MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

Čulina, Slobodan; Brezar, Vedran; Mallone, Roberto

doi:10.1530/eje-12-0693

Cited by 30 publications

(24 citation statements)

References 111 publications

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“…ROS damage and AGE accumulation are well known causes of aging and diabetes (Osawa and Kato, 2005;Nass et al, 2007). In addition, many autoantibodies associated with diabetes and aging have been detected (Morohoshi et al, 2012;Ziegler and Bonifacio, 2012;Culina et al, 2013). However, autoantibody production in this model has not yet been reported.…”

Section: Ajimentioning

confidence: 82%

Production of Cross-Reactive Autoantibody Binding to Bovine Serum Albumin in the D-Galactose-Induced Aging Mouse Model

Park¹

2014

American Journal of Immunology

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The D-galactose (D-gal)-induced animal model, generated by repeated subcutaneous D-gal injections over approximately 6 weeks, has been frequently used for diabetes and aging research. However, little research has investigated the direct correlation between D-gal and autoantibody formation despite several reports on diabetes-and aging-related autoantibodies. The purpose of this study was to determine whether repetitive injection of D-gal can induce autoantibody production in mice. First, we used Bovine Serum Albumin (BSA) and Advanced Glycation End products (AGE)-BSA as the test antigens. The immunoreactivity of serum samples from mice treated with D-gal for 6 weeks was evaluated using Enzyme-Linked Immunosorbent Assay (ELISA). We found that serum samples of D-gal-treated mice had significantly high antibody titers against both BSA and AGE-BSA. Furthermore, the result showed that aminoguanidine treatment, an AGE inhibitor tended to decrease this immunoreactivity. The results of competitive inhibition ELISA using BSA and AGE-BSA as the competitors suggested that the serum samples from D-gal-treated mice contained antibodies not only against BSA but also specific to AGE-BSA. To assess whether the immunoreactivity against BSA is comparable to that against Mouse Serum Albumin (MSA), we examined the reactivity of D-gal-induced antibodies against MSA. Unexpectedly, D-gal-induced antibodies did not react with MSA. This suggests that the production of antibodies by Dgal is in response to an unknown antigen(s), aside from MSA, in mice and that this unknown antigen(s) may share similar sequences or three-dimensional structures with BSA.

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Section: Ajimentioning

confidence: 82%

Production of Cross-Reactive Autoantibody Binding to Bovine Serum Albumin in the D-Galactose-Induced Aging Mouse Model

Park¹

2014

American Journal of Immunology

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“…The demonstration that insulin-producing cells are present in the thymus [24], a place not apparently related to the pancreas, together with our results revealing the protective role of B-1 cells against diabetes led us to hypothesize that B-1 cells might also produce this hormone.…”

Section: B-1 Cells Produce Insulin In Aperc Culturementioning

confidence: 61%

“…Thus, our data suggest that B-1 cells are able to produce or induce a factor in primary cultures that acts like insulin, as a constitutive characteristic of these cells. To investigate this hypothesis associated to the fact that there is insulin secretion in other sites not related to the pancreas [24], we investigated the presence of insulin in adherent cells from APerC cultures. Intriguingly, insulin-producing cells were found in this culture.…”

Section: Discussionmentioning

confidence: 99%

B‐1 cells produce insulin and abrogate experimental streptozotocin‐induced diabetes

et al. 2015

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The participation of B-1 cells in a murine model of spontaneous diabetes has been recently reported. Here, we describe the role of B-1 cells in streptozotocin (STZ) induced diabetes in mice. We demonstrated that XID (B-1 cell-deficient) mice are more susceptible to STZ treatment than WT mice, as evidenced by their higher blood glucose level in response to STZ. Unexpectedly, the XID mice that were i.p. transferred with purified B-1 cells, either before or after the STZ treatment, did not develop diabetes. These cell transfers provided long-lasting protection for the XID mice against STZ-induced diabetes, suggesting that B-1 cells play an important role in the experimental diabetes pathobiology. We also showed that B-1 cell culture supernatants were able to regulate the blood glucose level of the diabetic XID mice, and we identified insulin-producing cells when B-1 cells were differentiated in B-1 cell-derived phagocyte in vitro. These findings provide a novel role for B-1 cells in metabolic processes, presenting a new mechanism to explain the pathogenesis of diabetes and a possible therapeutical target. Keywords: B-1 cells r Experimental diabetes r Insulin r Streptozotocin r XID mice IntroductionType-1 diabetes is an organ-specific autoimmune disease in which T cells mediate the destruction of pancreatic β cells. The role played by T cells in the pathogenesis of diabetes has been extensively investigated. In 1996, Serreze et al. published the first study providing evidence that B lymphocytes play an important role in the development of diabetes [1]. Since then, the possible but controversial role of B cells in the outcome and evolution of this disease has been suggested in the literature. Although some authors have proposed the involvement of B cells in the development of autoimmune diabetes [2,3], others have suggested that B cells may not be necessary for the initiation of the autoimmune process [4].Correspondence: Prof. Mario Mariano e-mail: mariomu@uol.com.brThe different populations of B cells, denominated B-1 and B-2 cells, have been characterized in mice. B-1 cells differ from conventional B cells (B-2 cells) in their ontogeny, anatomical distribution, surface markers, antibody subtype production, selfrenewing ability, and the activity and localization of their precursors during adulthood [5,6]. B-1 cells are further subdivided into two subpopulations, B-1a and B-1b, based on the presence or absence of the CD5 molecule on their membrane, respectively [7,8], and are responsible for the secretion of "natural" antibodies that recognize polymeric antigens of high molecular weight [9,10]. B-1a cells produce autoreactive antibodies, suggesting the participation of these cells in autoimmune diseases in both humans and murine experimental models [11]. We have previously demonstrated that B-1 cells migrate toward a nonspecific inflammatory focus and that they are able to differentiate into mononuclear phagocytes (B-1 cell derived C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. ...

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“…25 The initiating events in T1D pathogenesis that trigger the provision of b-cell antigens (the first described target antigen is insulin) to dendritic cells and presentation to T cells for their activation are yet to be elucidated. 26 As depicted in the Fig 2, proinflammatory cytokines, produced by infiltrating leukocytes and islet cells, including interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), and interferon g (IFN-g), play a central role in b-cell failure and the development of diabetes. 27 The destruction is caused by infiltration of the islets of Langerhans by dendritic cells, macrophages, and T lymphocytes, is specific for insulinproducing b cells, and does not affect glucagon-producing (a) or somatostatinproducing (d) cells.…”

Section: Multifactorial Etiology Of T1dmentioning

confidence: 99%

Genetic and Epigenetic Factors in Etiology of Diabetes Mellitus Type 1

2013

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Diabetes mellitus type 1 (T1D) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors. Recent progress in understanding the genetic basis of T1D has resulted in an increased recognition of childhood diabetes heterogeneity. After the initial success of family-based linkage analyses, which uncovered the strong linkage and association between HLA gene variants and T1D, genome-wide association studies performed with high-density single-nucleotide polymorphism genotyping platforms provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remains to be performed. T1D is one of the most heritable common diseases, and among autoimmune diseases it has the largest range of concordance rates in monozygotic twins. This fact, coupled with evidence of various epigenetic modifications of gene expression, provides convincing proof of the complex interplay between genetic and environmental factors. In T1D, epigenetic phenomena, such as DNA methylation, histone modifications, and microRNA dysregulation, have been associated with altered gene expression. Increasing epidemiologic and experimental evidence supports the role of genetic and epigenetic alterations in the etiopathology of diabetes. We discuss recent results related to the role of genetic and epigenetic factors involved in development of T1D. Pediatrics

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MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

Cited by 30 publications

References 111 publications

Production of Cross-Reactive Autoantibody Binding to Bovine Serum Albumin in the D-Galactose-Induced Aging Mouse Model

Production of Cross-Reactive Autoantibody Binding to Bovine Serum Albumin in the D-Galactose-Induced Aging Mouse Model

B‐1 cells produce insulin and abrogate experimental streptozotocin‐induced diabetes

Genetic and Epigenetic Factors in Etiology of Diabetes Mellitus Type 1

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