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1.
Eur Rev Med Pharmacol Sci ; 24(21): 11409-11420, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33215463

RESUMO

OBJECTIVE: Diabetes is a lifestyle disease and it has become an epidemic worldwide in recent decades. In the ongoing COVID-19 pandemic situation, diabetes has become a serious health concern since large numbers of patients are vulnerable to die from the virus. Thus, diabetic patients affected by COVID-19 cause a major health crisis now. Reports show that large occurrence of diabetes makes it a serious comorbidity in COVID-19 patients. MATERIALS AND METHODS: It is crucial to understand how COVID-19 affects diabetes patients. This paper has reviewed published literature extensively to understand the pattern, importance, care, and medication. RESULTS: This review summarizes the association between COVID-19 and diabetes in terms of susceptibility for pneumonia and other diseases. It also discusses the harshness of COVID-19 with diabetes populations and immunological impacts. It further adds the ACE2 receptor role in diabetes with COVID-19 patients. CONCLUSIONS: Finally, this paper illustrates different types of diabetes management techniques, such as blood glucose management, self-management, mental health management, and therapeutic management. It also summarizes the current knowledge about diabetic patients with COVID-19 to fight this pandemic.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Suscetibilidade a Doenças/imunologia , Pneumonia Viral/imunologia , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/imunologia , Humanos , Hipoglicemiantes/administração & dosagem , Pâncreas/patologia , Pandemias/prevenção & controle , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/metabolismo , Replicação Viral/imunologia
2.
PLoS One ; 15(11): e0242049, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33186361

RESUMO

Islet autoantibodies are predominantly measured by radioassay to facilitate risk assessment and diagnosis of type 1 diabetes. However, the reliance on radioactive components, large sample volumes and limited throughput renders radioassay testing costly and challenging. We developed a multiplex analysis platform based on antibody detection by agglutination-PCR (ADAP) for the sample-sparing measurement of GAD, IA-2 and insulin autoantibodies/antibodies in 1 µL serum. The assay was developed and validated in 7 distinct cohorts (n = 858) with the majority of the cohorts blinded prior to analysis. Measurements from the ADAP assay were compared to radioassay to determine correlation, concordance, agreement, clinical sensitivity and specificity. The average overall agreement between ADAP and radioassay was above 91%. The average clinical sensitivity and specificity were 96% and 97%. In the IASP 2018 workshop, ADAP achieved the highest sensitivity of all assays tested at 95% specificity (AS95) rating for GAD and IA-2 autoantibodies and top-tier performance for insulin autoantibodies. Furthermore, ADAP correctly identified 95% high-risk individuals with two or more autoantibodies by radioassay amongst 39 relatives of T1D patients tested. In conclusion, the new ADAP assay can reliably detect the three cardinal islet autoantibodies/antibodies in 1µL serum with high sensitivity. This novel assay may improve pediatric testing compliance and facilitate easier community-wide screening for islet autoantibodies.


Assuntos
Aglutinação/imunologia , Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Adolescente , Adulto , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Anticorpos Anti-Insulina/imunologia , Masculino , Programas de Rastreamento , Reação em Cadeia da Polimerase/métodos , Sensibilidade e Especificidade , Adulto Jovem
3.
PLoS One ; 15(11): e0242092, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33206686

RESUMO

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-ß production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Células Supressoras Mieloides/imunologia , Adolescente , Contagem de Linfócito CD4 , Criança , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Interferon gama/metabolismo , Masculino , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
4.
J Vis Exp ; (164)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33165322

RESUMO

Fluorescent antigen production is a critical step in the identification of antigen-specific B cells. Here, we detailed the preparation, purification, and the use of four-arm, fluorescent PEG-antigen conjugates to selectively identify antigen-specific B cells through avid engagement with cognate B cell receptors. Using modular click chemistry and commercially available fluorophore kit chemistries, we demonstrated the versatility of preparing customized fluorescent PEG-conjugates by creating distinct arrays for proteolipid protein (PLP139-151) and insulin, which are important autoantigens in murine models of multiple sclerosis and type 1 diabetes, respectively. Assays were developed for each fluorescent conjugate in its respective disease model using flow cytometry. Antigen arrays were compared to monovalent autoantigen to quantify the benefit of multimerization onto PEG backbones. Finally, we illustrated the utility of this platform by isolating and assessing anti-insulin B cell responses after antigen stimulation ex vivo. Labeling insulin-specific B cells enabled the amplified detection of changes to co-stimulation (CD86) that were otherwise dampened in aggregate B cell analysis. Together, this report enables the production and use of fluorescent antigen arrays as a robust tool for probing B cell populations.


Assuntos
Antígenos/química , Antígenos/imunologia , Linfócitos B/imunologia , Corantes Fluorescentes/química , Polimerização , Animais , Química Click , Diabetes Mellitus Tipo 1/imunologia , Humanos , Camundongos , Esclerose Múltipla/imunologia
5.
Paediatr Respir Rev ; 36: 57-64, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32958428

RESUMO

The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG's effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Proteção Cruzada/imunologia , Imunidade Heteróloga/imunologia , Infecções por Mycobacterium não Tuberculosas/prevenção & controle , Vacinas contra a Tuberculose/uso terapêutico , Tuberculose/prevenção & controle , Vacina BCG/imunologia , Úlcera de Buruli/microbiologia , Úlcera de Buruli/prevenção & controle , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/imunologia , Lactente , Mortalidade Infantil , Hanseníase/microbiologia , Hanseníase/prevenção & controle , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/imunologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/imunologia , Vacinas contra a Tuberculose/imunologia
6.
Nat Metab ; 2(10): 1021-1024, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32879473

RESUMO

Here we report a case where the manifestations of insulin-dependent diabetes occurred following SARS-CoV-2 infection in a young individual in the absence of autoantibodies typical for type 1 diabetes mellitus. Specifically, a 19-year-old white male presented at our emergency department with diabetic ketoacidosis, C-peptide level of 0.62 µg l-1, blood glucose concentration of 30.6 mmol l-1 (552 mg dl-1) and haemoglobin A1c of 16.8%. The patient´s case history revealed probable COVID-19 infection 5-7 weeks before admission, based on a positive test for antibodies against SARS-CoV-2 proteins as determined by enzyme-linked immunosorbent assay. Interestingly, the patient carried a human leukocyte antigen genotype (HLA DR1-DR3-DQ2) considered to provide only a slightly elevated risk of developing autoimmune type 1 diabetes mellitus. However, as noted, no serum autoantibodies were observed against islet cells, glutamic acid decarboxylase, tyrosine phosphatase, insulin and zinc-transporter 8. Although our report cannot fully establish causality between COVID-19 and the development of diabetes in this patient, considering that SARS-CoV-2 entry receptors, including angiotensin-converting enzyme 2, are expressed on pancreatic ß-cells and, given the circumstances of this case, we suggest that SARS-CoV-2 infection, or COVID-19, might negatively affect pancreatic function, perhaps through direct cytolytic effects of the virus on ß-cells.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Diabetes Mellitus Tipo 1/complicações , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Betacoronavirus/imunologia , Biomarcadores , Infecções por Coronavirus/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-D/genética , Antígenos HLA-D/imunologia , Humanos , Imunoglobulina M/imunologia , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/imunologia , Masculino , Pandemias , Pneumonia Viral/imunologia , Adulto Jovem
7.
Nat Med ; 26(8): 1247-1255, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770166

RESUMO

Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk1. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common2,3 and is most severe in the very young4,5, in whom it can be life threatening and difficult to treat6-9. Autoantibody surveillance programs effectively prevent most ketoacidosis10-12 but require frequent evaluations whose expense limits public health adoption13. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible14 because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Cetose/sangue , Medição de Risco , Autoanticorpos/imunologia , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Insulina/deficiência , Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Cetose/imunologia , Masculino , Triagem Neonatal , Fatores de Risco
8.
Nat Immunol ; 21(10): 1244-1255, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32747817

RESUMO

Follicular helper T (TFH) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether TFH cells were decreased by costimulation blockade using the CTLA-4-immunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)+ TFH cells and other ICOS+ populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment TFH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS+ TFH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, TFH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade.


Assuntos
Abatacepte/uso terapêutico , Antígenos CD28/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Centro Germinativo/imunologia , Imunoterapia/métodos , Linfócitos T Auxiliares-Indutores/imunologia , Abatacepte/farmacologia , Animais , Biomarcadores Farmacológicos , Antígenos CD28/genética , Células Cultivadas , Biologia Computacional , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/terapia , Modelos Animais de Doenças , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Resultado do Tratamento
9.
PLoS One ; 15(8): e0238070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853219

RESUMO

Factors regulating self-antigen directed immune-responses in autoimmunity are poorly understood. Signal regulatory protein gamma (SIRPγ) is a human T-cell specific protein with genetic variants associated with type 1 diabetes (T1D). SIRPγ's function in the immune system remains unclear. We show that T1D and relapsing remitting multiple sclerosis (RRMS) subjects have significantly greater frequency of rs2281808 T genetic variant, that correlates with reduced SIRPγ-expression in T-cells. Importantly, reduced SIRPγ-expression in RRMS and T1D subjects was not restricted to T variant, suggesting SIRPγ-expression is also regulated by disease specific factors in autoimmunity. Interestingly, increased frequencies of SIRPγlow T-cells in RRMS and T1D positively correlated with proinflammatory molecules from T-cells. Finally, we show that SIRPγlow T-cells have enhanced pathogenecity in vivo in a GVHD model. These findings suggest that decreased-SIRPγ expression, either determined by genetic variants or through peripherally acquired processes, may have a mechanistic link to autoimmunity through induction of hyperactive T-cells.


Assuntos
Antígenos de Diferenciação/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Regulação da Expressão Gênica , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Receptores Imunológicos/genética , Linfócitos T/metabolismo , Adulto , Alelos , Animais , Autoimunidade , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Recidiva , Linfócitos T/imunologia , Adulto Jovem
10.
Scand J Immunol ; 92(5): e12961, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32853446

RESUMO

The new era of immune and reconstitution therapy of autoimmune disorders is ongoing. However, endocrine autoimmune diseases comprise a group of elaborating pathologies where the development of new treatment strategies remains slow. Substitution of the missing hormones is still standard practice, taking care of the devastating symptoms but not the cause of disease. As our knowledge of the genetic contribution to the aetiology of endocrine disorders increases and early diagnostic tools are available, it is now possible to identify persons at risk before they acquire full-blown disease. This review summarizes current knowledge and treatment of endocrine autoimmune disorders, focusing on type 1 diabetes, Addison's disease, autoimmune thyroid diseases and primary ovarian insufficiency. We explore which new therapies might be used in the different stages of the disease, focus on legalized therapy and elaborate on the ongoing clinical studies for these diseases and the research front, before hypothesizing on the way ahead.


Assuntos
Doença de Addison/imunologia , Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/imunologia , Doenças do Sistema Endócrino/imunologia , Insuficiência Ovariana Primária/imunologia , Doenças da Glândula Tireoide/imunologia , Doença de Addison/genética , Doença de Addison/terapia , Doenças Autoimunes/genética , Doenças Autoimunes/terapia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/terapia , Doenças do Sistema Endócrino/genética , Doenças do Sistema Endócrino/terapia , Feminino , Humanos , Imunoterapia/métodos , Modelos Imunológicos , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/terapia , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/terapia
11.
Nat Metab ; 2(9): 934-945, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719542

RESUMO

Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, thus raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells. Using a genome-scale CRISPR screen in a mouse model for T1D, we show that deleting RNLS, a genome-wide association study candidate gene for T1D, made beta cells resistant to autoimmune killing. Structure-based modelling identified the U.S. Food and Drug Administration-approved drug pargyline as a potential RNLS inhibitor. Oral pargyline treatment protected transplanted beta cells in diabetic mice, thus leading to disease reversal. Furthermore, pargyline prevented or delayed diabetes onset in several mouse models for T1D. Our results identify RNLS as a modifier of beta cell vulnerability and as a potential therapeutic target to avert beta cell loss in T1D.


Assuntos
Sistemas CRISPR-Cas , Diabetes Mellitus Tipo 1/tratamento farmacológico , Estudo de Associação Genômica Ampla , Células Secretoras de Insulina/efeitos dos fármacos , Monoaminoxidase/efeitos dos fármacos , Animais , Autoimunidade/efeitos dos fármacos , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Estresse do Retículo Endoplasmático , Inibidores Enzimáticos/farmacologia , Feminino , Células-Tronco Pluripotentes Induzidas/imunologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Transplante das Ilhotas Pancreáticas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Mutação , Pargilina/farmacologia
12.
Sci Rep ; 10(1): 12019, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694640

RESUMO

Recent advances in genetic analyses have significantly refined human type 1 diabetes (T1D) associated loci. The goal of such effort is to identify the causal genes and have a complete understanding of the molecular pathways that independently or interactively influence cellular processes leading to the destruction of insulin producing pancreatic ß cells. UBASH3A has been suggested as the underlying gene for a human T1D associated region on chromosome 21. To further evaluate the role of UBASH3A in T1D, we targeted Ubash3a in NOD mice using zinc-finger nuclease mediated mutagenesis. In both 10-week-old females and males, significantly more advanced insulitis was observed in UBASH3A-deficient than in wild-type NOD mice. Consistently, UBASH3A-deficient NOD mice developed accelerated T1D in both sexes, which was associated with increased accumulation of ß-cell autoreactive T cells in the spleen and pancreatic lymph node. Adoptive transfer of splenic T cells into NOD.Rag1-/- mice demonstrated that UBASH3A deficiency in T cells was sufficient to promote T1D development. Our results provide strong evidence to further support a role of UBASH3A in T1D. In addition to T1D, UBASH3A deficiency also promoted salivary gland inflammation in females, demonstrating its broad impact on autoimmunity.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença/genética , Receptores de Antígenos de Linfócitos T/deficiência , Receptores de Antígenos de Linfócitos T/genética , Sialadenite/metabolismo , Transferência Adotiva , Animais , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Feminino , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Mutagênese/efeitos dos fármacos , Nucleases de Dedos de Zinco/farmacologia
13.
Curr Opin Endocrinol Diabetes Obes ; 27(4): 187-193, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618630

RESUMO

PURPOSE OF REVIEW: To summarize a new form of autoimmune diabetes as an adverse event of specific cancer immunotherapies. Immune checkpoint inhibitors are revolutionary treatments in advanced cancers; however, they can cause type 1 diabetes following treatment with these state-of-the-art therapies. RECENT FINDINGS: A review of the literature showed that this new form of autoimmune diabetes has significant similarities with childhood-onset type 1 diabetes but also some distinctions. It frequently presents with severe diabetic ketoacidosis and almost half of the patients have type 1 diabetes-associated antibodies at presentation. Rapid loss of residual beta-cell function with a lack of honeymoon phase is typical. Certain human leukocyte antigen risk genes for prototypical type 1 diabetes that develops in children and young adults are also commonly found in patients with immune checkpoint inhibitor-induced type 1 diabetes. SUMMARY: Immune checkpoint inhibitor-induced type 1 diabetes presenting with diabetic ketoacidosis is a life-threatening adverse event of cancer immunotherapy. Healthcare providers should be aware of this adverse event to prevent morbidity and mortality related to diabetic ketoacidosis. Developing guidelines to identify and monitor risk groups are of utmost importance.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Diabetes Mellitus Tipo 1/etiologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Adolescente , Adulto , Anticorpos Monoclonais/uso terapêutico , Pontos de Checagem do Ciclo Celular/imunologia , Criança , Diabetes Mellitus Tipo 1/imunologia , Cetoacidose Diabética/etiologia , Cetoacidose Diabética/imunologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto Jovem
14.
Curr Opin Endocrinol Diabetes Obes ; 27(4): 225-230, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618634

RESUMO

PURPOSE OF REVIEW: Although type 1 diabetes (T1D) is characterized by destruction of the pancreatic beta cells by self-reactive T cells, it has become increasingly evident that B cells also play a major role in disease development, likely functioning as antigen-presenting cells. Here we review the biology of islet antigen-reactive B cells and their participation in autoimmune diabetes. RECENT FINDINGS: Relative to late onset, individuals who develop T1D at an early age display increased accumulation of insulin-reactive B cells in islets. This B-cell signature is also associated with rapid progression of disease and responsiveness to B-cell depletion therapy. Also suggestive of B-cell participation in disease is loss of anergy in high-affinity insulin-reactive B cells. Importantly, loss of anergy is seen in patient's healthy first-degree relatives carrying certain T1D risk alleles, suggesting a role early in disease development. SUMMARY: Recent studies indicate that islet-reactive B cells may play a pathogenic role very early in T1D development in young patients, and suggest utility of therapies that target these cells.


Assuntos
Linfócitos B/fisiologia , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Idade de Início , Animais , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Humanos , Insulina/imunologia , Linfócitos T/fisiologia , Fatores de Tempo
15.
Curr Opin Endocrinol Diabetes Obes ; 27(4): 240-247, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618636

RESUMO

PURPOSE OF REVIEW: The role of T cells specific for islet autoantigens is proven in pathogenesis of type 1 diabetes. Recently, there has been rapid expansion in the number of T-cell subsets identified, this has coincided with an increase in the repertoire of reported islet antigens mainly through the discovery of novel epitopes. A discussion of how these marry together is now warranted and timely. RECENT FINDINGS: In this review, we will discuss the autoreactivity against neo-epitopes. We then explore the growing array of T-cell subsets for both CD4 T cells, including follicular and peripheral T helper cells, and CD8 T cells, discussing evolution from naïve to exhausted phenotypes. Finally, we detail how subsets correlate with disease stage and loss of ß-cell function and are impacted by immunotherapy. SUMMARY: The expanding list of T-cell subsets may be potentially encouraging in terms of elucidating disease mechanisms and have a role as biomarkers for disease progression. Furthermore, T-cell subsets can be used in stratifying patients for clinical trials and for monitoring immunotherapy outcomes. However, the definition of subsets needs to be refined in order to ensure that there is a uniform approach in designating T-cell subset attributes that is globally applied.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Subpopulações de Linfócitos T/fisiologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Ilhotas Pancreáticas/imunologia , Subpopulações de Linfócitos T/imunologia
16.
Sci Rep ; 10(1): 12098, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694530

RESUMO

Chloroquine (CQ) and hydroxychloroquine, are promising anti-inflammatory drugs for the treatment of Diabetes mellitus (DM) to prevent associated complications. Therefore, this study evaluated the anti-inflammatory effects of CQ-free and CQ-incorporated polylactic acid nanoparticles (NPs) in the peripheral blood mononuclear cells (PBMCs) of patients with type 1 Diabetes mellitus (T1DM). In total, 25 normoglycemic individuals and 25 patients with T1DM aged 10-16 years were selected and glycemic controls evaluated. After cell viability assessed by MTT assay, T1DM PBMCs were subjected to a CQ concentration of 10 µM in three different conditions: not treated (NT), treated with CQ, and treated with CQ NPs. The cells were incubated for 48 h, and the mRNA expressions of cytokines IL1B, IFNG, TNFA, IL12, and IL10 were determined by relative quantification through real-time PCR at 24 h intervals. IL1B expression decreased in CQ and CQ NP-treated cells after 48 h (p < 0.001) and 24 h (p < 0.05) of treatment, respectively. IFNG and IL12 expressions significantly decreased (p < 0.001) in cells treated with CQ and CQ NPs at 24 and 48 h compared to NT. TNFA and IL10 expressions significantly decreased after 48 h (p < 0.001) and 24 h (p < 0.002), respectively, by both CQ and CQ NPs treatment. Despite being a preliminary in vitro study, CQ has anti-inflammatory activity in the primary cells of T1DM patients and could represent an alternative and adjuvant anti-inflammatory therapy to prevent diabetes complications.


Assuntos
Anti-Inflamatórios/farmacologia , Cloroquina/farmacologia , Citocinas/genética , Diabetes Mellitus Tipo 1/genética , Leucócitos Mononucleares/citologia , Poliésteres/química , Adolescente , Anti-Inflamatórios/química , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Criança , Cloroquina/química , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Nanopartículas
18.
Scand J Immunol ; 92(4): e12943, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32697399

RESUMO

Type 1 diabetes is an autoimmune disease typically starting in childhood that culminates in the destruction of insulin-producing beta cells in the pancreas. Although type 1 diabetes is considered to be a primarily T cell-mediated disease, B cells clearly participate in the autoimmune process, as autoantibodies recognizing pancreatic islet antigen commonly appear in circulation before the onset of the disease. T cells providing helper functions to B cells have recently been shown to be involved in the pathogenesis of a wide range of antibody-associated immune disorders. These T cells include CXCR5-positive follicular T helper (Tfh) cells, and a recently described closely related CXCR5-negative subset coined peripheral T helper (Tph) cells. Here, we review the current state of knowledge on different B cell helper T cell subsets, focusing on their potential involvement in the development of type 1 diabetes.


Assuntos
Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoimunidade/imunologia , Humanos
19.
Maturitas ; 137: 37-44, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32498935

RESUMO

An increasing number of new cases of autoimmune diabetes occur during adulthood. Most are cases of latent autoimmune diabetes in adults (LADA), a form of autoimmune diabetes with older mean age at onset, slower rate of beta-cell loss and longer period of insulin independence after onset when compared with type 1 diabetes. Unfortunately, patients with LADA are often misdiagnosed as having type 2 diabetes, the most frequent form of adult-onset diabetes, and show a sustained poor glycemic control over time. Recent evidence shows that this translates into a significantly increased risk of complications. Therefore, an enhanced awareness of LADA is essential. In this narrative review we aim to provide an update on knowledge about LADA pathophysiology and clinical implications by critically reporting the most recent evidence.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Adulto , Idade de Início , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/terapia , Humanos
20.
Medicine (Baltimore) ; 99(22): e20437, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481446

RESUMO

To study the changes of pancreas, thyroid, adrenal, parathyroid and gonadal organ-specific antibodies in patients with type 1 diabetic patients and to explore the risk of development to other endocrine gland autoimmune diseases.Fifty one patients with type 1 diabetes mellitus were selected. ELISA was used to detect islet, adrenal gland, Parathyroid, gonadal organ-specific antibody levels, the level of thyroid-related antibodies by lectrochemiluminescence.Compared with the healthy control group, the levels of the 17-α-OHAb, 21-OHAb, NALP5Ab, P450sccAb, and CaSRAb in the T1DM group were significantly higher. GADAb-positive patients were more likely to have TPOAb-positive patients than GADAb-negative patients, and the positive rate of 2 thyroid antibodies in GADAb-positive patients was significantly higher than that in GADAb-negative patients. The presence of these antibodies is related to the age of onset of type 1 diabetes or Patient age. In combination with 1 or 2 islet antibody-positive patients, the combined non-islet antibody positive rate was higher than that of islet antibody-negative patients.Patients with type 1 diabetes with other autoimmune diseases at risk significantly increased compared with normal, of which the most common thyroid autoimmune disease, thyroid antibodies and hormone levels should be routinely detected at the first visit and long-term follow-up.


Assuntos
Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Adolescente , Adulto , Anticorpos/sangue , Doenças Autoimunes/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
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