Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype

Skogberg, Gabriel; Lundberg, Vanja; Lindgrén, Susanne; Gudmundsdottir, Judith; Sandström, Kerstin; Kämpe, Olle; Annerén, Göran; Gustafsson, Jan Åke; Sunnegårdh, Jan; Post, Sjoerd van der; Telemo, Esbjörn; Berglund, Martin; Ekwall, Olov

doi:10.4049/jimmunol.1400742

Cited by 49 publications

(35 citation statements)

References 43 publications

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“…§One or more positive titer for GADA, IA-2A, or ZnT8A. ||DS-PNDM vs. non-DS PNDM, P = 0.006. than those in the study by Skogberg et al (28) (2 months-12 years); therefore, a potential temporal relationship of AIRE expression in DS thymus, possibly linked to AIRE's role in differentiation and turnover of thymocytes (29,30), could explain the difference. None of the cases were reported to have diabetes; however, 11 of 19 reported by Giménez-Barcons et al had organ-specific autoimmunity (hypothyroidism, Graves disease, or celiac disease).…”

Section: Discussioncontrasting

confidence: 53%

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

et al. 2019

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Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into b-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.Permanent neonatal diabetes (PNDM) is diagnosed before the age of 6 months, and a genetic diagnosis is possible for .82% of cases (1). Twenty-four causative PNDM genes have been identified (1-4), and four of these cause monogenic autoimmune PNDM that results from destruction of the b-cells very early in life (FOXP3, IL2RA, LRBA, and STAT3). Identifying novel causes of autoimmune neonatal diabetes can provide key insights into the development of autoimmunity and can provide new targets for therapeutic intervention.Down syndrome (DS) is caused by trisomy of chromosome 21 and has an incidence of 1:700 to 1:1,100 live births (5). Large studies have shown childhood-onset autoimmune diabetes is four times more common in DS than in the general population and has an intermediate HLA association (6). There have been three reported cases of DS with diabetes diagnosed before 6 months (DS-PNDM) (7,8). However, it is not known whether DS was the cause of PNDM or a coincidental finding in these patients. The aim of our study was to use our large international cohort of PNDM patients to assess whether DS can aetiologically cause PNDM. We assessed clinical phenotype, islet autoantibodies, and polygenic risk of T1D in patients with monogenic PNDM and DS-PNDM. RESEARCH DESIGN AND METHODS Study PopulationWe defined PNDM as diabetes diagnosed before the age of 6 months, which is treated with continual insulin treatment. We studied 1,522 DNA samples from two international collections of PNDM patients, 1,360 recruited in Exeter and 162 recruited in Chicago. These either had a confirmed monogenic etiology (82.9% [n = 1,262]) or had been tested (and were negative) for all 24 known genes (17.1% [n = 260]). Clinical information was provided by the referring physician via a comprehensive referral form. This includes a section for the reporting of extra pancreatic clinical features. Genetic Testing Testing of the Known GenesAll individuals diagnosed in the first 6 months of life were tested for mutations either by rapid Sanger sequencing of

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Section: Discussioncontrasting

confidence: 53%

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

et al. 2019

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“…Inactivating AIRE mutations lead to autoimmune polyendocrine syndrome type I (APS1), an autosomal recessive disease that shares specific autoantibodies with DS but different disease patterns. Hypoparathyroidism and Addison's disease, hallmarks of APS1, are extremely rare in DS patients, while Hashimoto's thyroiditis, Graves' disease (GD) and type 1 diabetes mellitus are the most typical DS-associated endocrine autoimmune diseases [10]. Contrasting data regarding thymic expression of AIRE in DS have been reported.…”

Section: Down's Syndromementioning

confidence: 99%

Endocrine Autoimmunity in Down's Syndrome

Guaraldi¹,

Giaccherino²,

Lanfranco³

et al. 2017

Frontiers of Hormone Research

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Since the mid 1900s, a significant increase of infectious, hematological, and autoimmune diseases has been reported in patients with Down's syndrome (DS), independent of sex, age, family history, and exposure to other risk factors, suggesting an intrinsic alteration of the immune system. Several in vitro and in vivo studies have demonstrated alterations of both cellular and humoral immunological response mainly, although not exclusively, secondary to alterations of the expression of autoimmune regulator gene (located on chromosome 21), leading to thymic structural and functional impairments. Autoimmune thyroid disorders (i.e. Hashimoto's thyroiditis and Graves' disease) and type 1 diabetes mellitus are the most common autoimmune endocrine disorders associated with DS, and present with some peculiar features. The underlying etiopathogenic mechanisms and clinical significance of some mild laboratory alterations are still poorly understood. For these aspects, together with the associated multiple comorbidities and intellectual impairment - that make DS patients dependent on care givers - and in the absence of definite guidelines, disease management is very challenging and should be patient-tailored.

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“…Exosomes are nano‐sized membrane enclosed vesicles of endocytic origin, and are released into the extracellular space by cells when multivesicular bodies fuse with the cell plasma membrane. Previous work have identified and characterized exosomes in murine 7 as well as human thymic tissue 8 , 9 . Unlike other human epithelial cell types 10 it is still however, not formally shown that the TEC population is able to produce these extracellular vesicles.…”

mentioning

confidence: 96%

“…Previous work have identified and characterized exosomes in murine 7 as well as human thymic tissue. 8,9 Unlike other human epithelial cell types 10 it is still however, not formally shown that the TEC population is able to produce these extracellular vesicles. Following the finding that B cells secrete antigen-presenting exosomes 11 several studies have shown exosomes to be capable of presenting antigens for T cells by themselves 12,13 or indirectly via uptake by dendritic cells (DCs).…”

mentioning

confidence: 99%

Human thymic epithelial primary cells produce exosomes carrying tissue‐restricted antigens

et al. 2015

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Exosomes are nano-sized vesicles released by cells into the extracellular space and have been shown to be present in thymic tissue both in mice and in humans. The source of thymic exosomes is however still an enigma and hence it is not known whether thymic epithelial cells (TECs) are able to produce exosomes. In this work, we have cultured human TECs and isolated exosomes. These exosomes carry tissue-restricted antigens (TRAs), for example, myelin basic protein and desmoglein 3. The presence of TRAs indicates a possible role for thymic epithelium-derived exosomes in the selection process of thymocytes. The key contribution of these exosomes could be to disseminate self-antigens from the thymic epithelia, thus making them more accessible to the pool of maturing thymocytes. This would increase the coverage of TRAs within the thymus, and facilitate the process of positive and negative selection.

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Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype

Cited by 49 publications

References 43 publications

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

Endocrine Autoimmunity in Down's Syndrome

Human thymic epithelial primary cells produce exosomes carrying tissue‐restricted antigens

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