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1.
Cell Mol Life Sci ; 77(1): 179-194, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31172216

RESUMO

It has been suggested that the persistence of coxsackieviruses-B (CV-B) in pancreatic beta cells plays a role in the pathogenesis of type 1 diabetes (T1D). Yet, immunological effectors, especially natural killer (NK) cells, are supposed to clear virus-infected cells. Therefore, an evaluation of the response of NK cells to pancreatic beta cells persistently infected with CV-B4 was conducted. A persistent CV-B4 infection was established in 1.1B4 pancreatic beta cells. Infectious particles were found in supernatants throughout the culture period. The proportion of cells containing viral protein VP1 was low (< 5%), although a large proportion of cells harbored viral RNA (around 50%), whilst cell viability was preserved. HLA class I cell surface expression was downregulated in persistently infected cultures, but HLA class I mRNA levels were unchanged in comparison with mock-infected cells. The cytolytic activities of IL-2-activated non-adherent peripheral blood mononuclear cells (PBMCs) and of NK cells were higher towards persistently infected cells than towards mock-infected cells, as assessed by an LDH release assay. Impaired cytolytic activity of IL-2-activated non-adherent PBMCs from patients with T1D towards infected beta cells was observed. In conclusion, pancreatic beta cells persistently infected with CV-B4 can be lysed by NK cells, implying that impaired cytolytic activity of these effector cells may play a role in the persistence of CV-B in the host and thus in the viral pathogenesis of T1D.


Assuntos
Infecções por Coxsackievirus/complicações , Diabetes Mellitus Tipo 1/virologia , Enterovirus Humano B/imunologia , Células Secretoras de Insulina/virologia , Células Matadoras Naturais/imunologia , Adulto , Linhagem Celular , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/imunologia , Humanos , Imunidade Celular , Células Secretoras de Insulina/imunologia , Pessoa de Meia-Idade
3.
Nat Med ; 25(12): 1865-1872, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792456

RESUMO

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.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/virologia , Enterovirus/isolamento & purificação , RNA Viral/isolamento & purificação , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Enterovirus/imunologia , Enterovirus/patogenicidade , Fezes/virologia , Feminino , Humanos , Lactente , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/virologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/virologia , Masculino , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/virologia
4.
Nat Biotechnol ; 37(12): 1446-1451, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712773

RESUMO

Vagus nerve stimulation can ameliorate autoimmune diseases such as rheumatoid arthritis by modulation of the immune system. Its efficacy for the treatment of type 1 diabetes has not been explored, in part because the nerves projecting to the pancreatic lymph nodes (pLNs) in mice are unmapped. Here, we map the nerve projecting to the pancreas and pLNs in mice and use a minimally invasive surgical procedure to implant micro-cuff electrodes onto the nerve. Pancreatic nerve electrical stimulation (PNES) resulted in ß-adrenergic receptor-mediated-accumulation of B and T cells in pLNs and reduced production of pro-inflammatory cytokines following lipopolysaccharide stimulation. Autoreactive T cells showed reduced proliferation in pLNs of mice receiving PNES as compared to sham controls. In a spontaneous mouse model of autoimmune diabetes, PNES inhibited disease progression in diabetic mice.


Assuntos
Diabetes Mellitus Tipo 1 , Terapia por Estimulação Elétrica , Pâncreas , Animais , Linfócitos B/imunologia , Glicemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Feminino , Insulina/metabolismo , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Pâncreas/imunologia , Pâncreas/inervação , Pâncreas/metabolismo , Linfócitos T/imunologia
5.
Lancet ; 394(10205): 1286-1296, 2019 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-31533907

RESUMO

Over several decades, studies have described the progression of autoimmune diabetes, from the first appearance of autoantibodies until, and after, the diagnosis of clinical disease with hyperglycaemia and insulin dependence. Despite the improved management of type 1 diabetes with exogenous insulin, most patients do not meet clinical glycaemic goals, and diabetes remains an important medical problem that affects children and adults. Clinical and preclinical studies have suggested strategies to prevent the diagnosis of type 1 diabetes in people at risk, but the outcomes of previous clinical trials have not met their primary endpoints of disease prevention or delay. The results from the TN-10 teplizumab prevention trial show that the diagnosis of type 1 diabetes can be delayed by treatment with a FcR non-binding monoclonal antibody to CD3 in people at high risk for disease. This Series paper discusses how this clinical achievement raises new questions about for whom, and when, immunological strategies might be developed to prevent type 1 diabetes, and how to achieve this goal.


Assuntos
Diabetes Mellitus Tipo 1/prevenção & controle , Anticorpos Monoclonais Humanizados/uso terapêutico , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/imunologia , Humanos
6.
Mol Immunol ; 114: 270-277, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400630

RESUMO

Accumulating evidence suggests a role for the complement system in the pathogenesis of diabetes and the vascular complications that characterise this condition. Complement proteins contribute to the development of type 1 diabetes (T1D) by enhancing the underlying organ-specific autoimmune processes. Complement upregulation and activation is also an important feature of insulin resistance and the development of type 2 diabetes (T2D). Moreover, animal and human studies indicate that complement proteins are involved in the pathogenic mechanisms leading to diabetic microvascular and macrovascular complications. The adverse vascular effects of complement appear to be related to enhancement of the inflammatory process and the predisposition to a thrombotic environment, eventually leading to vascular occlusion. Complement proteins have been considered as therapeutic targets to prevent or treat vascular disease but studies have been mainly conducted in animal models, while human work has been both limited and inconclusive so far. Further studies are needed to understand the potential role of complement proteins as therapeutic targets for reversal of the pathological processes leading to T1D and T2D and for the prevention/treatment of diabetic vascular complications.


Assuntos
Proteínas do Sistema Complemento/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Animais , Humanos , Resistência à Insulina/imunologia , Doenças Vasculares/imunologia
7.
Nat Commun ; 10(1): 3621, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399563

RESUMO

Susceptibility to many human autoimmune diseases is under strong genetic control by class II human leukocyte antigen (HLA) allele combinations. These genes remain by far the greatest risk factors in the development of type 1 diabetes and celiac disease. Despite this, little is known about HLA influences on the composition of the human gut microbiome, a potential source of environmental influence on disease. Here, using a general population cohort from the All Babies in Southeast Sweden study, we report that genetic risk for developing type 1 diabetes autoimmunity is associated with distinct changes in the gut microbiome. Both the core microbiome and beta diversity differ with HLA risk group and genotype. In addition, protective HLA haplotypes are associated with bacterial genera Intestinibacter and Romboutsia. Thus, general population cohorts are valuable in identifying potential environmental triggers or protective factors for autoimmune diseases that may otherwise be masked by strong genetic control.


Assuntos
Doenças Autoimunes/genética , Autoimunidade/genética , Diabetes Mellitus Tipo 1/imunologia , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Alelos , Bactérias/classificação , Bactérias/genética , Biodiversidade , Doença Celíaca/genética , Criança , Pré-Escolar , Fezes/microbiologia , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Lactente , RNA Ribossômico 16S/genética , Fatores de Risco , Suécia
8.
Arkh Patol ; 81(4): 78-82, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31407723

RESUMO

The study of the sociomedical problems of diabetes mellitus led to the discovery of latent autoimmune diabetes in adults (LADA), a special form of the disease. The slow onset of the disease, the clinical signs of type 2 diabetes mellitus concurrent with the autoantibody pancreatic ß-cell destruction mechanism that is characteristic of type 1 diabetes. Genetic factors play an important role in the genesis of the disease. Insulitis concurrent with intact or hypertrophic islets of the gland originally develops morphologically. Subsequently, the phenomena of islet atrophy and sclerosis are progressive. The disease is typical for young people (generally those aged 25-35 years) with normal body mass index, low blood C-peptide levels, with antibodies against ß-cells, primarily to glutamate decarboxylase, being detected. Insulin preparations should be used to treat these patients.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Autoimune Latente em Adultos , Adulto , Autoanticorpos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/imunologia , Glutamato Descarboxilase , Humanos , Diabetes Autoimune Latente em Adultos/diagnóstico , Diabetes Autoimune Latente em Adultos/imunologia , Adulto Jovem
9.
Ned Tijdschr Geneeskd ; 1632019 08 19.
Artigo em Holandês | MEDLINE | ID: mdl-31433147

RESUMO

BACKGROUND Checkpoint inhibitors are relatively new anti-cancer medicines that activate tumour cell immunity. CASE DESCRIPTION We describe two patients who presented to the emergency department due to severe ketoacidosis, this being the first symptom of diabetes in said patients. A few weeks prior to this, they each commenced treatment with the checkpoint inhibitor pembrolizumab. HbA1c level, assessed in one of the patients, was not elevated upon presentation. CONCLUSION Type 1 diabetes mellitus is a rare, but potentially life-threatening, complication of treatment with checkpoint inhibitors. However, routine measurement of glucose or HbA1c levels is not useful in patients who are treated with checkpoint inhibitors. Both patients and healthcare professionals should be (made) aware of the symptoms of hyperglycaemia, thereby ensuring immediate treatment with insulin in order to prevent severe ketoacidosis.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/imunologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/imunologia , Pontos de Checagem do Ciclo Celular/imunologia , Feminino , Humanos , Insulina , Masculino
10.
J Immunol Res ; 2019: 1780567, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467932

RESUMO

This study analyzed the expression of membrane OX40 and OX40L (mOX40 and mOX40L) and levels of soluble OX40 and OX40L (sOX40 and sOX40L) in T1D patients to determine their clinical significance. Peripheral blood (PB) was collected from patients with T1D and healthy control participants. Expression of mOX40 and mOX40L on immune cells was detected by flow cytometry. Levels of sOX40 and sOX40L in sera were measured by ELISA. We demonstrated for the first time enhanced sOX40 and sOX40L expression and reduced mOX40 and mOX40L levels in T1D patients which correlated with the clinical characteristics and inflammatory factors. These results suggest that OX40/OX40L signal may be promising biomarkers and associated with the pathogenesis of T1D.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Ligante OX40/metabolismo , Receptores OX40/metabolismo , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Ligante OX40/sangue , Receptores OX40/sangue , Adulto Jovem
12.
J Immunol Res ; 2019: 8785263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281853

RESUMO

Regulatory T cells (Tregs) play a critical role in controlling autoreactive T cells, and quantitative and/or qualitative deficiencies in Tregs are associated with autoimmune diseases, including type 1 diabetes (T1D), in both humans and mice. Both the incidence of T1D and percentages of peripheral Tregs in NOD mice vary considerably between animal facilities. In our animal facility, the incidence of T1D in NOD mice is high at 90-100% and the percentages of peripheral CD4+Foxp3+ cells in ~9-10-week-old female NOD mice are decreased compared to control (B6) mice shortly before high glucose is first detected (~12 weeks). These data suggest that there is an imbalance between Tregs and potentially pathogenic effector T cells at this age that could have significant impact on disease progression to overt diabetes. The goal of the current study was to investigate mechanisms that play a role in peripheral Treg : T effector cell balance in NOD mice, including differences in persistence/survival, peripheral homeostatic proliferation, and thymic production and output of CD4+ T cells. We found no differences in persistence/survival or homeostatic proliferation of either Tregs or effector T cells between NOD and B6 mice. Furthermore, although the percentages and absolute numbers of CD4+Foxp3+ cells in thymus were not decreased in NOD compared to B6 mice, the percentage of CD4+ recent thymic emigrants (RTE) that were Foxp3+ was significantly lower in 9-week-old NOD mice. Interestingly, the thymic output of CD4+Foxp3+ cells was not lower in NOD mice, whereas the thymic output of CD4+Foxp3- cells was significantly higher in NOD mice at that age compared to B6 mice. These data suggest that the higher thymic output of CD4+Foxp3- T cells contributes, at least in part, to the lower percentages of peripheral CD4+Foxp3+ Tregs in NOD mice and an imbalance between Tregs and T effector cells that may contribute to the development of full-blown diabetes.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Animais , Biomarcadores , Linfócitos T CD4-Positivos/metabolismo , Movimento Celular , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Imunomodulação , Imunofenotipagem , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Especificidade da Espécie , Linfócitos T Reguladores/metabolismo , Timo/metabolismo
13.
J Neuroinflammation ; 16(1): 138, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286987

RESUMO

BACKGROUND: Leukostasis is a key patho-physiological event responsible for capillary occlusion in diabetic retinopathy. Circulating monocytes are the main cell type entrapped in retinal vessels in diabetes. In this study, we investigated the role of the signal transducer and activator of transcription 3 (STAT3) pathway in diabetes-induced immune cell activation and its contribution to retinal microvascular degeneration. METHODS: Forty-one patients with type 1 diabetes (T1D) [mild non-proliferative diabetic retinopathy (mNPDR) (n = 13), active proliferative DR (aPDR) (n = 14), inactive PDR (iPDR) (n = 14)] and 13 age- and gender-matched healthy controls were recruited to the study. C57BL/6 J WT mice, SOCS3fl/fl and LysMCre/+SOCS3fl/fl mice were rendered diabetic by Streptozotocin injection. The expression of the phosphorylated human and mouse STAT3 (pSTAT3), mouse LFA-1, CD62L, CD11b and MHC-II in circulating immune cells was evaluated by flow cytometry. The expression of suppressor of cytokine signalling 3 (SOCS3) was examined by real-time RT-PCR. Mouse plasma levels of cytokines were measured by Cytometric Beads Array assay. Retinal leukostasis was examined following FITC-Concanavalin A perfusion and acellular capillary was examined following Isolectin B4 and Collagen IV staining. RESULTS: Compared to healthy controls, the expression of pSTAT3 in circulating leukocytes was statistically significantly higher in mNPDR but not aPDR and was negatively correlated with diabetes duration. The expression of pSTAT3 and its inhibitor SOCS3 was also significantly increased in leukocytes from diabetic mice. Diabetic mice had higher plasma levels of IL6 and CCL2 compared with control mice. LysMCre/+SOCS3fl/fl mice and SOCS3fl/fl mice developed comparative levels of diabetes, but leukocyte activation, retinal leukostasis and number of acellular capillaries were statistically significantly increased in LysMCre/+SOCS3fl/fl diabetic mice. CONCLUSION: STAT3 activation in circulating immune cells appears to contribute to retinal microvascular degeneration and may be involved in DR initiation in T1D.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Retinopatia Diabética/metabolismo , Leucócitos Mononucleares/metabolismo , Microvasos/metabolismo , Vasos Retinianos/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Estudos Transversais , Diabetes Mellitus Tipo 1/imunologia , Retinopatia Diabética/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microvasos/imunologia , Vasos Retinianos/imunologia
14.
ACS Chem Biol ; 14(7): 1436-1448, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31260253

RESUMO

Type 1 diabetes (T1D) is an autoimmune disorder which develops when insulin-producing, pancreatic beta cells are destroyed by an aberrant immune response. Current therapies for T1D either treat symptoms or cause global immunosuppression, which leave patients at risk of developing long-term complications or vulnerable to foreign pathogens. Antigen-specific immunotherapies have emerged as a selective approach for autoimmune diseases by inducing tolerance while mitigating global immunosuppression. We previously reported SAgAs with multiple copies of a multiple sclerosis (MS) autoantigen grafted onto hyaluronic acid (HA) as an efficacious therapy in experimental autoimmune encephalomyelitis. While the immune response of MS is distinct from that of T1D, the mechanism of SAgAs was hypothesized to be similar and via induction of immune tolerance to diabetes antigens. We synthesized SAgAs composed of HA polymer backbone conjugated with multiple copies of the T1D autoantigen mimotope p79 using aminooxy chemistry (SAgAp79) or using copper-catalyzed alkyne-azide cycloaddition (cSAgAp79) chemistry. SAgAs constructed using the hydrolyzable aminooxy linkage, thus capable of releasing p79, exhibited physicochemical properties similar to the triazole linkage. Both SAgAp79 versions showed high specificity and efficacy in stimulating epitope-specific T cells. SAgAs can be taken up by most immune cell populations but do not induce their maturation, and conventional dendritic cells are responsible for the brunt of antigen presentation within splenocytes. cSAgAp79 was more stimulatory than SAgAp79 both in vitro and in vivo, an effect that was ascribed to the peptide modification rather than the type of linkage. In summary, we provide here the first proof-of-principle that SAgA therapy could also be applicable to T1D.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Linfócitos T/imunologia , Animais , Apresentação do Antígeno , Células Cultivadas , Diabetes Mellitus Tipo 1/terapia , Epitopos/imunologia , Feminino , Imunoterapia Adotiva , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Análise Serial de Proteínas , Baço/imunologia
15.
Egypt J Immunol ; 26(1): 129-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31333003

RESUMO

T regulatory cells (Tregs) are a cornerstone regulator for immune responses and inflammatory reactions. Abnormal number or function of Tregs causes deranged immune response that increases the autoimmune disorders and inflammatory conditions. Type 1 diabetes mellitus is an autoimmune disease associated with many complications, of which, Cardiovascular complications are fundamental and responsible for profound morbidity and mortality. Understanding the immunopathogenesis of these disorders allows early diagnosis and better management by innovating new therapeutic targets. In this study, we aimed to detect the association between CD4+CD8+FOX3+ Tregs, T1DM, and associated cardiovascular complications. The study included 144 individuals divided into three groups, group 1 included 48 patients suffering from T1DM without cardiovascular complications, group II: included 48 type T1DM patients with cardiovascular complications. Group III: included 48 healthy control subjects. For all participants, markers for inflammation, and cardiovascular involvement were assessed. The percentage of CD4+ CD25+ FOXP3+ Regulatory T- cells (Tregs) was measured by flow cytometry using peripheral blood samples. The level of Treg was lowest in group II and highest in group III, the difference was highly significant P < 0.001. Treg in group I significantly correlated with age (r= 0.58, P=0.004), CK-mb (r= 0.61, P=0.04) and LDL (r= -.61, P=0.4). While in group II, it correlated with triglyceride level, (r= 0.65 and a P =- 0.02). In conclusion, Lower levels of Tregs are associated with cardiovascular complications in TIDM patients.


Assuntos
Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 1/complicações , Linfócitos T Reguladores/citologia , Biomarcadores , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/imunologia , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2
16.
N Engl J Med ; 381(7): 603-613, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31180194

RESUMO

BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo CD3/antagonistas & inibidores , Diabetes Mellitus Tipo 1/prevenção & controle , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Criança , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Método Duplo-Cego , Exantema/induzido quimicamente , Feminino , Teste de Tolerância a Glucose , Antígeno HLA-DR3 , Antígeno HLA-DR4 , Humanos , Contagem de Linfócitos , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Linfócitos T/imunologia , Adulto Jovem
17.
J Immunol Res ; 2019: 6179243, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214623

RESUMO

Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1ß, sIL-2Rα, sTNFRII, and TNFα in CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγ correlated significantly with the density of FOXP3+ Tregs in lamina propria of the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in the lamina propria of the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into the lamina propria and in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation.


Assuntos
Doença Celíaca/complicações , Doença Celíaca/metabolismo , Citocinas/sangue , Diabetes Mellitus Tipo 1/complicações , Mucosa Intestinal/metabolismo , Adolescente , Fatores Etários , Biomarcadores , Doença Celíaca/imunologia , Doença Celíaca/patologia , Criança , Pré-Escolar , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Estações do Ano , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
18.
Mediators Inflamm ; 2019: 2987901, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049023

RESUMO

The depression incidence is much higher in patients with diabetes mellitus (DM), and the majority of these cases remain under-diagnosed. Type 1 diabetes mellitus (T1D) is now widely thought to be an organ-specific autoimmune disease. As a chronic autoimmune condition, T1D is characterized by T cell-mediated selective loss of insulin-producing ß-cells. The age of onset of T1D is earlier than T2D, and T1D patients have an increased vulnerability to depression due to its diagnosis and treatment burden occurring in a period when the individuals are young. The literature has suggested that inflammatory cytokines play a wide role in both diseases. In this review, the mechanisms behind the initiation and propagation of the autoimmune response in T1D and depression are analyzed, and the contribution of cytokines to both conditions is discussed. This review outlines the immunological mechanism of T1D and depression, with a particular emphasis on the role of tumor necrosis factor-α (TNF-α), IL-1ß, and interferon-γ (IFN-γ) cytokines and their signaling pathways. The purpose of this review is to highlight the possible pathways of the cytokines shared by these two diseases via deciphering their cytokine cascades. They may provide a basic groundwork for future study of the possible mechanism that links these two diseases and to develop new compounds that target the same pathway but can conquer two diseases.


Assuntos
Citocinas/metabolismo , Depressão/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Inflamação/imunologia , Depressão/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Masculino
19.
BMC Endocr Disord ; 19(1): 44, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053128

RESUMO

Gestational Diabetes Mellitus (GDM) is the most common metabolic disorder in pregnancy, and it is associated with increased risk of morbidity in maternal-fetal outcomes. GDM is also associated with a higher risk to develop diabetes in the future. Diabetes-related autoantibodies (AABs) have been detected in a small percentage (usually less than 10%) of women with gestational diabetes. The prevalence in gestational diabetes of these autoimmune markers of type 1 diabetes (T1D) has been assessed in many studies, together with the risk of progression of AABs-positive GDM towards impaired glucose regulation (IFG or IGT) and overt diabetes after pregancy. The question whether it is necessary to test for T1D autoantibodies in all pregnancies with GDM is still debated. Here we examine the epidemiology of T1D autoantibodies in GDM, their clinical relevance in term of future risk of diabetes or impaired glucose regulation and in term of maternal-fetal outcomes, and discuss when it may be the most appropriate time to search for T1D autoantibodies in women with gestational diabetes.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Gestacional/sangue , Intolerância à Glucose/diagnóstico , Autoanticorpos/imunologia , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/imunologia , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/etiologia , Teste de Tolerância a Glucose , Humanos , Gravidez , Prognóstico
20.
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
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