiologia , Imunidade Humoral , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Infecções Respiratórias/epidemiologia
19.
J Clin Immunol ; 35(1): 87-91, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25370723

RESUMO

PURPOSE: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in the general population. It is defined as a serum IgA level below or equal to 0.07 g/l with normal IgM and IgG levels in children over the age of 4. However, a few cases of reversal of IgAD at later ages have been observed previously, especially in pediatric patients. This study aimed at investigating the frequency of reversal in a large cohort of children and young adults in order to evaluate the present definition of IgAD. METHODS: Clinical laboratory records from 654 pediatric IgA deficient patients, 4-13 years of age, were retrieved from five university hospitals in Sweden. Follow up in the children where IgA serum levels had been routinely measured was subsequently performed. In addition, follow up of the IgA-levels was also performed at 4, 8 and 16 years of age in children who were IgA deficient at the age of 4 years in a Swedish population-based birth cohort study in Stockholm (BAMSE). RESULTS: Nine out of 39 (23.1%) children who were identified as IgAD at 4 years of age subsequently increased their serum IgA level above 0.07 g/L. The average age of reversal was 9.53 ± 2.91 years. In addition, 30 out of the 131 (22.9%) children with serum IgAD when sampled between 5 and 9.99 years of age reversed their serum IgA level with time. The BAMSE follow up study showed a reversal of IgAD noted at 4 years of age in 8 out of 14 IgAD children at 16 years of age (5 at 8 years of age) where 4 were normalized their serum IgA levels while 4 still showed low serum levels of IgA, yet above the level defining IgAD. The results indicate that using 4 years of age, as a cut off for a diagnosis of IgAD may not be appropriate. CONCLUSIONS: Our findings suggest that a diagnosis of IgAD should not be made before the early teens using 0.07 g/L of IgA in serum as a cut off.


Assuntos
Deficiência de IgA/imunologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Deficiência de IgA/diagnóstico , Imunoglobulina A/sangue , Masculino , Remissão Espontânea , Suécia
20.
PLoS One ; 9(4): e93180, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24709954

RESUMO

PURPOSE: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet. METHODS: Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-seven IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected. RESULTS: Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti-DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not. CONCLUSIONS: IgG anti-tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.


Assuntos
Doença Celíaca/sangue , Proteínas de Ligação ao GTP/imunologia , Gliadina/imunologia , Deficiência de IgA/sangue , Imunoglobulina G/sangue , Transglutaminases/imunologia , Adulto , Biomarcadores/sangue , Doença Celíaca/complicações , Doença Celíaca/imunologia , Feminino , Humanos , Deficiência de IgA/complicações , Deficiência de IgA/imunologia , Imunoglobulina G/imunologia , Masculino
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