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1.
Nat Commun ; 11(1): 4859, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978401

RESUMO

Cell death is intrinsically linked with immunity. Disruption of an immune-activated MAPK cascade, consisting of MEKK1, MKK1/2, and MPK4, triggers cell death and autoimmunity through the nucleotide-binding leucine-rich repeat (NLR) protein SUMM2 and the MAPK kinase kinase MEKK2. In this study, we identify a Catharanthus roseus receptor-like kinase 1-like (CrRLK1L), named LETUM2/MEDOS1 (LET2/MDS1), and the glycosylphosphatidylinositol (GPI)-anchored protein LLG1 as regulators of mekk1-mkk1/2-mpk4 cell death. LET2/MDS1 functions additively with LET1, another CrRLK1L, and acts genetically downstream of MEKK2 in regulating SUMM2 activation. LET2/MDS1 complexes with LET1 and promotes LET1 phosphorylation, revealing an intertwined regulation between different CrRLK1Ls. LLG1 interacts with the ectodomain of LET1/2 and mediates LET1/2 transport to the plasma membrane, corroborating its function as a co-receptor of LET1/2 in the mekk1-mkk1/2-mpk4 cell death pathway. Thus, our data suggest that a trimeric complex consisting of two CrRLK1Ls LET1, LET2/MDS1, and a GPI-anchored protein LLG1 that regulates the activation of NLR SUMM2 for initiating cell death and autoimmunity.


Assuntos
Autoimunidade/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas Ligadas por GPI/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Autoimunidade/fisiologia , Proteínas de Transporte/imunologia , Catharanthus/genética , Catharanthus/metabolismo , Morte Celular/genética , Proteínas Ligadas por GPI/genética , Regulação da Expressão Gênica de Plantas , Glicosilfosfatidilinositóis , MAP Quinase Quinase Quinases/genética , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação , Proteínas de Plantas/imunologia , Plantas Geneticamente Modificadas , Interferência de RNA , Transcriptoma
4.
Neurology ; 94(22): e2290-e2301, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424051

RESUMO

OBJECTIVE: To delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies. METHODS: Retrospective assessment of patients recruited through laboratories specialized in autoimmune CNS disease. RESULTS: Ten children with serum CASPR2 antibodies were identified (age at manifestation 18 months to 17 years). Eight children with CASPR2 antibody titers from ≥1:160 to 1:5,120 had complex autoimmune diseases with an age-dependent clinical phenotype. Two children with structural epilepsy due to CNS malformations harbored nonspecific low-titer CASPR2 antibodies (serum titers 1:80). The clinical symptoms of the 8 children with high-titer CASPR2 antibodies were general weakness (8/8), sleep dysregulation (8/8), dysautonomia (8/8) encephalopathy (7/8), neuropathic pain (7/8), neuromyotonia (3/8), and flaccid paresis (3/8). Adolescents (3/8) showed pain, neuromyotonia, and encephalopathy, whereas younger children (5/8) displayed severe hypertension, encephalopathy, and hormonal dysfunction mimicking a systemic disease. No tumors were identified. Motor symptoms remitted with immunotherapy. Mild behavioral changes persisted in 1 child, and autism spectrum disorder was diagnosed during follow-up in a young boy. CONCLUSION: High-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children.


Assuntos
Autoanticorpos/sangue , Autoimunidade/fisiologia , Encefalopatias/sangue , Hipertensão/sangue , Proteínas de Membrana/sangue , Proteínas do Tecido Nervoso/sangue , Siringomielia/sangue , Adolescente , Autoanticorpos/imunologia , Encefalopatias/imunologia , Encefalopatias/terapia , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão/imunologia , Hipertensão/terapia , Imunoterapia/métodos , Lactente , Masculino , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Estudos Retrospectivos , Siringomielia/imunologia , Siringomielia/terapia
5.
Eur J Endocrinol ; 182(5): 473-480, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32229696

RESUMO

Objective: Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases. Design: Prospective twin cohort study. Methods: We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto's thyroiditis, atrophic gastritis, celiac disease, Graves' disease, type 1 diabetes, vitiligo and Addison's disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data. Results: Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2-9.2) than in dizygotic twins (median HR: 2.4, range: 1.1-10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23-0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49-0.71) for Graves' disease to 0.97 (95% CI: 0.91-1.00) for Addison's disease. Conclusions: Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.


Assuntos
Autoimunidade/fisiologia , Doença de Addison/genética , Autoimunidade/genética , Doença Celíaca/genética , Estudos de Coortes , Feminino , Gastrite Atrófica/genética , Predisposição Genética para Doença/genética , Doença de Graves/genética , Humanos , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
7.
Proc Natl Acad Sci U S A ; 117(3): 1799-1805, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31852823

RESUMO

Heterotrimeric G proteins are important transducers of receptor signaling, functioning in plants with CLAVATA receptors in controlling shoot meristem size and with pathogen-associated molecular pattern receptors in basal immunity. However, whether specific members of the heterotrimeric complex potentiate cross-talk between development and defense, and the extent to which these functions are conserved across species, have not yet been addressed. Here we used CRISPR/Cas9 to knock out the maize G protein ß subunit gene (Gß) and found that the mutants are lethal, differing from those in Arabidopsis, in which homologous mutants have normal growth and fertility. We show that lethality is caused not by a specific developmental arrest, but by autoimmunity. We used a genetic diversity screen to suppress the lethal Gß phenotype and also identified a maize Gß allele with weak autoimmune responses but strong development phenotypes. Using these tools, we show that Gß controls meristem size in maize, acting epistatically with G protein α subunit gene (Gα), suggesting that Gß and Gα function in a common signaling complex. Furthermore, we used an association study to show that natural variation in Gß influences maize kernel row number, an important agronomic trait. Our results demonstrate the dual role of Gß in immunity and development in a cereal crop and suggest that it functions in cross-talk between these competing signaling networks. Therefore, modification of Gß has the potential to optimize the trade-off between growth and defense signaling to improve agronomic production.


Assuntos
Subunidades beta da Proteína de Ligação ao GTP/metabolismo , Meristema/crescimento & desenvolvimento , Imunidade Vegetal/fisiologia , Brotos de Planta/crescimento & desenvolvimento , Zea mays/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Autoimunidade/fisiologia , Sistemas CRISPR-Cas , Subunidades beta da Proteína de Ligação ao GTP/química , Subunidades beta da Proteína de Ligação ao GTP/genética , Técnicas de Inativação de Genes , Meristema/citologia , Meristema/imunologia , Fenótipo , Brotos de Planta/citologia , Brotos de Planta/imunologia , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Transdução de Sinais , Transcriptoma
8.
Curr Opin Rheumatol ; 32(2): 192-199, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31842032

RESUMO

PURPOSE OF REVIEW: Th1, Th17, and Treg cells play distinct roles in autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. During the last 5 years we have learned that T-cell metabolism affects cell survival, differentiation and fate of T cells. RECENT FINDINGS: We highlight recent studies which have reported on T-cell metabolism in autoimmune diseases, differences in cellular metabolisms in T-cell subsets among various diseases and transcription factors which control the expression and function of central metabolic enzymes. SUMMARY: Distinct metabolic processes control the function of T-cell subsets in autoimmune disease and known transcription factors control the activity of metabolic enzymes. The revealed insights into the metabolic events of immune cells offer opportunities for new therapeutic approaches.


Assuntos
Doenças Autoimunes/metabolismo , Autoimunidade/fisiologia , Linfócitos T/metabolismo , Animais , Doenças Autoimunes/imunologia , Diferenciação Celular/imunologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/imunologia
9.
Proc Natl Acad Sci U S A ; 116(51): 25860-25869, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31796589

RESUMO

Environmental triggers acting at the intestinal barrier are thought to contribute to the initiation of autoimmune disorders. The transforming growth factor beta inhibitor Smad7 determines the phenotype of CD4+ T cells. We hypothesized that Smad7 in intestinal CD4+ T cells controls initiation of opticospinal encephalomyelitis (OSE), a murine model of multiple sclerosis (MS), depending on the presence of gut microbiota. Smad7 was overexpressed or deleted in OSE CD4+ T cells to determine the effect on clinical progression, T cell differentiation, and T cell migration from the intestine to the central nervous system (CNS). Smad7 overexpression worsened the clinical course of OSE and increased CNS inflammation and demyelination. It favored expansion of intestinal CD4+ T cells toward an inflammatory phenotype and migration of intestinal CD4+ T cells to the CNS. Intestinal biopsies from MS patients revealed decreased transforming growth factor beta signaling with a shift toward inflammatory T cell subtypes. Smad7 in intestinal T cells might represent a valuable therapeutic target for MS to achieve immunologic tolerance in the intestine and suppress CNS inflammation.


Assuntos
Autoimunidade/fisiologia , Linfócitos T CD4-Positivos/imunologia , Sistema Nervoso Central/metabolismo , Esclerose Múltipla/metabolismo , Proteína Smad7/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Encefalomielite/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Microbioma Gastrointestinal/fisiologia , Regulação da Expressão Gênica , Humanos , Tolerância Imunológica , Inflamação , Intestinos/patologia , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/patologia , Transdução de Sinais , Proteína Smad7/genética , Medula Espinal/patologia , Fator de Crescimento Transformador beta/metabolismo
10.
Best Pract Res Clin Endocrinol Metab ; 33(6): 101371, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31866206

RESUMO

Hypophysitis is a heterogeneous condition that leads to inflammation of the sella and/or suprasellar region, potentially resulting in hormonal deficiencies and/or mass effects. A preponderance of hypophysitis subtypes have an underlying autoimmune aetiology. The overall incidence and prevalence of hypophysitis has dramatically increased over the past decade, mainly due to increased awareness of the condition in the medical community, improvements in imaging techniques, and a rise in the occurrence of certain forms of hypophysitis such as IgG4 hypophysitis (IgG4Hy) and immune checkpoint inhibitor induced hypophysitis (ICIHy). The clinical presentation varies from an asymptomatic condition to a fatal disease often as a result of electrolyte abnormalities due to glucocorticoid deficiency in the context of adrenal crisis from central adrenal insufficiency. Milder forms of hypophysitis are treated with replacement of deficient hormones while more acute presentations with mass effects require glucocorticoid therapy, immunosuppressive therapy or surgery. Timely diagnosis and interventions are keys to prevention of the lethal complications of this disease. In this review, we provide an update on the recent advances in the field of pituitary autoimmunity, with an emphasis on autoimmune hypophysitis and novel forms of hypophysitis such as anti-PIT1 hypophysitis, IgG4Hy and ICIHy.


Assuntos
Hipofisite , Hipofisite Autoimune/diagnóstico , Hipofisite Autoimune/terapia , Autoimunidade/fisiologia , Técnicas de Diagnóstico Endócrino/tendências , Humanos , Hipofisite/classificação , Hipofisite/diagnóstico , Hipofisite/terapia , Inflamação/diagnóstico , Inflamação/terapia , Doenças da Hipófise/classificação , Doenças da Hipófise/diagnóstico , Doenças da Hipófise/terapia , Terapias em Estudo/tendências
11.
Proc Natl Acad Sci U S A ; 116(51): 25839-25849, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31776254

RESUMO

Naive CD4+ T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4+ T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 ß and γ isoforms (HP1ß/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K-AKT-mTOR axis and switch to glycolysis. While differentiation of naive TRIM28-/- T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28-/- regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1ß/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes.


Assuntos
Diferenciação Celular/fisiologia , Reprogramação Celular/fisiologia , Proteínas Cromossômicas não Histona/metabolismo , Epigênese Genética/fisiologia , Linfócitos T/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Animais , Autoimunidade/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Plasticidade Celular/fisiologia , Reprogramação Celular/genética , Colo/patologia , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Histonas/metabolismo , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transcriptoma , Proteína 28 com Motivo Tripartido/genética
12.
Chin Med J (Engl) ; 132(18): 2143-2149, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31478926

RESUMO

BACKGROUND: Thyroid autoimmunity (TAI) is prevalent among women of reproductive age and associated with adverse pregnancy outcomes. This study aimed to investigate the association between iron nutritional status and the prevalence of TAI in women during the first trimester of pregnancy and in non-pregnant women of childbearing age. METHODS: Cross-sectional analysis of 7463 pregnant women during the first trimester of pregnancy and 2185 non-pregnant women of childbearing age nested within the sub-clinical hypothyroid in early pregnancy study, a prospective collection of pregnant and non-pregnant women's data, was conducted in Liaoning province of China between 2012 and 2015. Serum thyrotropin, free thyroxine, thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibodies (TgAbs), serum ferritin, and urinary iodine were measured. Iron deficiency (ID) was defined as serum ferritin <15 µg/L and iron overload (IO) was defined as ferritin >150 µg/L. TPOAb-positive was defined as >34 U/mL and TgAb-positive was defined as >115 U/mL. Multilevel logistic regression was conducted to examine the association between TAI and different iron nutritional status after adjusting for potential confounders. RESULTS: The prevalence of isolated TPOAb-positive was markedly higher in women with ID than those without ID, in both pregnant and non-pregnant women (6.28% vs. 3.23%, χ = 10.264, P = 0.002; 6.25% vs. 3.70%, χ = 3,791, P = 0.044; respectively). After adjusting for confounders and the cluster effect of hospitals, ID remained associated with TPOAb-positive in pregnant and non-pregnant women (odds ratio [OR]: 2.111, 95% confidence interval [CI]: 1.241-3.591, P = 0.006; and OR: 1.822, 95% CI: 1.011-3.282, P = 0.046, respectively). CONCLUSION: ID was associated with a higher prevalence of isolated TPOAbs-positive, but not with isolated TgAb-positive, in both pregnant women during the first trimester of pregnancy and non-pregnant women of childbearing age, while IO was not associated with either isolated TPOAb-positive or isolated TgAb-positive. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-13003805, http://www.chictr.org.cn/index.aspx.


Assuntos
Autoimunidade/fisiologia , Ferro/deficiência , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Autoanticorpos/metabolismo , Estudos Transversais , Feminino , Humanos , Iodo/metabolismo , Gravidez , Prevalência , Tireoglobulina/metabolismo , Tireotropina/metabolismo , Tiroxina/metabolismo
13.
Nat Rev Endocrinol ; 15(11): 635-650, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31534209

RESUMO

Type 1 diabetes mellitus (T1DM) results from the destruction of pancreatic ß-cells that is mediated by the immune system. Multiple genetic and environmental factors found in variable combinations in individual patients are involved in the development of T1DM. Genetic risk is defined by the presence of particular allele combinations, which in the major susceptibility locus (the HLA region) affect T cell recognition and tolerance to foreign and autologous molecules. Multiple other loci also regulate and affect features of specific immune responses and modify the vulnerability of ß-cells to inflammatory mediators. Compared with the genetic factors, environmental factors that affect the development of T1DM are less well characterized but contact with particular microorganisms is emerging as an important factor. Certain infections might affect immune regulation, and the role of commensal microorganisms, such as the gut microbiota, are important in the education of the developing immune system. Some evidence also suggests that nutritional factors are important. Multiple islet-specific autoantibodies are found in the circulation from a few weeks to up to 20 years before the onset of clinical disease and this prediabetic phase provides a potential opportunity to manipulate the islet-specific immune response to prevent or postpone ß-cell loss. The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments.


Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/metabolismo , Exposição Ambiental/efeitos adversos , Tolerância Imunológica/fisiologia , Animais , Diabetes Mellitus Tipo 1/genética , Humanos
15.
Am J Case Rep ; 20: 1364-1368, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31522189

RESUMO

BACKGROUND Recent discoveries in the field of immunometabolism, and on the role of the serine-threonine kinase mTOR as a sensor of nutrients, integrator of cellular signaling pathways, and regulator of metabolism, have widened our understanding of the connection between nutrition, health, and diseases. Epidemiological studies have shown that higher sugar-sweetened beverage consumption is associated with increased risk of developing chronic diseases, including cardiovascular disease, type 2 diabetes mellitus, obesity, non-alcoholic fatty liver disease, gout, and rheumatoid arthritis and to worse symptoms in some patients with rheumatoid arthritis. Anabolic metabolism has been demonstrated to favor the differentiation of proinflammatory T lymphocytes while katabolic metabolism to favor regulatory T lymphocyte differentiation. CASE REPORT In a 66-year old male, the onset of gonarthritis and enthesitis and worsening of these symptoms 3 months later were associated with excessive intake of desserts. Two weeks after starting strict avoidance of sugar containing nutrients and beverages symptoms disappeared. During the next 6 months, on 3 occasions, the exceptional consumption of a dessert was followed by a mild and transient recurrence of the symptoms. CONCLUSIONS The repeatedly observed recurrence of enthesitis/arthritis symptoms following sugar intake and its disappearance following avoidance of sugar, represents an extreme example of a link between metabolism and local inflammation in the reported individual. The rapid absorption of the monosaccharides glucose and fructose from the intestine, where they derive from hydrolysis of the disaccharide sucrose (sugar) might lead to overactivation of mTOR if not counterbalanced by other mTOR interfering mechanisms.


Assuntos
Artrite/induzido quimicamente , Açúcares da Dieta/efeitos adversos , Entesopatia/induzido quimicamente , Articulação do Joelho/fisiopatologia , Idoso , Artrite/fisiopatologia , Autoimunidade/fisiologia , Ativação Enzimática , Humanos , Masculino , Serina-Treonina Quinases TOR/metabolismo
16.
Methods Mol Biol ; 2024: 1-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364040

RESUMO

The immune system in a broad sense is a mechanism that allows a living organism to discriminate between "self" and "nonself." Examples of immune systems occur in multicellular organisms as simple and ancient as sea sponges. In fact, complex multicellular life would be impossible without the ability to exclude external life from the internal environment. This introduction to the immune system will explore the cell types and soluble factors involved in immune reactions, as well as their location in the body during development and maintenance. Additionally, a description of the immunological events during an innate and adaptive immune reaction to an infection will be discussed, as well as a brief introduction to autoimmunity, cancer immunity, vaccines, and immunotherapies.


Assuntos
Imunidade Adaptativa/fisiologia , Autoimunidade/fisiologia , Sistema Imunitário/metabolismo , Imunidade Adaptativa/genética , Animais , Autoimunidade/genética , Humanos , Sistema Imunitário/imunologia , Inflamação/genética , Inflamação/imunologia
17.
Neurology ; 93(10): e954-e963, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31371564

RESUMO

OBJECTIVE: To describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein-3 (AP3). METHODS: Archived serum and CSF specimens (from 616,025 screened) harboring unclassified synaptic antibodies mimicking amphiphysin-immunoglobulin G (IgG) on tissue-based indirect immunofluorescence assay (IFA) were re-evaluated for novel IgG staining patterns. Autoantigens were identified by western blot and mass spectrometry. Recombinant western blot and cell-binding assay (CBA) were used to confirm antigen specificity. Clinical data were obtained retrospectively. RESULTS: Serum (10) and CSF (6) specimens of 10 patients produced identical IFA staining patterns throughout mouse nervous system tissues, most prominently in cerebellum (Purkinje neuronal perikarya, granular layer synapses, and dentate regions), spinal cord gray matter, dorsal root ganglia, and sympathetic ganglia. The antigen revealed by mass spectrometry analysis and confirmed by recombinant assays (western blot and CBA) was AP3B2 in all. Of 10 seropositive patients, 6 were women; median symptom onset age was 42 years (range 24-58). Clinical information was available for 9 patients, all with subacute onset and rapidly progressive gait ataxia. Neurologic manifestations were myeloneuropathy (3), peripheral sensory neuropathy (2), cerebellar ataxia (2), and spinocerebellar ataxia (2). Five patients received immunotherapy; none improved, but they did not worsen over the follow-up period (median 36 months; range 3-94). Two patients (both with cancer) died. One of 50 control sera was positive by western blot only (but not by IFA or CBA). CONCLUSION: AP3B2 (previously named ß-neuronal adaptin-like protein) autoimmunity appears rare, is accompanied by ataxia (sensory or cerebellar), and is potentially treatable.


Assuntos
Complexo 3 de Proteínas Adaptadoras/metabolismo , Subunidades beta do Complexo de Proteínas Adaptadoras/metabolismo , Autoimunidade/fisiologia , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/metabolismo , Imunoglobulina G/metabolismo , Adulto , Animais , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Células Cultivadas , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Ratos
18.
Pediatr Rheumatol Online J ; 17(1): 33, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266504

RESUMO

BACKGROUND: The etiology of Juvenile Idiopathic Arthritis (JIA) is poorly understood. The purpose of this study was to examine the possible influence of early nutrition on later development of JIA. METHODS: In a population-based prospective birth cohort of 15,740 children we collected nutritional data, including fish consumption, and biological samples during pregnancy, at birth and at different ages. 16 years after study inclusion we identified 42 children with JIA, of whom 11 were positive for Antinuclear Antibodies (ANA). Heavy metals were analysed in cord blood of all 42 JIA patients and 40 age and sex-matched controls. A multivariable logistic regression model, adjusted for relevant factors, was used as well as Mann-Whitney U-test. RESULTS: Fish consumption more than once a week during pregnancy as well as during the child's first year of life was associated with an increased risk of JIA (aOR 4.5 (1.95-10.4); p < 0.001 and aOR 5.1 (2.1-12.4) p < 0.001) and of ANA-positivity (aOR 2.2 (1.4-3.6); p = 0.002 and p < 0.001). Concentrations of Al, Cd, Hg and Li in cord blood were significantly higher in the JIA-group than in controls. The ANA-positive, all of whom had consumed fish >once/week their first year, had significantly higher concentrations of Al (p < 0.001), Cd (p = 0.003), and Li (p < 0.001) in cord blood than controls. Frequency of fish consumption correlated with concentrations of Cd (p = 0.003), Li (p = 0.015) and Hg (p = 0.011). CONCLUSIONS: Moderate exposure to heavy metals, associated with fish consumption, during pregnancy and early childhood may cause effects on the immune system of the offspring, resulting in ANA positivity and JIA.


Assuntos
Artrite Juvenil/imunologia , Autoimunidade/fisiologia , Metais Pesados/efeitos adversos , Adolescente , Animais , Anticorpos Antinucleares/metabolismo , Criança , Pré-Escolar , Dieta/efeitos adversos , Feminino , Sangue Fetal/química , Peixes/imunologia , Peixes/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Metais Pesados/metabolismo , Linhagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Estudos Prospectivos , Fatores de Risco
19.
J Neuroinflammation ; 16(1): 133, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31266507

RESUMO

BACKGROUND: Treatments for autoimmune diseases aim to dampen autoreactivity while preserving normal immune function. In CD4+ T cells, the transcription factor Oct1/Pou2f1 is a dispensable transcription factor for T cell development and response to primary infection, but promotes expression of target genes, including Il2 and Ifng, under conditions of antigen reencounter. As a result, they are more strongly expressed upon secondary stimulation. Such repeated antigen encounters occur in memory recall responses, in autoimmunity where self-antigen can be recognized multiple times, and in chronic infection where foreign antigen is persistent. Based on these previous findings, we hypothesized that Oct1 loss would protect animals from autoimmunity but maintain normal responses to pathogens in the CNS. OBJECTIVE: We used a conditional mouse Oct1 (Pou2f1) allele and a CD4-Cre driver to determine the effect of T cell-specific Oct1 loss on autoimmune- and viral-induced neuroinflammation using an autoantigen-driven EAE model of autoimmunity and a JHMV model of viral infection. RESULTS: Oct1 conditional deletion mitigated clinical scores and reduced infiltrating T cells and cytokine production in the EAE model. Consistently, Oct1-deficient CD4+ T cells stimulated in vitro showed increased expression of markers associated with T cell anergy, particularly in the absence of co-stimulatory signals. In contrast, anti-viral T cell effector functions are intact in the absence of Oct1, with no changes in neuroinflammation, infiltrating T cells or cytokine production. CONCLUSION: Our findings uncover a significant difference between the effect of Oct1 loss on autoimmune and anti-pathogen responses, which potentially could be exploited for therapeutic benefit.


Assuntos
Autoimunidade/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Mediadores da Inflamação/metabolismo , Fatores de Crescimento Neural/metabolismo , Fator 1 de Transcrição de Octâmero/deficiência , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/imunologia , Fator 1 de Transcrição de Octâmero/genética , Fator 1 de Transcrição de Octâmero/imunologia
20.
Autoimmun Rev ; 18(9): 102351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31323361

RESUMO

OBJECTIVE: Uveitis is the most common ophthalmological finding in the practice of rheumatology and clinical immunology. The condition is frequently idiopathic but about 60 causes of uveitis have been described. Our aim was to analyze the clinical patterns and etiologies of uveitis in a tertiary referral center. METHODS: The records of 912 consecutive patients referred to the department of internal medicine (Lyon University Hospital, Lyon, France) for the diagnostic work-up of uveitis were examined. Demographic, clinical, anatomical, and etiological features of uveitis were analyzed. RESULTS: The mean age at onset was 48.8 years; 59.8% of the patients were women and 78.2% were Caucasians. Anterior uveitis was the most common type of uveitis (40.6%), followed by panuveitis (31.7%), posterior (18.75%) and intermediate uveitis (9%). 46.9% of the patients had idiopathic uveitis. The most common etiologies were systemic diseases (37.3%), such as sarcoidosis (17.1%), HLA-B27-related uveitis and/or spondyloarthritis (12.5%), and tuberculosis (7.5%). CONCLUSION: We describe one of the largest cohorts of consecutive uveitis patients referred to a department of internal medicine. The high percentage of uveitis associated with underlying (systemic) diseases highlights the need for a multidisciplinary approach, in order to reduce the diagnostic delay.


Assuntos
Autoimunidade/fisiologia , Uveíte/epidemiologia , Uveíte/imunologia , Doença Aguda , Adulto , Idoso , Diagnóstico Tardio , Feminino , França/epidemiologia , Antígeno HLA-B27/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reumatologia , Sarcoidose/complicações , Sarcoidose/epidemiologia , Espondilartrite/complicações , Espondilartrite/epidemiologia , Centros de Atenção Terciária , Uveíte/complicações , Uveíte/genética
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