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1.
J Neuroimmunol ; 341: 577189, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32087461

RESUMO

Anti-GAD65 antibodies have been identified in both acute/subacute seizures (limbic encephalitis and extralimbic encephalitis) and chronic isolated epilepsy. The evidence of high serum titers and intrathecal synthesis play a fundamental role in diagnosis but poorly correlate with disease severity or response to therapies. It remains controversial whether anti-GAD65 Abs are the pathogenic entity or only serve as a surrogate marker for autoimmune disorders mediated by cytotoxic T cells. Unlike other immune-mediated epilepsy, although multiple combinations of therapeutics are used, the efficacy and prognosis of patients with GAD65-epilepsy patients are poor. Besides, GAD65-epilepsy is more prone to relapse and potentially evolve into a more widespread CNS inflammatory disorder. This article reviews the recent advances of GAD65-epilepsy, focusing on the diagnosis, epidemiology, pathophysiology, clinical features, and treatment, to better promote the recognition and provide proper therapy for this condition.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Encefalite/imunologia , Epilepsia/imunologia , Glutamato Descarboxilase/imunologia , Especificidade de Anticorpos , Autoantígenos/química , Doenças Autoimunes do Sistema Nervoso/terapia , Terapia Combinada , Progressão da Doença , Encefalite/epidemiologia , Encefalite/terapia , Epilepsia/diagnóstico por imagem , Epilepsia/epidemiologia , Epilepsia/terapia , Epitopos/química , Epitopos/imunologia , Glutamato Descarboxilase/química , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Imunoterapia , Encefalite Límbica/imunologia , Encefalite Límbica/terapia , Modelos Moleculares , Neuroimagem , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Plasmaferese , Conformação Proteica , Psicocirurgia , Linfócitos T Citotóxicos/imunologia
2.
Diabetes ; 69(3): 465-476, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32029481

RESUMO

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Metaboloma , Sintomas Prodrômicos , Alanina/metabolismo , Aminoácidos de Cadeia Ramificada , Pré-Escolar , Ácido Desidroascórbico/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Ácidos Graxos/metabolismo , Feminino , Predisposição Genética para Doença , Glutamato Descarboxilase/imunologia , Humanos , Lactente , Recém-Nascido , Anticorpos Anti-Insulina/imunologia , Estudos Longitudinais , Masculino , Metionina/metabolismo , Fosfatidiletanolaminas/metabolismo , Prolina/metabolismo , Risco , Triglicerídeos/metabolismo , Ácido gama-Aminobutírico/metabolismo
4.
Ann Transplant ; 24: 608-616, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31767825

RESUMO

BACKGROUND Pancreas transplantation can be a viable treatment option for patients with type 1 diabetes mellitus (T1DM), especially for those who are candidates for kidney transplantation. T1DM may rarely recur after pancreas transplantation, causing the loss of pancreatic graft. The aim of this study was to describe the prevalence of T1DM recurrence after pancreas transplantation in our series. MATERIAL AND METHODS Eighty-one patients transplanted from 2002 to 2015 were included. Autoantibody testing (GADA and IA-2) was performed before pancreas transplantation and during the follow-up. RESULTS The series includes 48 males and 33 females, mean age 37.4±5.7 years and mean duration of diabetes 25.5±6.5 years. Patients received simultaneous pancreas kidney (SPK) transplantation. After SPK transplantation, 56 patients retained pancreatic graft, 8 patients died, and 17 patients lost their pancreatic graft. T1DM recurrence occurred in 2 of the 81 transplanted patients, yielding a prevalence of 2.5%, with an average time of appearance of 3.3 years after transplant. Pancreatic enzymes were normal in the 2 patients, ruling out pancreatic rejection. T1DM recurrence was confirmed histologically, showing selective lymphoid infiltration of the pancreatic islets. CONCLUSIONS T1DM recurrence after pancreas transplantation is infrequent; however, it is one of the causes of pancreatic graft loss that should always be ruled out. Negative autoimmunity prior to transplantation does not ensure that T1DM does not recur.


Assuntos
Diabetes Mellitus Tipo 1/cirurgia , Transplante de Pâncreas , Adulto , Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Glutamato Descarboxilase/imunologia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Humanos , Transplante de Rim , Masculino , Estudos Prospectivos , Recidiva , Reoperação
5.
Epileptic Disord ; 21(5): 437-442, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31649008

RESUMO

AIMS: To delineate common epilepsy features associated with the presence of glutamic acid decarboxylase autoantibodies (GAD65-Ab). METHODS: Three consecutive cases of GAD65-Ab encephalitis patients, followed in our neurological department, were investigated with regards to clinical semiology and EEG. RESULTS: These patients presented new-onset subtle ictal clinical features. Patients 1 and 2 described prolonged and transitory feelings of "déjà vu - déjà vécu" and a "dreamy state". Patient 3 was admitted for subsequent transient aphasia events followed by paroxysmal behavioural disturbances. Epileptic origin of the symptoms was confirmed using either a standard EEG (observation of temporal status epilepticus in one case) or a prolonged EEG (focal epileptiform activity during an asymptomatic period for two patients). All patients suffered from clinical focal status epilepticus. Patients 1 and 2 presented with temporo-mesial seizures in agreement with the definition for limbic encephalitis, whereas Patient 3 presented with neocortical (lateral temporal and frontal lobe) seizures arguing for a non-limbic encephalitis. A high level of GAD65-Ab was found in cerebral spinal fluid, confirming a diagnosis of epilepsy associated with GAD65-Ab encephalitis. CONCLUSION: Encephalitis seems to be a frequent neurological syndrome associated with GAD65-Ab disorders. Epilepsy may be more frequent and severe than currently suggested, as ictal semiology may be subtle for these outpatients in whom standard EEG is commonly falsely reassuring. Subtle focal status epilepticus is a particular semiology of the GAD65-Ab encephalitis spectrum.


Assuntos
Autoanticorpos/imunologia , Encefalite/imunologia , Glutamato Descarboxilase/imunologia , Estado Epiléptico/imunologia , Adulto , Eletroencefalografia/métodos , Epilepsia/imunologia , Feminino , Humanos , Encefalite Límbica/imunologia , Pessoa de Meia-Idade , Convulsões/imunologia
6.
Monoclon Antib Immunodiagn Immunother ; 38(5): 201-208, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31603741

RESUMO

Type 1 diabetes mellitus is an autoimmune syndrome defined by the presence of autoreactive T and B cells, which results in destruction of insulin-producing beta cells. Autoantibodies against GAD65 (glutamic acid decarboxylase 65)-a membrane-bound enzyme on pancreatic beta cells, contribute to beta cells' destruction and the loss of pancreatic functions. Mouse FcγRIIb on B lymphocytes possesses an inhibitory effect on the activity of these cells. We hypothesized that it may be possible to suppress GAD65-specific B cells in mice with diabetes using chimeric molecules, containing an anti-FcγRIIb antibody, coupled to peptide B/T epitopes derived from the GAD65 protein. With these engineered chimeras, we expect to selectively co-cross-link the anti-GAD65-specific B cell receptor (BCR) and FcγRIIb, thus delivering a suppressive signal to the targeted B cells. An anti-FcγRIIb monoclonal antibody and two synthetic peptide epitopes derived from the GAD65 molecule were used for chimeras' construction. The suppressive activity of the engineered molecules was tested in vivo in mice with streptozotocin (STZ)-induced type 1 diabetes. These chimeric molecules exclusively bind disease-associated B cells by recognizing their GAD65-specific BCR and selectively deliver a strong inhibitory signal through their surface FcγRIIb receptors. A reduction in the number of anti-GAD65 IgG antibody-secreting plasmocytes and an increased percentage of apoptotic B lymphocytes were observed after treatment with protein-engineered antibodies of mice with STZ-induced type 1 diabetes.


Assuntos
Linfócitos B/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Epitopos/imunologia , Glutamato Descarboxilase/imunologia , Proteínas Recombinantes/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Especificidade de Anticorpos , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Autoanticorpos/metabolismo , Linfócitos B/imunologia , Linfócitos B/patologia , Glicemia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1 , Epitopos/genética , Feminino , Glutamato Descarboxilase/genética , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Ratos , Receptores de IgG/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
8.
Seizure ; 71: 318-321, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31525611

RESUMO

PURPOSE: Individuals with type 1 diabetes mellitus (T1D) are at higher risk of epilepsy. T1D is a progressive immune-mediated disease and the etiology of epilepsy remains unknown in most. Glutamic acid decarboxylase (GAD) catalyzes GABA formation. GABA-secreting neurons and pancreatic beta cells are the major cells expressing GAD. METHODS: Cross-sectional study. Patients with T1D from a multiethnic population underwent GADA measurement to investigate possible association between T1D and epilepsy of unknown etiology. RESULTS: T1D patients were analyzed (n = 375). Overall frequency of epilepsy was 5.9% (n = 22). Frequency of epilepsy of unknown etiology was 3.2% (n = 12). Of these, 8 (2.1%) had idiopathic generalized epilepsy (IGE) and 4 (1.1%) MRI-negative temporal lobe epilepsy (TLE). Patients with T1D and epilepsy of unknown etiology did not show differences in GADA frequency (83.3% vs 50%; p = 0.076); however, their titers were higher (106.9 ±â€¯136.5 IU/mL; median 7; IQR 1.65-256 vs 10.2 ±â€¯14.5 IU/ml; median 4.3; IQR 1.9-8.9; p = 0.019) compared to patients without epilepsy. Moreover, epilepsy of unknown etiology was associated with GADA titers ≥ 100 UI/mL [odds ratio (OR) 4.42, 95% CI 2.36-8.66]. CONCLUSION: Epilepsy frequency was elevated in patients with T1D and multiethnic background. Presence of epilepsy of unknown etiology was associated with high titers of GADA in this population with long-standing T1D, which has different ethnic and genetic background compared to previous studies. Further prospective studies are required to identify if GADA presence or its persistence are directly responsible for epilepsy in individuals with T1D.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Epilepsia/sangue , Epilepsia/epidemiologia , Glutamato Descarboxilase/imunologia , Adulto , Brasil/epidemiologia , Comorbidade , Estudos Transversais , Diabetes Mellitus Tipo 1/etnologia , Epilepsia/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Acta Diabetol ; 56(11): 1225-1230, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31367990

RESUMO

AIMS: To investigate the possibility of identifying a subtype of latent autoimmune diabetes in adults (LADA), T-LADA (T cell responses-positive and autoantibody-negative) from patients with phenotypic type 2 diabetes (T2D) by enzyme-linked immunospot (ELISPOT). METHODS: Eighty-two patients with phenotypic T2D were studied. Autoantibodies against glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 and zinc transporter 8 were measured by radioligand assay. Thirty-nine Ab+ and 43 Ab- patients with phenotypic T2D were enrolled for T cell assay of responses to GAD65 and C-peptide antigen by ELISPOT. RESULTS: (1) Eleven of 43 Ab- participants with phenotypic T2D were demonstrated interferon (IFN)-γ secreting T cells by ELISPOT, while 13 of 39 Ab+ patients with phenotypic T2D were positive for T cells responses to islet antigens. (2) The onset ages of T cell+ people with phenotypic T2D were younger than that of T cell- individuals (42.7 ± 9.3 vs. 48.2 ± 10.2 years, P = 0.025). Moreover, T cell+ patients with T2D displayed a significantly lower fasting C-peptide (FCP) compared with T cell- participants [0.28 (0.02-0.84) vs. 0.42 (0.05-1.26) nmol/L, P = 0.013]. (3) Ab-T+ group had a significantly lower FCP compared with Ab-T- group [0.31 (0.13-0.84) vs. 0.51 (0.07-1.26) nmol/L, P = 0.023]. CONCLUSIONS: By measuring T cell responses to islet antigens in patients with phenotypic T2D, we identified a specific subtype of LADA who may be associated with worse basal ß-cell function than classic T2D (Ab-T-).


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Diabetes Autoimune Latente em Adultos/imunologia , Fenótipo , Linfócitos T/imunologia , Adulto , Autoanticorpos/imunologia , Peptídeo C/metabolismo , Diabetes Mellitus Tipo 2/sangue , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Diabetes Autoimune Latente em Adultos/sangue , Diabetes Autoimune Latente em Adultos/classificação , Masculino , Pessoa de Meia-Idade , Transportador 8 de Zinco/imunologia
10.
Diabetes Metab Syndr ; 13(3): 1833-1835, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31235102

RESUMO

AIMS: Diabetes mellitus is a metabolic disease that manifested as hyperglycemia due to the defect in secretion or function of insulin. This study aimed was to survey about frequency type I and II diabetes in newly diagnosed diabetic patients base on c-peptide and anti-glutamate acid decarboxylase (GAD) tests. MATERIALS & METHODS: This study was conducted as a prospective study on 70 diabetic patients aged 15-45 years old who referred to diabetes clinics in Ahvaz city during 2012-2014 and their diabetes was diagnosed for the first time, but their type of diabetes was not clinically definitive. Patients with anti-GAD positive and fasting C-peptide level of less than 0.65 were diagnosed as type I diabetes. Patients with anti-GAD negative fasting C-peptide level of greater than or equal to 0.65 were considered as type II diabetes. RESULTS: Eighty two patients (49 males and 33 females) with a mean age of 21.64 ±â€¯4.36 years (range 15-34) and a mean BMI of 22.05 ±â€¯4.41 kg/m2 (range 14-18) were studied. Twenty three patients (28.5%) had type I diabetes and 59 patients (71.95%) had type II diabetes. In patients with type I diabetes, the mean BMI was 24.86 ±â€¯2.36 kg/m2 and the number of patients with family history (56.22%) was higher. In type II diabetic patients, the number of women (62.71%) was higher than that of men. CONCLUSION: Anti-GAD test can be used as a predictive test for early diagnosis of disease and screening of people with a diagnosis of diabetes based on the type of diabetes.


Assuntos
Biomarcadores/sangue , Glicemia/análise , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Adolescente , Adulto , Autoanticorpos/sangue , Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Seguimentos , Glutamato Descarboxilase/imunologia , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Prospectivos , Adulto Jovem
11.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207885

RESUMO

Characterization of multiple antibody epitopes has revealed the necessity of specific groups of amino acid residues for reactivity. This applies to the majority of antibody-antigen interactions, where especially charged and hydrophilic amino acids have been reported to be essential for antibody reactivity. This study describes thorough characterization of glutamic acid decarboxylase (GAD) 65 antigenic epitopes, an immunodominant autoantigen in type 1 diabetes (T1D). As linear epitopes are sparsely described for GAD65 in T1D, we aimed to identify and thoroughly characterize two GAD65 antibodies using immunoassays. A monoclonal antibody recognized an epitope in the N-terminal domain of GAD65, 8FWSFGSE14, whereas a polyclonal antibody recognized two continuous epitopes in the C-terminal domain, corresponding to amino acids 514RTLED518 and 549PLGDKVNF556. Hydrophobic amino acids were essential for antibody reactivity, which was verified by competitive inhibition assays. Moreover, the epitopes were located in flexible linker regions and turn structures. These findings confirm the versatile nature of antibody-antigen interactions and describe potential continuous epitopes related to T1D, which predominantly have been proposed to be of discontinuous nature.


Assuntos
Epitopos/química , Glutamato Descarboxilase/química , Motivos de Aminoácidos , Anticorpos Monoclonais/imunologia , Epitopos/imunologia , Glutamato Descarboxilase/imunologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular
12.
Diabetes Res Clin Pract ; 152: 53-57, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31063857

RESUMO

BACKGROUND: T1DM is divided into 1A (immune-mediated), 1B (virus-triggered, genetic and idiopathic). Presence of auto-antibodies may be correlated to glycemic control. AIM: Assessment relation between the autoantibodies and the poor glycemic control in T1DM. METHODS: 60 patients T1DM 30 males, 30 females, subjected to full history, clinical, anthropometric assessment and laboratory assessment of fasting C-peptide, FBS, 2 h PP glucose, HbA1c, GADA, ICA and IAA level. Classified into two groups; Group I: negative auto-antibodies, Group II: positive auto-antibodies, Group II was further classified into 3 sub-groups, Group II a:1 positive autoantibody, Group II b: 2 positive autoantibodies and Group II c: 3 positive autoantibodies. RESULTS: HbA1c was significantly higher in group II than group I (11.85 ±â€¯1.61% vs. 8.52 ±â€¯0.41%, p = 0.000). HbA1c was highest in group IIc followed by IIb then IIa (12.25 ±â€¯1.48% vs. 11.57 ±â€¯1.59% vs. 10.78 ±â€¯1.73%, p = 0.038). Total insulin units per day was significantly higher in group II than group I (109.83 ±â€¯7.77 U/day vs. 100.83 ±â€¯1.83 U/day, p = 0.007). Duration of diabetes was significantly higher in group I than group II (10.17 ±â€¯1.94 years vs. 8.11 ±â€¯2.20 years, p = 0.033). HbA1c, total insulin units per day and duration of diabetes were independent predictive factors for presence of autoantibodies (p = 0.007, p = 0.033 and p = 0.043 respectively). CONCLUSION: Autoantibodies affect the glycemic control presented by high HbA1c; also it causes increase in total insulin units needed by patients; the more autoantibodies, the higher HbA1c, the more insulin units required to control glycemic state.


Assuntos
Autoanticorpos/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Adolescente , Adulto , Autoanticorpos/imunologia , Peptídeo C/sangue , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Egito/epidemiologia , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Insulina/imunologia , Anticorpos Anti-Insulina/sangue , Masculino , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Adulto Jovem
13.
Islets ; 11(2): 33-43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31084527

RESUMO

Pancreatic islets play an essential role in regulating blood glucose levels. Age-dependent development of glucose intolerance and insulin resistance results in hyperglycemia, which in turn stimulates insulin synthesis and secretion from aged islets, to fulfill the increased demand for insulin. However, the mechanism underlying enhanced insulin secretion remains unknown. Glutamic acid decarboxylase 67 (GAD67) catalyzes the conversion of glutamate into γ-aminobutyric acid (GABA) and CO2. Both glutamate and GABA can affect islet function. Here, we investigated the role of GAD67 in insulin secretion in young (3 month old) and aged (24 month old) C57BL/6J male mice. Unlike young mice, aged mice displayed glucose-intolerance and insulin-resistance. However, aged mice secreted more insulin and showed lower fed blood glucose levels than young mice. GAD67 levels in primary islets increased with aging and in response to high glucose levels. Inhibition of GAD67 activity using a potent inhibitor of GAD, 3-mercaptopropionic acid, abrogated glucose-stimulated insulin secretion from a pancreatic ß-cell line and from young and aged islets. Collectively, our results suggest that blood glucose levels regulate GAD67 expression, which contributes to ß-cell responses to impaired glucose homeostasis caused by advanced aging.


Assuntos
Envelhecimento/metabolismo , Glutamato Descarboxilase/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , RNA Mensageiro/metabolismo , Ácido 3-Mercaptopropiônico/farmacologia , Fatores Etários , Animais , Autoanticorpos/sangue , Linhagem Celular , Senescência Celular , Inibidores Enzimáticos/farmacologia , Células Secretoras de Glucagon/metabolismo , Glucose/farmacologia , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/imunologia , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
J Neuroimmunol ; 332: 135-137, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31015081

RESUMO

We present a case of a 65-year-old African American male, immunosuppressed on Tacrolimus, who initially presented with cerebellar ataxia and rapidly developed Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) with positive anti-glutamic acid decarboxylase (GAD65) antibodies, no underlying malignancy, and normal neuroimaging. PERM is a rare spectrum of Stiff Person Syndrome (SPS), which is strongly associated with anti-GAD antibodies and characterized by flare-ups and remissions of encephalopathy, myelopathy and rigidity with myoclonus. PERM is diagnosed clinically and has been successfully treated with both Intravenous Immunoglobulin (IVIg) and plasmapheresis. Our patient was successfully treated with IVIg. On day 14 after starting IVIg treatment, his neurological symptoms started to improve and ultimately returned to baseline.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes do Sistema Nervoso/etiologia , Ataxia Cerebelar/complicações , Encefalomielite/etiologia , Glutamato Descarboxilase/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Rigidez Muscular/etiologia , Rigidez Muscular Espasmódica/etiologia , Idoso , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/terapia , Ataxia Cerebelar/imunologia , Encefalomielite/imunologia , Encefalomielite/terapia , Humanos , Hospedeiro Imunocomprometido , Imunoterapia , Transplante de Rim , Masculino , Rigidez Muscular/imunologia , Rigidez Muscular/terapia , Plasmaferese , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/terapia , Indução de Remissão , Rigidez Muscular Espasmódica/imunologia , Rigidez Muscular Espasmódica/terapia
15.
J Diabetes Investig ; 10(6): 1480-1489, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30919585

RESUMO

AIMS/INTRODUCTION: To elucidate the relationship between titers of islet autoantibodies, the C-X-C motif chemokine 10 - a circulating chemokine that activates T-helper 1 cells leading to ß-cell destruction - and ß-cell function in type 1 diabetes. MATERIALS AND METHODS: In total, 58 type 1 diabetes patients positive for glutamic decarboxylase-65 autoantibodies (GADA)-radioimmunoassay (mean age 54.1 years; 27 acute-onset cases and 31 slowly progressive cases) were enrolled; serum C-X-C motif chemokine 10 (n = 50), zinc transporter 8 autoantibodies (n = 50) and GADA (n = 58) by an enzyme-linked immunosorbent assay, and insulinoma-associated antigen-2 autoantibodies by radioimmunoassay (n = 50) were measured. The ratio of 100 × random C-peptide (ng/mL)-to-plasma glucose levels (mg/dL; C-peptide index [CPI]) was measured. RESULTS: The CPI significantly decreased in both groups with the progression of disease duration. GADA titers by radioimmunoassay and enzyme-linked immunosorbent assay were strongly correlated with the CPI in acute-onset type 1 diabetes patients with a shorter disease duration (≤10 years), but not in those with a longer duration or slowly progressive type 1 diabetes. Neither insulinoma-associated antigen-2 nor zinc transporter 8 autoantibodies titers were correlated with the CPI. Serum C-X-C motif chemokine 10 levels in both groups were significantly higher than in non-diabetic controls, and persisted at high levels even in those with chronic duration. CONCLUSIONS: Among islet autoantibodies, the intensity of the humoral immune response, as defined by GADA titers, reflected the degree of residual ß-cell function in acute-onset type 1 diabetes patients with short duration. Prolonged disease activity might accelerate ß-cell impairment in both subtypes of type 1 diabetes.


Assuntos
Autoanticorpos/sangue , Biomarcadores/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Glutamato Descarboxilase/imunologia , Secreção de Insulina , Ilhotas Pancreáticas/fisiopatologia , Adulto , Estudos de Casos e Controles , Quimiocina CXCL10/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Tempo
16.
J Diabetes Investig ; 10(6): 1590-1592, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30860651

RESUMO

We report a case of missed diagnosis of maturity-onset diabetes of the young type 5 uncovered during pregnancy with a previous diagnosis of type 1 diabetes. Maturity-onset diabetes of the young type 5 cannot be excluded in early-onset diabetes with positive islet-related autoantibodies and type 1 diabetes-prone human leukocyte antigen subtypes. Abdominal ultrasound should be used in all patients with pre-gestational diabetes, and maturity-onset diabetes of the young type 5 should be considered when renal abnormality is presented.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Glutamato Descarboxilase/imunologia , Adulto , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diagnóstico Diferencial , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Mutação , Gravidez , Prognóstico
18.
Endocrine ; 64(1): 48-54, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30783963

RESUMO

PURPOSE: The aim of this work was to investigate, in patients with newly diagnosed Graves' disease (GD), the frequency of islet autoantibodies including autoantibodies against Zink transporter 8 (ZnT8A), as well as to investigate the relation between thyroid autoantibodies, islet autoantibodies and diabetes both before GD diagnosis and at follow-up. METHODS: Blood samples from 278 patients with newly diagnosed GD were analyzed for autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA2-A), three variants of zinc transporter 8 (ZnT8A), thyroid peroxidase (TPOA) and the TSH receptor (TRAb). Information on other autoimmune diseases, as well as development of diabetes during follow up was gathered from patient's medical journal. RESULTS: At GD diagnosis, 13.7% were positive for islet autoantibodies, with the majority being positive for GADA (8.7%) and ZnT8A (7.6%). TPOA were found positive in 71% and TRAb in 83%. No association was found between islet autoantibodies and thyroid autoantibodies or diabetes diagnosis during follow up. Positive association was found between islet autoantibodies and all forms of diabetes, diagnosed both before and after GD (OR: 2.5, CI: 1.1-6.8, p = 0.03) but not to other autoimmune diseases at GD diagnosis. CONCLUSIONS: The incidence of GADA and ZnT8A in patients with GD is high and might indicate wide range endocrine autoimmunity, as well as risk for non-autoimmune diabetes rather than exclusively mark beta cell autoimmunity and type 1 diabetes.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Glutamato Descarboxilase/imunologia , Doença de Graves/diagnóstico , Transportador 8 de Zinco/imunologia , Adulto , Autoimunidade , Comorbidade , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Feminino , Seguimentos , Doença de Graves/sangue , Doença de Graves/epidemiologia , Doença de Graves/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência
19.
Scand J Clin Lab Invest ; 79(1-2): 123-125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30727763

RESUMO

The GAD65 and IA-2 antibodies (Abs) are biomarkers of the development of type 1 diabetes mellitus (T1DM) in both children and adults. The upper reference limit for the autoantibodies made by the manufacture was established on an adult Chinese population. Here, we established upper reference limits for Northern European adults and children in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines. Serum samples from healthy Danish children (0-18 years) and adults (18-70 years) were analysed for GAD65Ab and IA-2Ab using MAGLUMI 800 Chemiluminescence Immunoassay (CLIA). The Kruskal-Wallis test was used for evaluating differences between gender and age groups. No gender or age differences were found for neither GAD65Ab nor IA-2Ab, and a combined upper reference limit for both children and adults could be established. An upper reference limit of 5.1 IU/mL was defined for GAD65Ab and 11.5 U/mL for IA-2Ab. Our results showed a substantial discrepancy with the reference limits established by the manufacturer.


Assuntos
Autoanticorpos/sangue , Glutamato Descarboxilase/antagonistas & inibidores , Imunoensaio/normas , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/antagonistas & inibidores , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/etnologia , Diabetes Mellitus Tipo 1/imunologia , Europa (Continente) , Grupo com Ancestrais do Continente Europeu , Feminino , Expressão Gênica , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/imunologia , Voluntários Saudáveis , Humanos , Lactente , Recém-Nascido , Luminescência , Masculino , Pessoa de Meia-Idade , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Valores de Referência
20.
Endocr J ; 66(4): 329-336, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30760658

RESUMO

This research aimed to examine the relationship between anti-glutamic acid decarboxylase antibody (GADA) titers and clinical parameters at onset and to clarify the association between clinical severity and GADA titers in GADA-positive fulminant type 1 diabetes. This cross-sectional observational study included 20 cases with GADA-positive fulminant type 1 diabetes (4 cases from our hospital and 16 from cases reported in the literature). The association between GADA titers and clinical parameters [age, sex, body weight, body mass index, period from appearance of any prodromal symptoms to diagnosis, period from development of hyperglycemic symptoms to diagnosis, GADA titer, HbA1c level, blood pH and HCO3- level, serum levels of ketone bodies and pancreatic exocrine enzymes] were analyzed. Spearman's rank correlation coefficient (rs) was used for the correlation analysis. The results showed that there was a significant inverse correlation between GADA titers and the "period from appearance of any prodromal symptoms to diagnosis" (rs = -0.559, p < 0.05). Moreover, GADA titers were inversely correlated with blood pH and HCO3- level (rs = -0.576, p < 0.05, rs = -0.578, p < 0.05, respectively), and positively correlated with serum levels of total ketone bodies, acetoacetate, and 3-hydroxybutyrate (rs = 0.661, p < 0.05; rs = 0.700, p < 0.05; and rs = 0.782, p < 0.01, respectively). These findings suggest that higher GADA titers may be linked to more severe clinical severity of GADA-positive fulminant type 1 diabetes at onset. This association may be attributed to possible pre-existence of autoimmunity-related ß-cell damage before the onset of fulminant type 1 diabetes.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Glutamato Descarboxilase/imunologia , Adulto , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Avaliação de Sintomas , Adulto Jovem
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