Immune mechanisms in type 1 diabetes

Wållberg, Maja; Cooke, Anne

doi:10.1016/j.it.2013.08.005

Cited by 138 publications

(98 citation statements)

References 104 publications

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“…Additionally, microarray profiling of human β cells obtained through laser-capture microdissection revealed a three-fold increase in the expression of chemokines CCL2 and CCL13 in T2D subjects compared with controls, providing molecular evidence of immune cell infiltration and islet inflammation in human T2D patients (46). These results suggest that islet inflammation in T2D is mainly driven by innate immunity, whereas inflammation in type 1 diabetes (T1D) is known to be mainly driven by adaptive immunity (47,48). Several studies also showed that prolonged exposure to high glucose levels causes β cells to secrete IL-1β, which contributes to islet inflammation in human islets in vitro (49) and in mice (50).…”

Section: Islet Macrophages Link β Cell Dysfunction and Islet Inflammamentioning

confidence: 96%

Islet inflammation in type 2 diabetes and physiology

Eguchi¹,

Nagai²

2017

Journal of Clinical Investigation

277

197

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Section: Islet Macrophages Link β Cell Dysfunction and Islet Inflammamentioning

confidence: 96%

Islet inflammation in type 2 diabetes and physiology

Eguchi¹,

Nagai²

2017

Journal of Clinical Investigation

277

197

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“…The genetics of T1D in mice and humans point primarily to a dysfunction of CD4 + T cells, because class II genes of the MHC, and several other loci that modify T-cell activation and regulation, are linked to T1D susceptibility (1).…”

mentioning

confidence: 99%

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Magnuson

Thurber

Köhler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Type-1 diabetes in the nonobese diabetic (NOD) mouse starts with an insulitis stage, wherein a mixed population of leukocytes invades the pancreas, followed by overt diabetes once enough insulin-producing β-cells are destroyed by invading immunocytes. Little is known of the dynamics of lymphocyte movement into the pancreas during disease progression. We used the Kaede transgenic mouse, whose photoconvertible fluorescent reporter permits noninvasive labeling and subsequent tracking of immunocytes, to investigate pancreatic infiltrate dynamics and the requirement for antigen specificity during progression of autoimmune diabetes in the unmanipulated NOD mouse. Our results indicate that the insulitic lesion is very open with constant cell influx and active turnover, predominantly of B and T lymphocytes, but also CD11b + c + myeloid cells. Both naïve-and memory-phenotype lymphocytes trafficked to the insulitis, but Foxp3 + regulatory T cells circulated less than their conventional CD4 + counterparts. Receptor specificity for pancreatic antigens seemed irrelevant for this homing, because similar kinetics were observed in polyclonal and antigen-specific transgenic contexts. This "open" configuration was also observed after reversal of overt diabetes by anti-CD3 treatment. These results portray insulitis as a dynamic lesion at all stages of disease, continuously fed by a mixed influx of immunocytes, and thus susceptible to evolve over time in response to immunologic or environmental influences.Treg | cell tracer | reporter T ype-1 diabetes (T1D) is an organ-specific autoimmune disease initiated by a breakdown in T lymphocyte tolerance to islet-cell antigens; it comprises two stages: an occult phase of pancreatic inflammation, which reduces the number and function of insulin-producing β-cells and eventually provokes sufficient damage to result in the overt phase of diabetes, when insulin production is insufficient for proper glucose homeostasis. The genetics of T1D in mice and humans point primarily to a dysfunction of CD4 + T cells, because class II genes of the MHC, and several other loci that modify T-cell activation and regulation, are linked to T1D susceptibility (1).In nonobese diabetic (NOD) mice and other animal models (2), this initial inflammatory phase takes the form of insulitis, wherein a mixed population of leukocytes invades the islets of Langerhans. Insulitis starts around 3-4 wk of age and amplifies progressively until the onset of clinically overt diabetes (predominantly between 14 and 25 wk of age); it involves a wide array of cell types-T and B lymphocytes as well as myeloid cells-macrophages and dendritic cells (3), which can take on the organization of typical tertiary lymphoid structures (4). Importantly, insulitis variably affects different islets in a given animal, heavily infiltrated islets coexisting with fully intact and functional ones, even in advanced prediabetic mice.Inflammation in islets of human patients has been harder to evaluate, because access to material is obviously more difficult...

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“…T1DM is a consequence of the autoimmune elimination of the insulin-producing pancreatic β-cells, which eventually ceases insulin production and hence the absorption of glucose by the tissues of the body (ADA 2013, Wållberg andCooke 2013). Approximately 5-10% of all diabetic patients present T1DM, which can occur even in the elderly, although it usually arises during childhood and adolescence (ADA 2013).…”

Section: T1dmmentioning

confidence: 99%

“…Approximately 5-10% of all diabetic patients present T1DM, which can occur even in the elderly, although it usually arises during childhood and adolescence (ADA 2013). For the development of T1DM, an immune response with strong proinflammatory features against the pancreatic β-cell antigens must arise and the control of the autoimmune responses must be impaired so those responses can become chronic, leading to the elimination of β-cells (Wållberg and Cooke 2013).…”

Section: T1dmmentioning

confidence: 99%

“…The exact cause of this form of diabetes has not been elucidated, but it has been suggested that several susceptibility genes combined with environmental insults contribute to the development of this disease (ADA 2013, Wållberg andCooke 2013). Regarding the genetic background, the HLA genes located on chromosome 6p21 confer the highest genetic risk for T1DM; other genes including those encoding insulin (INS) on 11p15, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) on 2q33, protein tyrosine phosphatase, non-receptor type 22 (PTPN22) on 1p13, and interleukin 2 receptor alpha (IL2RA) on 10p15, also present strong associations with the disorder , Barrett et al 2009, Bell et al 1984, Nisticò et al 1996, Lowe et al 2007.…”

Section: T1dmmentioning

confidence: 99%

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Perfis de Expressão Gênica e Possíveis Interações entre microRNAs e mRNAs em Diabetes Mellitus Tipo 1 com Enfoque em Resposta ao Estresse Oxidativo e Reparo do DNA

Takahashi¹

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-Conselho Nacional de Desenvolvimento Científico e Tecnológico -CNPq.-Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -CAPES. Nalon por toda a atenção, apoio, ajuda, dedicação e simpatia.Aos professores membros da banca examinadora, pela disponibilidade e contribuições para este trabalho. Aos técnicos do laboratório de Citogenética e Mutagênese do Departamento de Genética da FMRP-USP, Luiz Augusto da Costa Júnior e Sueli AparecidaNeves, pelo apoio técnico, carinho, companheirismo, simpatia e grande amizade.Aos amigos do Laboratório de Citogenética e Mutagênese, pelo excelente ambiente de trabalho, pela amizade e pelos momentos únicos de descontração! Danilo, por todos os ensinamentos, conselhos, orientações e discussões produtivas, fundamentais para a execução deste trabalho, além da companhia e apoio; Giovana (gracinha roxa), por ter me enturmado no lab desde o primeiro dia, pela amizade que se fortalece cada dia mais, por sempre estar ao meu lado me apoiando e me dando conselhos profissionais e pessoais; Paulo (Cop), pelos desabafos e pelas orientações e discussões produtivas, apesar de me fazer passar frio; Léo, pelos desabafos e pelas risadas; Ana Paula, pelas orientações e discussões produtivas; Ana Clara, pelas conversas e risadas; Verônica, pelas conversas e ótima convivência; João Paulo (Johnny), por ser naturalmente engraçado; Andrés, William, Sara e Murilo, pela ótima convivência. Aos ex-alunos do lab: Fernanda C.pelas conversas produtivas e ótima convivência; Flavinha, pelo bom humor e simpatia e, apesar de não estar mais no lab, continua sendo minha outra gracinha roxa; Felipe (Magal), Tiago, Gustavo, Fernanda P. e Raquel, pela ótima convivência. Só tenho a agradecer! Aos Danilo, Giovana e Paulo, pela correção da tese e pelos vários momentos de comilança, fofocas e risadas. Muito obrigada! A todos os integrantes do laboratório de Genética e Biologia Molecular de Fungos (técnicos, pós-graduandos, pós-doutorandos), por sempre me receberem tão bem, em especial Larissa, Nalu e Gabi, pelos ensinamentos e amizade. O Diabetes Mellitus tipo 1 (DM1) resulta de um ataque autoimune contra as células β pancreáticas, extinguindo a produção de insulina e levando à hiperglicemia. Evidências indicam uma associação entre o estresse oxidativo (que pode causar danos no DNA) e o DM1, sendo que apenas alguns trabalhos da literatura relataram a expressão de genes relacionados à respostas ao estresse oxidativo e reparo do DNA em DM1. Ainda, os microRNAs (reguladores pós-transcricionais da expressão gênica) estão envolvidos em vários processos biológicos e condições patológicas, mas informação sobre a expressão dos microRNAs em DM1 ainda é escassa. A fim de proporcionar um melhor entendimento sobre as vias de regulação de genes participantes de processos biológicos relevantes para o DM1, o presente estudo consistiu em analisar os perfis de expressão gênica (método de microarranjos) de microRNAs e de mRNAs (bem como de algumas proteínas) provenientes de células mononucleares do sangue periférico (PBMCs, do inglês...

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Immune mechanisms in type 1 diabetes

Cited by 138 publications

References 104 publications

Islet inflammation in type 2 diabetes and physiology

Islet inflammation in type 2 diabetes and physiology

Population dynamics of islet-infiltrating cells in autoimmune diabetes

Perfis de Expressão Gênica e Possíveis Interações entre microRNAs e mRNAs em Diabetes Mellitus Tipo 1 com Enfoque em Resposta ao Estresse Oxidativo e Reparo do DNA

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