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1.
Nutrients ; 13(10)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34684667

RESUMO

Are free carnitine concentrations on newborn screening (NBS) 48-72 h after birth lower in patients who develop type 1 diabetes than in controls? A retrospective case-control study of patients with type 1 diabetes was conducted. NBS results of patients from a Sydney hospital were compared against matched controls from the same hospital (1:5). Multiple imputation was performed for estimating missing data (gestational age) using gender and birthweight. Conditional logistic regression was used to control for confounding and to generate parameter estimates (α = 0.05). The Hommel approach was used for post-hoc analyses. Results are reported as medians and interquartile ranges. A total of 159 patients were eligible (80 females). Antibodies were detectable in 86. Median age at diagnosis was 8 years. Free carnitine concentrations were lower in patients than controls (25.50 µmol/L;18.98-33.61 vs. 27.26; 21.22-34.86 respectively) (p = 0.018). Immunoreactive trypsinogen was higher in this group (20.24 µg/L;16.15-29-52 vs. 18.71; 13.96-26.92) (p = 0.045), which did not persist in the post-hoc analysis. Carnitine levels are lower and immunoreactive trypsinogen might be higher, within 2-3 days of birth and years before development of type 1 diabetes as compared to controls, although the differences were well within reference ranges and provide insight into the pathogenesis into neonatal onset of type 1 diabetes development rather than use as a diagnostic tool. Given trypsinogen's use for evaluation of new-onset type 1 diabetes, larger studies are warranted.


Assuntos
Carnitina/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Triagem Neonatal , Tripsinogênio/imunologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
2.
Front Immunol ; 12: 667889, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512622

RESUMO

Type 1 diabetes (T1D) is the most common paediatric endocrine disease, and its frequency has been found to increase worldwide. Similar to all conditions associated with poorly regulated glucose metabolism, T1D carries an increased risk of infection. Consequently, careful compliance by T1D children with schedules officially approved for child immunization is strongly recommended. However, because patients with T1D show persistent and profound limitations in immune function, vaccines may evoke a less efficient immune response, with corresponding lower protection. Moreover, T1D is an autoimmune condition that develops in genetically susceptible individuals and some data regarding T1D triggering factors appear to indicate that infections, mainly those due to viruses, play a major role. Accordingly, the use of viral live attenuated vaccines is being debated. In this narrative review, we discussed the most effective and safe use of vaccines in patients at risk of or with overt T1D. Literature analysis showed that several problems related to the use of vaccines in children with T1D have not been completely resolved. There are few studies regarding the immunogenicity and efficacy of vaccines in T1D children, and the need for different immunization schedules has not been precisely established. Fortunately, the previous presumed relationship between vaccine administration and T1D appears to have been debunked, though some doubts regarding rotavirus vaccines remain. Further studies are needed to completely resolve the problems related to vaccine administration in T1D patients. In the meantime, the use of vaccines remains extensively recommended in children with this disease.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Vacinação , Vacinas Virais/administração & dosagem , Viroses/prevenção & controle , Diabetes Mellitus Tipo 1/epidemiologia , Humanos , Hospedeiro Imunocomprometido , Imunogenicidade da Vacina , Medição de Risco , Fatores de Risco , Vacinação/efeitos adversos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Virais/efeitos adversos , Viroses/epidemiologia , Viroses/imunologia , Viroses/virologia
3.
PLoS Comput Biol ; 17(9): e1009413, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34570760

RESUMO

Persistent destruction of pancreatic ß-cells in type 1 diabetes (T1D) results from multifaceted pancreatic cellular interactions in various phase progressions. Owing to the inherent heterogeneity of coupled nonlinear systems, computational modeling based on T1D etiology help achieve a systematic understanding of biological processes and T1D health outcomes. The main challenge is to design such a reliable framework to analyze the highly orchestrated biology of T1D based on the knowledge of cellular networks and biological parameters. We constructed a novel hybrid in-silico computational model to unravel T1D onset, progression, and prevention in a non-obese-diabetic mouse model. The computational approach that integrates mathematical modeling, agent-based modeling, and advanced statistical methods allows for modeling key biological parameters and time-dependent spatial networks of cell behaviors. By integrating interactions between multiple cell types, model results captured the individual-specific dynamics of T1D progression and were validated against experimental data for the number of infiltrating CD8+T-cells. Our simulation results uncovered the correlation between five auto-destructive mechanisms identifying a combination of potential therapeutic strategies: the average lifespan of cytotoxic CD8+T-cells in islets; the initial number of apoptotic ß-cells; recruitment rate of dendritic-cells (DCs); binding sites on DCs for naïve CD8+T-cells; and time required for DCs movement. Results from therapy-directed simulations further suggest the efficacy of proposed therapeutic strategies depends upon the type and time of administering therapy interventions and the administered amount of therapeutic dose. Our findings show modeling immunogenicity that underlies autoimmune T1D and identifying autoantigens that serve as potential biomarkers are two pressing parameters to predict disease onset and progression.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Animais , Autoantígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Comunicação Celular/imunologia , Biologia Computacional , Simulação por Computador , Células Dendríticas/imunologia , Células Dendríticas/patologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Humanos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD , Modelos Imunológicos , Software , Análise de Sistemas
4.
J Immunol ; 207(8): 2051-2059, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526376

RESUMO

Ag-specific immunotherapy to restore immune tolerance to self-antigens, without global immune suppression, is a long-standing goal in the treatment of autoimmune disorders such as type 1 diabetes (T1D). However, vaccination with autoantigens such as insulin or glutamic acid decarboxylase have largely failed in human T1D trials. Induction and maintenance of peripheral tolerance by vaccination requires efficient autoantigen presentation by APCs. In this study, we show that a lipophilic modification at the N-terminal end of CD4+ epitopes (lipo-peptides) dramatically improves peptide Ag presentation. We designed amphiphilic lipo-peptides to efficiently target APCs in the lymph nodes by binding and trafficking with endogenous albumin. Additionally, we show that lipophilic modification anchors the peptide into the membranes of APCs, enabling a bivalent cell-surface Ag presentation. The s.c. injected lipo-peptide accumulates in the APCs in the lymph node, enhances the potency and duration of peptide Ag presentation by APCs, and induces Ag-specific immune tolerance that controls both T cell- and B cell-mediated immunity. Immunization with an amphiphilic insulin B chain 9-23 peptide, an immunodominant CD4+ T cell epitope in NOD mice, significantly suppresses the activation of T cells, increases inhibitory cytokine production, induces regulatory T cells, and delays the onset and lowers the incidence of T1D. Importantly, treatment with a lipophilic ß-cell peptide mixture delays progression to end-stage diabetes in acutely diabetic NOD mice, whereas the same doses of standard soluble peptides were not effective. Amphiphilic modification effectively enhances Ag presentation for peptide-based immune regulation of autoimmune diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Epitopos de Linfócito T/metabolismo , Insulina/metabolismo , Fragmentos de Peptídeos/metabolismo , Tensoativos/metabolismo , Albuminas , Animais , Apresentação do Antígeno , Feminino , Humanos , Tolerância Imunológica , Imunização , Imunomodulação , Insulina/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fragmentos de Peptídeos/imunologia
5.
J Immunol ; 207(8): 1990-2004, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34507949

RESUMO

In type 1 diabetes (T1D) autoreactive CD8 T cells infiltrate pancreatic islets and destroy insulin-producing ß cells. Progression to T1D onset is a chronic process, which suggests that the effector activity of ß-cell autoreactive CD8 T cells needs to be maintained throughout the course of disease development. The mechanism that sustains diabetogenic CD8 T cell effectors during the course of T1D progression has not been completely defined. Here we used single-cell RNA sequencing to gain further insight into the phenotypic complexity of islet-infiltrating CD8 T cells in NOD mice. We identified two functionally distinct subsets of activated CD8 T cells, CD44highTCF1+CXCR6- and CD44highTCF1-CXCR6+, in islets of prediabetic NOD mice. Compared with CD44highTCF1+CXCR6- CD8 T cells, the CD44highTCF1-CXCR6+ subset expressed higher levels of inhibitory and cytotoxic molecules and was more prone to apoptosis. Adoptive cell transfer experiments revealed that CD44highTCF1+CXCR6- CD8 T cells, through continuous generation of the CD44highTCF1-CXCR6+ subset, were more capable than the latter population to promote insulitis and the development of T1D. We further showed that direct IL-27 signaling in CD8 T cells promoted the generation of terminal effectors from the CD44highTCF1+CXCR6- population. These results indicate that islet CD44highTCF1+CXCR6- CD8 T cells are a progenitor-like subset with self-renewing capacity, and, under an IL-27-controlled mechanism, they differentiate into the CD44highTCF1-CXCR6+ terminal effector population. Our study provides new insight into the sustainability of the CD8 T cell response in the pathogenesis of T1D.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Interleucina-27/metabolismo , Linfócitos T Citotóxicos/imunologia , Animais , Diferenciação Celular , Autorrenovação Celular , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Células Secretoras de Insulina/imunologia , Camundongos , Camundongos Endogâmicos NOD
6.
Front Immunol ; 12: 722979, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489972

RESUMO

The immunopathology of type I diabetes (T1D) presents a complicated case in part because of the multifactorial origin of this disease. Typically, T1D is thought to occur as a result of autoimmunity toward islets of Langerhans, resulting in the destruction of insulin-producing cells (ß cells) and thus lifelong reliance on exogenous insulin. However, that explanation obscures much of the underlying mechanism, and the actual precipitating events along with the associated actors (latent viral infection, diverse immune cell types and their roles) are not completely understood. Notably, there is a malfunctioning in the regulation of cytotoxic CD8+ T cells that target endocrine cells through antigen-mediated attack. Further examination has revealed the likelihood of an imbalance in distinct subpopulations of tolerogenic and cytotoxic natural killer (NK) cells that may be the catalyst of adaptive immune system malfunction. The contributions of components outside the immune system, including environmental factors such as chronic viral infection also need more consideration, and much of the recent literature investigating the origins of this disease have focused on these factors. In this review, the details of the immunopathology of T1D regarding NK cell disfunction is discussed, along with how those mechanisms stand within the context of general autoimmune disorders. Finally, the rarer cases of latent autoimmune, COVID-19 (viral), and immune checkpoint inhibitor (ICI) induced diabetes are discussed as their exceptional pathology offers insight into the evolution of the disease as a whole.


Assuntos
Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Autoanticorpos/imunologia , Doenças Autoimunes/patologia , COVID-19/complicações , Diabetes Mellitus Tipo 1/etiologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Viroses/complicações
7.
Nat Commun ; 12(1): 5074, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417463

RESUMO

ß cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human ß cells with inflammation but its expression is reduced in surviving ß cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate ß cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO ß cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between ß cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in ß cells may reduce activating pathologic immune cells and killing of ß cells.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 1/patologia , Inflamação/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sequência de Bases , Citotoxicidade Imunológica , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Dioxigenases , Progressão da Doença , Feminino , Humanos , Imunidade , Inflamação/genética , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Linfócitos T/imunologia , Transcrição Genética
8.
Front Immunol ; 12: 616215, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447366

RESUMO

Tolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the initiating antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy employs an oral administration of PPI-Fc, i.e. PPI fused with an IgG Fc to bind the intestinal neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring during breastfeeding. Neonatal oral PPI-Fc vaccination did not prevent diabetes development in PPI T-cell receptor-transgenic G9C8.NOD mice. However, PPI-Fc was efficiently transferred through the intestinal epithelium in an Fc- and FcRn-dependent manner, was taken up by antigen presenting cells, and reached the spleen and thymus. Although not statistically significant, neonatal oral PPI-Fc vaccination delayed diabetes onset in polyclonal Ins2 -/-.NOD mice that spontaneously develop accelerated diabetes. Thus, this strategy shows promise in terms of systemic and thymic antigen delivery via the intestinal FcRn pathway, but the current PPI-Fc formulation/regimen requires further improvements to achieve diabetes prevention.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 1/prevenção & controle , Antígenos de Histocompatibilidade Classe I/imunologia , Insulina/farmacologia , Precursores de Proteínas/farmacologia , Receptores Fc/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Timo/imunologia , Administração Oral , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Insulina/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Precursores de Proteínas/genética , Receptores Fc/genética , Proteínas Recombinantes de Fusão/genética
9.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360736

RESUMO

Myeloid regulatory cell-based therapy has been shown to be a promising cell-based medicinal approach in organ transplantation and for the treatment of autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Crohn's disease and multiple sclerosis. Dendritic cells (DCs) are the most efficient antigen-presenting cells and can naturally acquire tolerogenic properties through a variety of differentiation signals and stimuli. Several subtypes of DCs have been generated using additional agents, including vitamin D3, rapamycin and dexamethasone, or immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-ß). These cells have been extensively studied in animals and humans to develop clinical-grade tolerogenic (tol)DCs. Regulatory macrophages (Mregs) are another type of protective myeloid cell that provide a tolerogenic environment, and have mainly been studied within the context of research on organ transplantation. This review aims to thoroughly describe the ex vivo generation of tolDCs and Mregs, their mechanism of action, as well as their therapeutic application and assessment in human clinical trials.


Assuntos
Artrite Reumatoide , Terapia Baseada em Transplante de Células e Tecidos , Células Dendríticas , Diabetes Mellitus Tipo 1 , Tolerância Imunológica , Macrófagos , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/terapia , Colecalciferol/farmacologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Humanos , Interleucina-10/farmacologia , Macrófagos/imunologia , Macrófagos/transplante , Fator de Crescimento Transformador beta/farmacologia
10.
Front Immunol ; 12: 690783, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335595

RESUMO

Type 1 diabetes (T1D) is characterized by the unresolved autoimmune inflammation and islet ß cell destruction. The islet resident antigen-presenting cells (APCs) including dendritic cells and macrophages uptake and process the ß cell-derived antigens to prime the autoreactive diabetogenic T cells. Upon activation, those autoreactive T cells produce copious amount of IFN-γ, TNF-α and IL-1ß to induce ß cell stress and death. Autoimmune attack and ß cell damage intertwine together to push forward this self-destructive program, leading to T1D onset. However, ß cells are far beyond a passive participant during the course of T1D development. Herein in this review, we summarized how ß cells are actively involved in the initiation of autoimmune responses in T1D setting. Specifically, ß cells produce modified neoantigens under stressed condition, which is coupled with upregulated expression of MHC I/II and co-stimulatory molecules as well as other immune modules, that are essential properties normally exhibited by the professional APCs. At the cellular level, this subset of APC-like ß cells dynamically interacts with plasmacytoid dendritic cells (pDCs) and manifests potency to activate autoreactive CD4 and CD8 T cells, by which ß cells initiate early autoimmune responses predisposing to T1D development. Overall, the antigen-presenting function of ß cells helps to explain the tissue specificity of T1D and highlights the active roles of structural cells played in the pathogenesis of various immune related disorders.


Assuntos
Apresentação do Antígeno , Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/imunologia , Animais , Humanos , Ilhotas Pancreáticas/imunologia
11.
EMBO J ; 40(17): e107621, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34369608

RESUMO

The enormous diversity of antibody specificities is generated by random rearrangement of immunoglobulin gene segments and is important for general protection against pathogens. Since random rearrangement harbors the risk of producing self-destructive antibodies, it is assumed that autoreactive antibody specificities are removed during early B-cell development leading to a peripheral compartment devoid of autoreactivity. Here, we immunized wild-type mice with insulin as a common self-antigen and monitored diabetes symptoms as a measure for autoimmune disease. Our results show that autoreactive anti-insulin IgM and IgG antibodies associated with autoimmune diabetes can readily be generated in wild-type animals. Surprisingly, recall immunizations induced increased titers of high-affinity insulin-specific IgM, which prevented autoimmune diabetes. We refer to this phenomenon as adaptive tolerance, in which high-affinity memory IgM prevents autoimmune destruction by competing with self-destructive antibodies. Together, this study suggests that B-cell tolerance is not defined by the absolute elimination of autoreactive specificities, as harmful autoantibody responses can be generated in wild-type animals. In contrast, inducible generation of autoantigen-specific affinity-matured IgM acts as a protective mechanism preventing self-destruction.


Assuntos
Anticorpos Neutralizantes/imunologia , Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Imunoglobulina M/imunologia , Memória Imunológica , Insulina/imunologia , Animais , Linfócitos B/imunologia , Feminino , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos C57BL
12.
J Biol Chem ; 297(4): 101131, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34461100

RESUMO

A number of human autoinflammatory diseases manifest with severe inflammatory bone destruction. Mouse models of these diseases represent valuable tools that help us to understand molecular mechanisms triggering this bone autoinflammation. The Pstpip2cmo mouse strain is among the best characterized of these; it harbors a mutation resulting in the loss of adaptor protein PSTPIP2 and development of autoinflammatory osteomyelitis. In Pstpip2cmo mice, overproduction of interleukin-1ß (IL-1ß) and reactive oxygen species by neutrophil granulocytes leads to spontaneous inflammation of the bones and surrounding soft tissues. However, the upstream signaling events leading to this overproduction are poorly characterized. Here, we show that Pstpip2cmo mice deficient in major regulator of Src-family kinases (SFKs) receptor-type protein tyrosine phosphatase CD45 display delayed onset and lower severity of the disease, while the development of autoinflammation is not affected by deficiencies in Toll-like receptor signaling. Our data also show deregulation of pro-IL-1ß production by Pstpip2cmo neutrophils that are attenuated by CD45 deficiency. These data suggest a role for SFKs in autoinflammation. Together with previously published work on the involvement of protein tyrosine kinase spleen tyrosine kinase, they point to the role of receptors containing immunoreceptor tyrosine-based activation motifs, which after phosphorylation by SFKs recruit spleen tyrosine kinase for further signal propagation. We propose that this class of receptors triggers the events resulting in increased pro-IL-1ß synthesis and disease initiation and/or progression.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Interleucina-1beta/imunologia , Antígenos Comuns de Leucócito/imunologia , Neutrófilos/imunologia , Osteomielite/imunologia , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Interleucina-1beta/genética , Antígenos Comuns de Leucócito/genética , Camundongos , Camundongos Knockout , Neutrófilos/patologia , Osteomielite/genética , Osteomielite/patologia , Índice de Gravidade de Doença , Transdução de Sinais/genética , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia
13.
Sci Rep ; 11(1): 17142, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433860

RESUMO

The notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing ß cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/patologia , Processamento de Imagem Assistida por Computador/métodos , Ilhotas Pancreáticas/patologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Movimento Celular , Diabetes Mellitus Tipo 1/imunologia , Feminino , Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos NOD , Microscopia de Fluorescência/métodos
14.
J Fam Pract ; 70(6S): S47-S52, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34432624

RESUMO

KEY TAKEAWAYS: • Type 1 diabetes (T1D) is an autoimmune disease that progresses through 3 distinct stages. • T1D can be diagnosed at any age, with a peak incidence at 10-14 years of age. • The incidence of T1D in the United States is rising. • Screening for T1D autoantibodies has positive clinical consequences, including reduction of diabetic ketoacidosis events, improved glycemic control, and positive impact on short- and long-term complications. • Primary care clinicians can play a critical role in promoting islet autoantibody screening.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Humanos , Ilhotas Pancreáticas/imunologia
15.
Biomolecules ; 11(8)2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34439776

RESUMO

The loss of cardioprotection observed in premenopausal, diabetic women may result from the interplay between epigenetic, metabolic, and immunological factors. The aim of this study was to evaluate the concentration of sirtuin 1, visfatin, and IL-27 in relation to cardiovascular parameters and Hashimoto's disease (HD) in young, asymptomatic women with type 1 diabetes mellitus (T1DM). Thyroid ultrasound, carotid intima-media thickness (cIMT) measurement, electrocardiography, and echocardiography were performed in 50 euthyroid females with T1DM (28 with HD and 22 without concomitant diseases) and 30 controls. The concentrations of serum sirtuin 1, visfatin and IL-27 were assessed using ELISA. The T1DM and HD group had higher cIMT (p = 0.018) and lower left ventricular global longitudinal strain (p = 0.025) compared to females with T1DM exclusively. In women with a double diagnosis, the sirtuin 1 and IL-27 concentrations were non-significantly higher than in other groups and significantly positively correlated with each other (r = 0.445, p = 0.018) and thyroid volume (r = 0.511, p = 0.005; r = 0.482, p = 0.009, respectively) and negatively correlated with relative wall thickness (r = -0.451, p = 0.016; r = -0.387, p = 0.041, respectively). These relationships were not observed in the control group nor for the visfatin concentration. These results suggest that sirtuin 1 and IL-27 contribute to the pathogenesis of early cardiac dysfunction in women with T1DM and HD.


Assuntos
Aterosclerose/genética , Citocinas/genética , Diabetes Mellitus Tipo 1/genética , Doença de Hashimoto/genética , Interleucinas/genética , Nicotinamida Fosforribosiltransferase/genética , Sirtuína 1/genética , Adulto , Aterosclerose/diagnóstico por imagem , Aterosclerose/imunologia , Aterosclerose/patologia , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Citocinas/sangue , Citocinas/imunologia , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Ecocardiografia , Epigênese Genética , Feminino , Expressão Gênica , Doença de Hashimoto/diagnóstico por imagem , Doença de Hashimoto/imunologia , Doença de Hashimoto/patologia , Humanos , Interleucinas/sangue , Interleucinas/imunologia , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/sangue , Nicotinamida Fosforribosiltransferase/imunologia , Pré-Menopausa/sangue , Pré-Menopausa/imunologia , Sirtuína 1/sangue , Sirtuína 1/imunologia
16.
Cells ; 10(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34440644

RESUMO

Mast cells are highly differentiated, widely distributed cells of the innate immune system, that are currently considered as key regulators of both innate and adaptive immunity. Mast cells play a key role in health and survival mechanisms, especially as sentinel cells that can stimulate protective immune responses. On the other hand, it has been shown that mast cells are involved in the pathogenesis of several diseases, and recently a possible pathogenetic role of mast cells in diabetes has been proposed. In this review we summarize the evidence on the increased presence of mast cells in the pancreas of subjects with type 1 diabetes, which is due to the autoimmune destruction of insulin secreting beta cells, and discuss the differences with type 2 diabetes, the other major form of diabetes. In addition, we describe some of the pathophysiological mechanisms through which mast cells might exert their actions, which could be targeted to potentially protect the beta cells in autoimmune diabetes.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/sangue , Mastócitos/metabolismo , Animais , Comunicação Celular , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Humanos , Resistência à Insulina , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Mastócitos/imunologia
17.
Genes (Basel) ; 12(6)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205929

RESUMO

Genetic analyses of human type 1 diabetes (T1D) have yet to reveal a complete pathophysiologic mechanism. Inbred rats with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1B/Du) can illuminate such mechanisms. Using T1D-susceptible LEW.1WR1 rats that express RT1B/Du and a susceptible allele of the Ubd promoter, we demonstrate that germline knockout of Tcrb-V13S1A1, which encodes the Vß13a T cell receptor ß chain, completely prevents diabetes. Using the RT1B/Du-identical LEW.1W rat, which does not develop T1D despite also having the same Tcrb-V13S1A1 ß chain gene but a different allele at the Ubd locus, we show that knockout of the Ubash3a regulatory gene renders these resistant rats relatively susceptible to diabetes. In silico structural modeling of the susceptible allele of the Vß13a TCR and its class II RT1u ligand suggests a mechanism by which a germline TCR ß chain gene could promote susceptibility to T1D in the absence of downstream immunoregulation like that provided by UBASH3A. Together these data demonstrate the critical contribution of the Vß13a TCR to the autoimmune synapse in T1D and the regulation of the response by UBASH3A. These experiments dissect the mechanisms by which MHC class II heterodimers, TCR and regulatory element interact to induce autoimmunity.


Assuntos
Autoimunidade/genética , Diabetes Mellitus Tipo 1/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Animais , Diabetes Mellitus Tipo 1/imunologia , Genótipo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Insulina/química , Insulina/imunologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Ligação Proteica , Ratos , Ratos Endogâmicos Lew , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
20.
J Pediatr Endocrinol Metab ; 34(10): 1303-1309, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34291625

RESUMO

OBJECTIVES: The COVID-19 pandemic is a global health problem with high morbidity and mortality. This study aimed to investigate patients who were diagnosed with type 1 diabetes during the pandemic and evaluate the effect of the pandemic on the clinical findings of these patients by comparing them with findings from a year prior. METHODS: Patients diagnosed with type 1 diabetes mellitus between 2019 and 2021 were separated into two groups: Patients diagnosed prepandemic and those diagnosed during the pandemic. RESULTS: The number of newly diagnosed diabetes cases increased from 46 in the prepandemic period to 74 in the pandemic period. The number of cases diagnosed with diabetic ketoacidosis (DKA) in the clinic increased from 58.7 to 91.9%. We found that moderate and severe DKA rates from 18.5 and 14.8% to 23.5 and 22.1%, respectively. Besides, the average HbA1c was higher, while the average bicarbonate was lower in cases diagnosed during the pandemic period compared to the prepandemic period (p=0.048 and p<0.001, respectively). We found that celiac autoantibody positivity antibodies to glutamic acid decarboxylase (anti GAD) positivity, and islet cell antibodies (ICA), ICA and anti GAD positivity coexistence were higher (p=0.045, p=0.008, and p=0.007, respectively) among the patients diagnosed during the pandemic. CONCLUSIONS: We observed an increase in the number of patients newly diagnosed with type 1 diabetes mellitus, an increase in autoantibody positivity, and higher rates and severity of DKA during the COVID-19 pandemic period compared to the prepandemic period.


Assuntos
COVID-19/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , SARS-CoV-2 , Adolescente , Autoanticorpos/análise , Criança , Pré-Escolar , Estudos Transversais , Diabetes Mellitus Tipo 1/imunologia , Cetoacidose Diabética/epidemiologia , Humanos , Lactente , Masculino , Centros de Atenção Terciária , Turquia/epidemiologia
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