Sequence Variation in Promoter of Ica1 Gene, Which Encodes Protein Implicated in Type 1 Diabetes, Causes Transcription Factor Autoimmune Regulator (AIRE) to Increase Its Binding and Down-regulate Expression

M., Bonner, Samantha; Pietropaolo, Susan L.; Fan, Yong; Chang, Ying; Sethupathy, Praveen; Morran, Michael P.; Beems, Megan; Giannoukakis, Nick; Trucco, Giuliana; Palumbo, Michael; Solimena, Michele; Pugliese, Alberto; Polychronakos, Constantin; Trucco, Massimo; Pietropaolo, Massimo

doi:10.1074/jbc.m111.319020

Cited by 16 publications

(23 citation statements)

References 57 publications

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“…This could be due to the lack of the MHC class II molecule I-E or, alternatively, due to the inability of AIREs (autoimmune regulators) to induce expression of self-antigens in mTECs (medullary thymic epithelial cells). NOD mice have reduced thymic expression of the AAg ICA69 (islet cell autoantigen of 69 kDa), and the gene encoding this protein carries a SNP in the promoter region important for AIRE binding [102]. This could explain the reduced thymic expression of this self-antigen and the potential for reduced deletion of thymocytes with specificity for it.…”

Section: Developmentmentioning

confidence: 96%

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

2013

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T1D (Type 1 diabetes) is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Studies in T1D patients have been limited by the availability of pancreatic samples, a protracted pre-diabetic phase and limitations in markers that reflect β-cell mass and function. The NOD (non-obese diabetic) mouse is currently the best available animal model of T1D, since it develops disease spontaneously and shares many genetic and immunopathogenic features with human T1D. Consequently, the NOD mouse has been extensively studied and has made a tremendous contribution to our understanding of human T1D. The present review summarizes the key lessons from NOD mouse studies concerning the genetic susceptibility, aetiology and immunopathogenic mechanisms that contribute to autoimmune destruction of β-cells. Finally, we summarize the potential and limitations of immunotherapeutic strategies, successful in NOD mice, now being trialled in T1D patients and individuals at risk of developing T1D.

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Section: Developmentmentioning

confidence: 96%

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

2013

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“…To investigate ICA69 autoimmunity (Bonner et al, 2012; Pietropaolo et al, 1993), in an elegant recent study two genetically modified mouse lines were generated to modulate thymic ICA69 expression: the heterozygous ICA69del/wt line and the thymic medullary epithelial cell-specific deletion Aire-ΔICA69 line (Fan et al, 2014). Suboptimal central negative selection of ICA69-reactive T-cells was observed in both lines.…”

Section: Genetic Susceptibilitymentioning

confidence: 99%

Immunogenetics of type 1 diabetes mellitus

Morran

Vonberg

Khadra

et al. 2015

Molecular Aspects of Medicine

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114

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors. Similar to the majority of autoimmune diseases, T1DM usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens, which precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies in the serum of T1DM patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects, (i.e. HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from T1DM in multiple populations.A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development. Viral infections may play a role in the chain of events leading to disease, albeit conclusive evidence linking infections with T1DM remains to be firmly established. Two syndromes have been described in which an immunemediated form of diabetes occurs as the result of a single gene defect. These syndromes are termed autoimmune polyglandular syndrome type I (APS-I) or autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), and X-linked poyendocrinopathy, immune dysfunction and diarrhea (XPID). These two syndromes are unique models to understand the mechanisms involved in the loss of tolerance to self-antigens in autoimmune diabetes and its associated organ-specific autoimmune disorders. A growing number of animal models of these diseases have greatly helped elucidate the immunologic mechanisms leading to autoimmune diabetes.

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“…It has been noticed that several autoimmune disorders, such as vitiligo [10], autoimmune hepatitis [11], type 1 diabetes mellitus [12], myasthenia gravis [13] and systemic sclerosis [14], might be affected by the genetic variability of AIRE gene. A recent GWA study in Japanese population has been identified two SNPs, rs2075876 and rs760426, in the AIRE gene was significant associated with RA risk [2].…”

Section: Introductionmentioning

confidence: 99%

Association of rs2075876 polymorphism of AIRE gene with rheumatoid arthritis risk

et al. 2015

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Sequence Variation in Promoter of Ica1 Gene, Which Encodes Protein Implicated in Type 1 Diabetes, Causes Transcription Factor Autoimmune Regulator (AIRE) to Increase Its Binding and Down-regulate Expression

Cited by 16 publications

References 57 publications

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

Immunogenetics of type 1 diabetes mellitus

Association of rs2075876 polymorphism of AIRE gene with rheumatoid arthritis risk

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