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Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet beta cell microchimerism.

ABSTRACT: Maternal cells have recently been found in the circulation and tissues of mothers' immune-competent children, including in adult life, and is referred to as maternal microchimerism (MMc). Whether MMc confers benefits during development or later in life or sometimes has adverse effects is unknown. Type 1 diabetes (T1D) is an autoimmune disease that primarily affects children and young adults. To identify and quantify MMc, we developed a panel of quantitative PCR assays targeting nontransmitted, nonshared maternal-specific HLA alleles. MMc was assayed in peripheral blood from 172 individuals, 94 with T1D, 54 unaffected siblings, and 24 unrelated healthy subjects. MMc levels, expressed as the genome equivalent per 100,000 proband cells, were significantly higher in T1D patients than unaffected siblings and healthy subjects. Medians and ranges, respectively, were 0.09 (0-530), 0 (0-153), and 0 (0-7.9). Differences between groups were evident irrespective of HLA genotypes. However, for patients with the T1D-associated DQB1*0302-DRB1*04 haplotype, MMc was found more often when the haplotype was paternally (70%) rather than maternally transmitted (14%). In other studies, we looked for female islet beta cells in four male pancreases from autopsies, one from a T1D patient, employing FISH for X and Y chromosomes with concomitant CD45 and beta cell insulin staining. Female islet beta cells (presumed maternal) formed 0.39-0.96% of the total, whereas female hematopoietic cells were very rare. Thus, T1D patients have higher levels of MMc in their circulation than unaffected siblings and healthy individuals, and MMc contributes to islet beta cells in a mother's progeny.

SUBMITTER: Nelson JL

PROVIDER: S-EPMC1785262 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet beta cell microchimerism.

Nelson J Lee JL Gillespie Kathleen M KM Lambert Nathalie C NC Stevens Anne M AM Loubiere Laurence S LS Rutledge Joe C JC Leisenring Wendy M WM Erickson Timothy D TD Yan Zhen Z Mullarkey Meghan E ME Boespflug Nick D ND Bingley Polly J PJ Gale Edwin A M EA

Proceedings of the National Academy of Sciences of the United States of America 20070123 5

Maternal cells have recently been found in the circulation and tissues of mothers' immune-competent children, including in adult life, and is referred to as maternal microchimerism (MMc). Whether MMc confers benefits during development or later in life or sometimes has adverse effects is unknown. Type 1 diabetes (T1D) is an autoimmune disease that primarily affects children and young adults. To identify and quantify MMc, we developed a panel of quantitative PCR assays targeting nontransmitted, n ...[more]

PMID: 17244711

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Project description:Aims/Hypothesis: Galectin 3 appears to play a proinflammatory role in several inflammatory and autoimmune diseases. Also, there is evidence that galectin 3 plays a role in both type-1 and type-2 diabetes. During obesity, hematopoietic cell-derived galectin 3 induces insulin resistance. While the role of galectin 3 expressed in islet-invading immune cells in both type-1 and type-2 diabetes has been studied, the importance of the expression of this molecule on the target pancreatic β cells has not been defined. Methods: To clarify the role of galectin 3 expression in β cells during obesity-induced diabetogenesis, we developed transgenic mice selectively overexpressing galectin 3 in β cells and tested their susceptibility to obesity-induced type-2 diabetes. Obesity was induced with a 16-week high-fat diet regime. Pancreatic β cells were tested for susceptibility to apoptosis induced by non-esterified fatty acids and cytokines as well as parameters of oxidative stress. Results: Our results demonstrated that overexpression of galectin 3 increases β-cell apoptosis in HFD conditions and increases the percentage of proinflammatory F4/80+ macrophages in islets that express galectin 3 and TLR4. In isolated islets, we have shown that galectin 3 overexpression increases cytokine and palmitate-triggered β-cell apoptosis and also increases NO2--induced oxidative stress of β cells. Also, in pancreatic lymph nodes, macrophages were shifted toward a proinflammatory TNF-α-producing phenotype. Conclusions/Interpretation: By complementary in vivo and in vitro approaches, we have shown that galectin 3-overexpression facilitates β-cell damage, enhances cytokine and palmitate-triggered β-cell apoptosis, and increases NO2--induced oxidative stress in β cells. Further, the results suggest that increased expression of galectin 3 in the pancreatic β cells affects the metabolism of glucose and glycoregulation in mice on a high-fat diet, affecting both fasting glycemic values and glycemia after glucose loading.

Project description:There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.

Dataset Information

Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet beta cell microchimerism.

Publications

Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet beta cell microchimerism.

Similar Datasets

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