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1.
Allergol. immunopatol ; 48(1): 18-25, ene.-feb. 2020. tab
Artículo en Inglés | IBECS | ID: ibc-186587

RESUMEN

Introduction and objectives: Connective tissue diseases are inflammatory, autoimmune diseases and threaten quality of life. To determine the relationship between staining patterns of antinuclear antibodies and antibodies against extractable nuclear antigens in patients with connective tissue disease. Materials and methods: Observational, basic, analytical and transversal study. Study conducted in the Immunology Service of the Arzobispo Loayza National Hospital between January 2017 and June 2017. We analyzed 291 samples of patients with CTD and for the detection of anti-nuclear antibody staining patterns, the immunological kit and observation with microscope of at 40X Immunofluorescence and for the detection of the antibodies against extractable nuclear antigens. The Immunoblot method was employed. Statistical analyses were carried out with the statistical package SPSS version 21 for Windows. We used the Pearson Chi-square test for the categorical variables, a value of p < 0.05 was considered significant. Results: There was a significant relationship p < 0.05 of the homogeneous pattern, the mottled pattern with Anti-histones (p = 0.000), Anti-nucleosomes (p = 0.000), Anti-Ro 52 (p = 0.000), Anti-SSA (p = 0.001), Anti-SSB (p = 0.003), Anti-dsDNA (p = 0.000) with the Pearson Chi-square test. There was a significant relationship of p < 0.05 of the centromeric pattern with Anti-Cenp B (p = 0.000) with Fisher's exact statistic. Conclusions: There was a significant relationship between the anti-nuclear antibody staining patterns and the antibodies to the core extractable antigens in patients with systemic lupus erythematosus, Sjögren's syndrome, Calcinosis, Raynaud's phenomenon, esophageal Dysmotility, sclerodactyly and Telangiectasia (CREST), Scleroderma and Polymyositis


No disponible


Asunto(s)
Humanos , Anticuerpos Antinucleares/análisis , Anticuerpos/análisis , Antígenos Nucleares/inmunología , Enfermedades del Tejido Conjuntivo/inmunología , Autoinmunidad/inmunología , ADN/análisis , Enfermedades del Tejido Conjuntivo/diagnóstico , Estudios Transversales , Microscopía Fluorescente , Técnica del Anticuerpo Fluorescente Indirecta , Proteína A Centromérica , Autoanticuerpos/inmunología
2.
Isr Med Assoc J ; 22(2): 100-103, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32043327

RESUMEN

BACKGROUND: Autoimmune hepatitis (AIH) may be associated with other autoimmune diseases. Autoantibodies are common in AIH suggesting their potential role in the pathogenesis of the disease. Among these autoantibodies, thyroid autoantibodies have been reported in patients with chronic hepatitis, with greater prevalence in patients with chronic hepatitis C infection. OBJECTIVES: To assess the prevalence of thyroid dysfunction among patients with AIH. METHODS: In this case-control, retrospective study, we examined patients diagnosed with AIH according to both the original and revised international AIH group scoring systems. Patients with other hepatic pathologies were excluded AIH was evaluated as an independent risk factor for thyroid disease by a logistic regression model. Univariate and multivariate regression analyses were conducted using hypothyroidism and hyperthyroidism as the dependent variables. RESULTS: Our cohort comprised 163 patients diagnosed with AIH and 1104 healthy age- and gender-matched controls. Hypothyroidism was more prevalent among those with AIH compared to controls (17.7% vs. 5%, respectively, 95% confidence interval [95%CI] 1.68-2.48, P < 0.001). Hyperthyroidism was more prevalent in AIH patients compared to controls (odds ratio 3.2% and 1.2%, respectively, 95%CI 1.68-2.47, P < 0.001). Using a multivariate logistic analysis, we found an independent association between AIH and hypothyroidism but not with hyperthyroidism. CONCLUSIONS: Thyroid dysfunction is more prevalent in patients with AIH. Whether thyroid dysfunction is the cause or a risk factor for AIH, or vice versa, is still unclear. Screening for thyroid dysfunction is warranted after AIH is diagnosed.


Asunto(s)
Hepatitis Autoinmune , Hipotiroidismo , Glándula Tiroides/inmunología , Adulto , Autoanticuerpos/análisis , Autoinmunidad/inmunología , Estudios de Casos y Controles , Femenino , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/inmunología , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/epidemiología , Hepatitis Autoinmune/inmunología , Humanos , Hipotiroidismo/diagnóstico , Hipotiroidismo/epidemiología , Hipotiroidismo/inmunología , Israel/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Medición de Riesgo , Pruebas de Función de la Tiroides/métodos , Pruebas de Función de la Tiroides/estadística & datos numéricos
3.
Autoimmun Rev ; 19(2): 102456, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31838166

RESUMEN

Improved anti-tumour responses under immune checkpoint inhibition (ICI) are associated with concomitant autoimmune disease development termed immune related adverse events (irAEs), of which approximately 5% are rheumatic in nature. Generally, oncologists and other specialists vigorously treat irAEs in spite of the generally accepted beneficial effect of irAEs on tumour survival. Herein, we highlight mechanistic insights on how tumour responses and certain types of autoimmunity appear to be inextricably linked around CD8+ T-cell mediated responses and that strategies that interfere with such shared immunopathgenesis could impact of survival. We discuss the possible circumstances in which intensive immunosuppressive therapy for irAEs that occur with ICIs might blunt anti-tumour immunity. We also discuss potential therapeutic strategies for emergent ICI related autoimmunity and propose some treatment considerations and research questions to minimize the impact of overzealous immunosuppression strategies on tumour responses. Thus, refraining from using powerful therapeutic armamentarium to treat irAEs, especially when these are not considered as life-threating might improve the prognosis of ICI therapy.


Asunto(s)
Inmunosupresión/efectos adversos , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Autoinmunidad/inmunología , Linfocitos T CD8-positivos/inmunología , Humanos , Pronóstico , Tasa de Supervivencia
4.
Nat Med ; 25(12): 1865-1872, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31792456

RESUMEN

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. ß cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to ß cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.


Asunto(s)
Autoinmunidad/inmunología , Diabetes Mellitus Tipo 1/virología , Enterovirus/aislamiento & purificación , ARN Viral/aislamiento & purificación , Adolescente , Autoinmunidad/genética , Niño , Preescolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Enterovirus/inmunología , Enterovirus/patogenicidad , Heces/virología , Femenino , Humanos , Lactante , Insulina/metabolismo , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/virología , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/patología , Islotes Pancreáticos/virología , Masculino , Páncreas/inmunología , Páncreas/patología , Páncreas/virología
5.
Nat Commun ; 10(1): 4877, 2019 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-31653831

RESUMEN

The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan - from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation.


Asunto(s)
Autoinmunidad/inmunología , Dieta , Encefalomielitis Autoinmune Experimental/inmunología , Microbioma Gastrointestinal/inmunología , Linfocitos T/inmunología , Triptófano , Animales , Proteínas en la Dieta , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/microbiología , Microbioma Gastrointestinal/genética , Ratones , Esclerosis Múltiple , ARN Ribosómico 16S/genética
6.
Nat Commun ; 10(1): 4882, 2019 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-31653839

RESUMEN

Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. Regardless, an unknown number of autoreactive CD4+Foxp3- T cells escape negative selection and in the periphery require continuous suppression by CD4+Foxp3+ regulatory cells (Tregs). Here, we compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4+Foxp3- cells from converting to pathogenic effectors in healthy mice. These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including self-peptides that select them in the thymus. Our data thus suggest that identification of most potentially autoreactive CD4+ T cells in the peripheral repertoire is critical to harness or redirect these cells for therapeutic advantage.


Asunto(s)
Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Autoantígenos/inmunología , Tolerancia Central/inmunología , Células Dendríticas/inmunología , Factores de Transcripción Forkhead/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Ratones , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T Reguladores/inmunología , Timo
7.
PLoS Pathog ; 15(10): e1008094, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31652291

RESUMEN

Stomatal closure defense and apoplastic defense are two major immunity mechanisms restricting the entry and propagation of microbe pathogens in plants. Surprisingly, activation of plant intracellular immune receptor NLR genes, while enhancing whole plant disease resistance, was sometimes linked to a defective stomatal defense in autoimmune mutants. Here we report the use of high temperature and genetic chimera to investigate the inter-dependence of stomatal and apoplastic defenses in autoimmunity. High temperature inhibits both stomatal and apoplastic defenses in the wild type, suppresses constitutive apoplastic defense responses and rescues the deficiency of stomatal closure response in autoimmune mutants. Chimeric plants have been generated to activate NLR only in guard cells or the non-guard cells. NLR activation in guard cells inhibits stomatal closure defense response in a cell autonomous manner likely through repressing ABA responses. At the same time, it leads to increased whole plant resistance accompanied by a slight increase in apoplastic defense. In addition, NLR activation in both guard and non-guard cells affects stomatal aperture and water potential. This study thus reveals that NLR activation has a differential effect on immunity in a cell type specific matter, which adds another layer of immune regulation with spatial information.


Asunto(s)
Arabidopsis/inmunología , Resistencia a la Enfermedad/genética , Proteínas NLR/metabolismo , Estomas de Plantas/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Autoinmunidad/genética , Autoinmunidad/inmunología , Quimera/genética , Regulación de la Expresión Génica de las Plantas , Calor , Receptores Inmunológicos/metabolismo
8.
Trans Am Clin Climatol Assoc ; 130: 145-155, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31516178

RESUMEN

Ketosis-prone diabetes (KPD) is a heterogeneous condition characterized by patients who present with diabetic ketoacidosis but lack the phenotype of autoimmune type 1 diabetes. Here I review progress in our understanding of KPD and its place in the expanding universe of "atypical diabetes." I focus on investigations of our collaborative research group at Baylor College of Medicine and the University of Washington using a longitudinally followed, heterogeneous, multiethnic cohort of KPD patients. We have identified clinically and pathophysiologically distinct KPD subgroups, separable by the presence or absence of islet autoimmunity and the presence or absence of beta cell functional reserve. The resulting "Aß" classification of KPD accurately predicts long-term glycemic control and insulin dependence. I describe key characteristics of the KPD subgroups, their natural histories, and our investigations into their immunologic, genetic, and metabolic etiologies. These studies serve as a paradigm for the investigation of atypical forms of diabetes.


Asunto(s)
Autoanticuerpos/inmunología , Diabetes Mellitus/clasificación , Cetoacidosis Diabética/metabolismo , Células Secretoras de Insulina/metabolismo , Afroamericanos , Americanos Asiáticos , Autoinmunidad/inmunología , Diabetes Mellitus/inmunología , Diabetes Mellitus/metabolismo , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Cetoacidosis Diabética/inmunología , Grupo de Ascendencia Continental Europea , Hispanoamericanos , Humanos , Secreción de Insulina , Síndrome
9.
Isr Med Assoc J ; 21(7): 454-459, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31507120

RESUMEN

BACKGROUND: Platelets have the ability to influence the immune system and the inflammatory process and may be strongly involved in the whole pathogenic process of chronic inflammatory joint diseases, such as rheumatoid arthritis. They may play a significant role even before the clinical onset of the disease, contributing to the loss of tolerance of the immune system and the induction of autoimmunity. Subsequently, they can interact with the most important cellular players involved in autoimmunity and inflammation, namely innate immunity cells and T cells and eventually contribute to the building of inflammation in the synovium, thus inducing the activation, migration, and proliferation of fibroblasts that eventually lead to joint damage. Due to their peculiar features, studying the behavior of platelets is a challenging task; however, platelets may prove to be valuable therapeutic targets in the future.


Asunto(s)
Artritis Reumatoide/inmunología , Plaquetas/inmunología , Sinovitis/inmunología , Artritis Reumatoide/patología , Autoinmunidad/inmunología , Fibroblastos/inmunología , Humanos , Inmunidad Innata/inmunología , Inflamación/inmunología , Inflamación/patología , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Sinovitis/patología , Linfocitos T/inmunología
10.
Isr Med Assoc J ; 21(7): 480-486, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31507125

RESUMEN

BACKGROUND: Serum rheumatoid factors are autoantibodies of different isotypes directed against the Fc fraction of immunoglobulin G (IgG) and represent paradigmatic autoantibodies that have been largely used in clinical practice for decades. Traditionally IgG has been associated with rheumatoid arthritis and more recently included also in the classification criteria for SjÓ§gren's syndrome. Researchers have established that rheumatoid factors are positive in a variety of infectious, autoimmune, and neoplastic disorders, thus requiring a comprehensive evaluation of seropositive patients. Of note, hepatitis B and C viruses represent a crossroad that includes the high rheumatoid factor seroprevalence and chronic inflammatory disease, as well as progression to non-Hodgkin's lymphomas. Chronic antigen stimulation is the likely common ground of these processes and rheumatoid factors may represent mere bystanders or drivers of pathology. Mixed cryoglobulinemia and lymphoproliferative disease are prime examples of the deleterious effects of rheumatoid factor-B cell activity, possibly associated with hepatitis B and C. More importantly, they show a clear association in a physiological host response to infection, chronic inflammation, and the slide toward autoimmunity and malignancy. The association between hepatitis B and C infections and the appearance of serum rheumatoid factors is further supported by prevalence data, which support a coexistence of these markers in a significant proportion of cases, with viral infections being frequent causes of rheumatoid factors in patients without a rheumatic condition. We provide a comprehensive overview of the known connections between hepatitis B and C infections and rheumatoid factors.


Asunto(s)
Hepatitis B/inmunología , Hepatitis C/inmunología , Factor Reumatoide/inmunología , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Crioglobulinemia/inmunología , Humanos , Trastornos Linfoproliferativos/inmunología , Neoplasias/inmunología , Factor Reumatoide/sangre
12.
Nat Rev Drug Discov ; 18(9): 669-688, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31363227

RESUMEN

Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely suppress or activate the immune system but selectively regulates immune responses. The different metabolic requirements of the diverse cells that constitute an immune response provide a unique opportunity to separate effector functions from regulatory functions. Likewise, cells can be metabolically reprogrammed to promote either their short-term effector functions or long-term memory capacity. Studies in the growing field of immunometabolism support a paradigm of 'cellular selectivity based on demand', in which generic inhibitors of ubiquitous metabolic processes selectively affect cells with the greatest metabolic demand and have few effects on other cells of the body. Targeting metabolism, rather than particular cell types or cytokines, in metabolically demanding processes such as autoimmunity, graft rejection, cancer and uncontrolled inflammation could lead to successful strategies in controlling the pathogenesis of these complex disorders.


Asunto(s)
Autoinmunidad/inmunología , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/metabolismo , Inmunomodulación/efectos de los fármacos , Metabolismo/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Modelos Biológicos
13.
PLoS One ; 14(7): e0218575, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31365539

RESUMEN

Natural antibodies are an innate-like subset of serum antibodies involved in host defense, tumor surveillance, homeostasis, and autoimmunity. Defining the natural antibody repertoire is critical for identifying biomarkers, developing vaccines, controlling and preventing autoimmunity, and understanding the development and organization of the immune system. While natural antibodies to protein antigens have been studied in depth, little is known about natural antibodies to carbohydrate antigens. To address this, we profiled IgM from umbilical cord blood and matched maternal sera on a glycan microarray. Since standard methods to detect maternal contamination in cord serum did not have sufficient sensitivity for our study, we developed a highly sensitive microarray-based assay. Using this method, we found that over 50% of the cord samples had unacceptable levels of maternal contamination. For the cord samples with high purity, anti-glycan IgM antibodies were prevalent and recognized a broad range of non-human and human glycans. Using principal component analysis and hierarchical clustering, cord IgM repertoires showed a high degree of similarity with each other but were distinct from maternal IgM repertoires. Our results demonstrate that many anti-glycan antibodies in human serum are natural antibodies and provide new insights into the development of anti-glycan antibody repertoires.


Asunto(s)
Autoanticuerpos/sangre , Autoinmunidad/inmunología , Sangre Fetal/inmunología , Sistema Inmunológico , Anticuerpos Antiidiotipos/sangre , Biomarcadores/sangre , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Recién Nacido , Polisacáridos/sangre
14.
Autoimmun Rev ; 18(10): 102367, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31404705

RESUMEN

Aggregation of immuno-proteomic data reveals that i) herpesviruses and synaptic proteins -in particular Synapsin-1 and Bassoon - share a large number of hexapeptides that also recur in hundreds of epitopes experimentally validated as immunopositive in the human host, and ii) the shared peptides are also spread among human epilepsy-related proteins. The data indicate that cross-reactive processes may be associated with pathogenetic mechanisms in epilepsy, thus suggesting a role of autoimmunity in etiopathology of epilepsies after herpesvirus-infections.


Asunto(s)
Autoinmunidad/inmunología , Epilepsia/etiología , Epítopos/inmunología , Herpes Simple/complicaciones , Herpesviridae/inmunología , Fragmentos de Péptidos/inmunología , Sinapsinas/inmunología , Animales , Reacciones Cruzadas , Epilepsia/patología , Herpes Simple/inmunología , Humanos
15.
Int Arch Allergy Immunol ; 180(2): 150-158, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31284281

RESUMEN

INTRODUCTION: Regulatory lymphocytes (CD4+ T regulatory cells [Treg], CD8+ Treg, and B regulatory cells [Breg]) play a critical role in immune homeostasis and tolerance. Common variable immunodeficiency (CVID) is associated with increased susceptibility to infections and increased frequency of inflammatory and autoimmune diseases. CD4+ Treg cell abnormalities have been reported in CVID; however, CD8+ Treg cells have not been reported in CVID. The objective of this study was to evaluate CD4+ Treg and CD8+ Treg cells in CVID patients. METHODS: In 25 patients with CVID and age-matched healthy controls, Treg cells, evaluated in freshly isolated peripheral blood mononuclear cells (natural; nCD4+ Treg and nCD8+ Treg) and following in vitro activation with anti-CD3/CD28 monoclonal antibodies (induced; iCD4+ Treg and iCD8+ Treg) as well as Breg cells were analyzed with specific monoclonal antibodies and isotype controls using flow cytometry. RESULTS: The proportions of nCD4+ Treg (CD4+ CD127low CD25high FoxP3+), iCD4+ Treg (CD4+ CD127low CD25high FoxP3+), iCD8+ Treg (CD8+ CD25high CD183+ FoxP3+), and Breg (CD19+ CD24high CD38high) lymphocytes were significantly lower in patients with CVID than in controls. CONCLUSIONS: Altered regulatory lymphocytes may play a role in the pathogenesis and autoimmunity and inflammation associated with CVID.


Asunto(s)
Linfocitos B Reguladores/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunodeficiencia Variable Común/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Anciano , Envejecimiento/inmunología , Autoinmunidad/inmunología , Femenino , Humanos , Inflamación/inmunología , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Adulto Joven
17.
EBioMedicine ; 45: 578-587, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31262710

RESUMEN

BACKGROUND: Sphingomyelin synthase 1 (SMS1) has been reported to participate in hepatitis and atherosclerosis. However, its role in autoimmune response is not clear. This study investigates the possible involvement of SMS1 in B-cell activation and lupus-like autoimmunity. METHODS: SMS1 knockout lupus-like animal model and SLE patient samples were utilized. B-cell activation and associated signal transduction were detected by flow cytometry, confocal analysis and western blotting. The SMS1 expression in B cells was measured by real-time qPCR. FINDINGS: SMS1 deficiency suppressed B-cell activation in culture, which was restored by exogenous SM supplementation. The BCR-mediated early signal transduction including the colocalization of BCR with F-actin or pY/pBtk, and the phosphorylation of intracellular Fyn and Syk were impaired in SMS1 knockout B cells. Furthermore, SMS1 knockout mice showed reduced production and deposition of autoantibodies, accompanied by less severe kidney pathological changes after pristane induction. SMS1 deficiency also displayed lower autoantibody titers and 24 h urine protein excretion in bm12-induced lupus, which were associated with reduced B-cell activation. Adoptively transferred wide-type B cells partially recovered B-cell activation and autoantibody production in SMS1 deficient bm12-induced lupus mice. Moreover, the SMS1 mRNA level in B cells of SLE patients was increased and positively correlated with the serum anti-dsDNA level, IgG and globulin titers. INTERPRETATION: These data suggest that SMS1 is involved in lupus-like autoimmunity via regulating BCR signal transduction and B cell activation. (Word count for the abstract: 230).


Asunto(s)
Autoinmunidad/genética , Linfocitos B/inmunología , Lupus Eritematoso Sistémico/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Actinas/genética , Animales , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Autoinmunidad/inmunología , Linfocitos B/metabolismo , Femenino , Citometría de Flujo , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Noqueados
18.
Neurology ; 93(8): e815-e822, 2019 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-31315972

RESUMEN

OBJECTIVE: To describe a novel antibody biomarker of neurologic paraneoplastic autoimmunity specific for phosphodiesterase 10A (PDE10A), a striatum-enriched phosphodiesterase, and to characterize the clinical phenotype of patients with PDE10A immunoglobulin G (IgG). METHODS: We describe 7 patients with autoantibodies specific for PDE10A identified in the Mayo Clinic Neuroimmunology Laboratory. Patient specimens (sera, 7; CSF, 4) produced identical basal ganglia-predominant synaptic staining of murine brain tissue by indirect immunofluorescence. The autoantigen was identified by immunoprecipitation and mass spectrometry as PDE10A, and confirmed by antigen-specific recombinant Western blot and cell-based assays, and immune absorption experiments. RESULTS: The median patient age was 70 years (range 66-76); 4 were men. Four patients with clinical information available had movement disorders (hyperkinetic in 3 [chorea, ballismus, dystonia] and parkinsonism in 1). All patients but one had cancer (lung [adenocarcinoma 1, squamous cell carcinoma 1, poorly differentiated mesenchymal carcinoma 1], renal adenocarcinoma 2, and pancreatic adenocarcinoma 1). Two of the 7 patients developed hyperkinetic movement disorders during treatment with immune checkpoint inhibitors (nivolumab and pembrolizumab), though none of 26 cancer control patients treated with immune checkpoint inhibitors harbored PDE10A IgG in their serum. MRIs from those 2 patients with hyperkinetic movement disorders demonstrated fluid-attenuated inversion recovery/T2 basal ganglia hyperintensities, and their CSF harbored unique oligoclonal bands. One of those 2 patients had substantial improvement after corticosteroids. One patient's renal adenocarcinoma expressed PDE10A by immunohistochemistry. CONCLUSIONS: PDE10A IgG defines a novel rare neurologic autoimmune syndrome and expands the spectrum of diagnosable paraneoplastic CNS disorders. The intracellular location of PDE10A suggests a T-cell-mediated pathology targeting cells displaying MHC1-bound PDE10A peptides.


Asunto(s)
Autoinmunidad/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeo , Síndromes Paraneoplásicos/inmunología , Hidrolasas Diéster Fosfóricas/inmunología , Anciano , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Ganglios Basales/patología , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos del Movimiento/inmunología , Neoplasias/inmunología , Neuroimagen , Síndromes Paraneoplásicos/sangre , Síndromes Paraneoplásicos/líquido cefalorraquídeo
19.
J Pediatr Endocrinol Metab ; 32(9): 979-985, 2019 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-31301677

RESUMEN

Background Primary ovarian insufficiency (POI) can be seen in adolescents secondary to genetic or autoimmune conditions, or gonadotoxic therapies. Often times, its underlying cause is not identified. It is a rare condition in pediatrics, but a thorough evaluation is required for a timely diagnosis and optimizing outcomes. Objectives We aim to describe the clinical phenotype of idiopathic POI in an adolescent population seen in a referral center, and evaluate its diagnostic approach. Methods All patients evaluated between 2012 and 2018 were identified using the diagnostic codes for POI. Medical records were manually reviewed and clinical information was extracted. Cases were excluded from the final sample if they were found to have incomplete diagnostic information, Turner syndrome, eating disorders, gonadal surgeries and/or a history of oncological conditions or treatments. Results Forty-eight patients with POI were identified, and only seven met the established criteria. Anti-ovarian and anti-thyroid antibodies were evaluated in 100% and 86%, respectively, while only 29% were tested for anti-adrenal autoimmunity. The karyotype was obtained consistently, while the fragile X mental retardation 1 (FMR1) gene expansion was only assessed in approximately a third of the patients. Finally, only 29% of patients received reproductive counseling or referral to a fertility specialist. Conclusions Diagnostic evaluation for POI appears to be challenging to pediatric providers. Anti-ovarian antibodies are frequently obtained despite the lack of their clinical significance in POI, while anti-adrenal antibodies, which are the preferred diagnostic test, are not commonly obtained. Reproductive orientation or referral is seldom provided to the adolescent population.


Asunto(s)
Autoinmunidad/inmunología , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Infertilidad Femenina/complicaciones , Insuficiencia Ovárica Primaria/diagnóstico , Adolescente , Niño , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Fenotipo , Insuficiencia Ovárica Primaria/epidemiología , Insuficiencia Ovárica Primaria/etiología , Pronóstico , Reproducción , Pruebas de Función de la Tiroides , Estados Unidos/epidemiología
20.
Nat Commun ; 10(1): 3392, 2019 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-31358739

RESUMEN

Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO409-428), can induce anti-MPO autoimmunity. The peptide (6PGD391-410) is part of a plasmid-encoded 6-phosphogluconate dehydrogenase found in some S. aureus strains. It induces anti-MPO T-cell autoimmunity and MPO-ANCA in mice, whereas related sequences do not. Mice immunized with 6PGD391-410, or with S. aureus containing a plasmid expressing 6PGD391-410, develop glomerulonephritis when MPO is deposited in glomeruli. The peptide induces anti-MPO autoreactivity in the context of three MHC class II allomorphs. Furthermore, we show that 6PGD391-410 is immunogenic in humans, as healthy human and AAV patient sera contain anti-6PGD and anti-6PGD391-410 antibodies. Therefore, our results support the idea that bacterial plasmids might have a function in autoimmune disease.


Asunto(s)
Autoinmunidad/inmunología , Proteínas Bacterianas/inmunología , Complejo Antigénico de Nefritis de Heymann/inmunología , Péptidos/inmunología , Peroxidasa/inmunología , Staphylococcus aureus/inmunología , Secuencia de Aminoácidos , Animales , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Proteínas Bacterianas/genética , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Glomerulonefritis/inmunología , Complejo Antigénico de Nefritis de Heymann/metabolismo , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Péptidos/genética , Peroxidasa/metabolismo , Plásmidos/genética , Staphylococcus aureus/genética , Staphylococcus aureus/fisiología
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