Humoral beta-cell autoimmunity, ager gene polymorphism and circulating soluble RAGE in preclinical and clinical type 1 diabetes

Kirsi M. Salonen

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

The incidence of type 1 diabetes has been increasing over recent decades. The reason for the increase, and the initial trigger for the autoimmune process remain unknown. Children with significantly increased risk for type 1 diabetes can be recognized from the general population based on their HLA-genotype and a panel of autoantigen-specific antibody assays. Recently a novel autoantibody specificity was discovered, the ZnT8 autoantibodies (ZnT8A). The advanced glycation end products (AGEs) are produced via glycation reactions between reducing sugars and proteins. AGEs and their interaction with the receptor for AGEs (RAGE), have been implicated to play a role in the pathogenesis and complications of diabetes. The soluble form of RAGE (sRAGE) is counteracting the effects of proinflammatory, membrane-bound RAGE. A decrease in sRAGE has been observed in various studies on acute inflammation. Polymorphisms of the gene encoding RAGE, AGER, are associated with the risk and the complications of diabetes according to previous studies. This thesis set out to define the characteristics of ZnT8A and RAGE in clinical and pre-clinical type 1 diabetes. Among the newly diagnosed children with type 1 diabetes, 63% tested positive for ZnT8A. ZnT8A were associated with age and metabolic state at diagnosis as well as to HLA genotype. ZnT8A-assay did not improve the detection rate of beta-cell autoimmunity. Concentrations of sRAGE correlated positively with age in children with newly diagnosed type 1 diabetes, but not in controls. Diabetic ketoacidosis at diagnosis and the high-risk HLA-genotype were related to lower sRAGE. Two polymorphic variants of the AGER gene, associated with increased risk for type 1 diabetes, correlated with reduced sRAGE. Prediabetic children had higher sRAGE than autoantibody-negative controls. A reduction in sRAGE coincides with the appearance of autoantibodies in children progressing to overt type 1 diabetes, but not in healthy controls, or in children seroconverting to autoantibody positivity later in childhood. After the seroconversion, the sRAGE concentrations remained stable. The RAGE/AGE ratio was higher in the cases than in the controls. To conclude, sRAGE, which has been considered cytoprotective in previous studies, is positively associated with older age at disease onset, protection from metabolic decompensation at diagnosis and AGER genotypes with a lower risk for type 1 diabetes. Children, who seroconvert to humoral islet cell autoimmunity early in childhood, experience a drop in sRAGE coinciding with the appearance of the first autoantibodies. They have higher sRAGE and sRAGE/AGE-ratio than the controls before seroconversion. These observed associations might be a result of an intrinsic protective mechanism, which fails at seroconversion.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-2287-2
Electronic ISBNs978-951-51-2288-9
Publication statusPublished - 2016
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3123 Gynaecology and paediatrics
  • 3121 Internal medicine
  • 3111 Biomedicine

Cite this

@phdthesis{0fdac0f0b0494ffb8ae3113eef710eb9,
title = "Humoral beta-cell autoimmunity, ager gene polymorphism and circulating soluble RAGE in preclinical and clinical type 1 diabetes",
abstract = "The incidence of type 1 diabetes has been increasing over recent decades. The reason for the increase, and the initial trigger for the autoimmune process remain unknown. Children with significantly increased risk for type 1 diabetes can be recognized from the general population based on their HLA-genotype and a panel of autoantigen-specific antibody assays. Recently a novel autoantibody specificity was discovered, the ZnT8 autoantibodies (ZnT8A). The advanced glycation end products (AGEs) are produced via glycation reactions between reducing sugars and proteins. AGEs and their interaction with the receptor for AGEs (RAGE), have been implicated to play a role in the pathogenesis and complications of diabetes. The soluble form of RAGE (sRAGE) is counteracting the effects of proinflammatory, membrane-bound RAGE. A decrease in sRAGE has been observed in various studies on acute inflammation. Polymorphisms of the gene encoding RAGE, AGER, are associated with the risk and the complications of diabetes according to previous studies. This thesis set out to define the characteristics of ZnT8A and RAGE in clinical and pre-clinical type 1 diabetes. Among the newly diagnosed children with type 1 diabetes, 63{\%} tested positive for ZnT8A. ZnT8A were associated with age and metabolic state at diagnosis as well as to HLA genotype. ZnT8A-assay did not improve the detection rate of beta-cell autoimmunity. Concentrations of sRAGE correlated positively with age in children with newly diagnosed type 1 diabetes, but not in controls. Diabetic ketoacidosis at diagnosis and the high-risk HLA-genotype were related to lower sRAGE. Two polymorphic variants of the AGER gene, associated with increased risk for type 1 diabetes, correlated with reduced sRAGE. Prediabetic children had higher sRAGE than autoantibody-negative controls. A reduction in sRAGE coincides with the appearance of autoantibodies in children progressing to overt type 1 diabetes, but not in healthy controls, or in children seroconverting to autoantibody positivity later in childhood. After the seroconversion, the sRAGE concentrations remained stable. The RAGE/AGE ratio was higher in the cases than in the controls. To conclude, sRAGE, which has been considered cytoprotective in previous studies, is positively associated with older age at disease onset, protection from metabolic decompensation at diagnosis and AGER genotypes with a lower risk for type 1 diabetes. Children, who seroconvert to humoral islet cell autoimmunity early in childhood, experience a drop in sRAGE coinciding with the appearance of the first autoantibodies. They have higher sRAGE and sRAGE/AGE-ratio than the controls before seroconversion. These observed associations might be a result of an intrinsic protective mechanism, which fails at seroconversion.",
keywords = "Adolescent, Advanced Glycosylation End Product-Specific Receptor, Age Factors, Autoimmune Diseases, +diagnosis, +immunology, Autoantibodies, +blood, Cation Transport Proteins, Child, Child, Preschool, Disease Progression, Diabetes Mellitus, Type 1, +genetics, Glycosylation End Products, Advanced, HLA-DR Antigens, Immunity, Humoral, Infant, Prediabetic State, +pathology, Receptors, Immunologic, 3123 Gynaecology and paediatrics, 3121 Internal medicine, 3111 Biomedicine",
author = "Salonen, {Kirsi M.}",
note = "M1 - 79 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:",
year = "2016",
language = "English",
isbn = "978-951-51-2287-2",
publisher = "[K. M. Salonen]",
address = "Finland",

}

Humoral beta-cell autoimmunity, ager gene polymorphism and circulating soluble RAGE in preclinical and clinical type 1 diabetes. / Salonen, Kirsi M.

Helsinki : [K. M. Salonen], 2016. 79 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Humoral beta-cell autoimmunity, ager gene polymorphism and circulating soluble RAGE in preclinical and clinical type 1 diabetes

AU - Salonen, Kirsi M.

N1 - M1 - 79 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:

PY - 2016

Y1 - 2016

N2 - The incidence of type 1 diabetes has been increasing over recent decades. The reason for the increase, and the initial trigger for the autoimmune process remain unknown. Children with significantly increased risk for type 1 diabetes can be recognized from the general population based on their HLA-genotype and a panel of autoantigen-specific antibody assays. Recently a novel autoantibody specificity was discovered, the ZnT8 autoantibodies (ZnT8A). The advanced glycation end products (AGEs) are produced via glycation reactions between reducing sugars and proteins. AGEs and their interaction with the receptor for AGEs (RAGE), have been implicated to play a role in the pathogenesis and complications of diabetes. The soluble form of RAGE (sRAGE) is counteracting the effects of proinflammatory, membrane-bound RAGE. A decrease in sRAGE has been observed in various studies on acute inflammation. Polymorphisms of the gene encoding RAGE, AGER, are associated with the risk and the complications of diabetes according to previous studies. This thesis set out to define the characteristics of ZnT8A and RAGE in clinical and pre-clinical type 1 diabetes. Among the newly diagnosed children with type 1 diabetes, 63% tested positive for ZnT8A. ZnT8A were associated with age and metabolic state at diagnosis as well as to HLA genotype. ZnT8A-assay did not improve the detection rate of beta-cell autoimmunity. Concentrations of sRAGE correlated positively with age in children with newly diagnosed type 1 diabetes, but not in controls. Diabetic ketoacidosis at diagnosis and the high-risk HLA-genotype were related to lower sRAGE. Two polymorphic variants of the AGER gene, associated with increased risk for type 1 diabetes, correlated with reduced sRAGE. Prediabetic children had higher sRAGE than autoantibody-negative controls. A reduction in sRAGE coincides with the appearance of autoantibodies in children progressing to overt type 1 diabetes, but not in healthy controls, or in children seroconverting to autoantibody positivity later in childhood. After the seroconversion, the sRAGE concentrations remained stable. The RAGE/AGE ratio was higher in the cases than in the controls. To conclude, sRAGE, which has been considered cytoprotective in previous studies, is positively associated with older age at disease onset, protection from metabolic decompensation at diagnosis and AGER genotypes with a lower risk for type 1 diabetes. Children, who seroconvert to humoral islet cell autoimmunity early in childhood, experience a drop in sRAGE coinciding with the appearance of the first autoantibodies. They have higher sRAGE and sRAGE/AGE-ratio than the controls before seroconversion. These observed associations might be a result of an intrinsic protective mechanism, which fails at seroconversion.

AB - The incidence of type 1 diabetes has been increasing over recent decades. The reason for the increase, and the initial trigger for the autoimmune process remain unknown. Children with significantly increased risk for type 1 diabetes can be recognized from the general population based on their HLA-genotype and a panel of autoantigen-specific antibody assays. Recently a novel autoantibody specificity was discovered, the ZnT8 autoantibodies (ZnT8A). The advanced glycation end products (AGEs) are produced via glycation reactions between reducing sugars and proteins. AGEs and their interaction with the receptor for AGEs (RAGE), have been implicated to play a role in the pathogenesis and complications of diabetes. The soluble form of RAGE (sRAGE) is counteracting the effects of proinflammatory, membrane-bound RAGE. A decrease in sRAGE has been observed in various studies on acute inflammation. Polymorphisms of the gene encoding RAGE, AGER, are associated with the risk and the complications of diabetes according to previous studies. This thesis set out to define the characteristics of ZnT8A and RAGE in clinical and pre-clinical type 1 diabetes. Among the newly diagnosed children with type 1 diabetes, 63% tested positive for ZnT8A. ZnT8A were associated with age and metabolic state at diagnosis as well as to HLA genotype. ZnT8A-assay did not improve the detection rate of beta-cell autoimmunity. Concentrations of sRAGE correlated positively with age in children with newly diagnosed type 1 diabetes, but not in controls. Diabetic ketoacidosis at diagnosis and the high-risk HLA-genotype were related to lower sRAGE. Two polymorphic variants of the AGER gene, associated with increased risk for type 1 diabetes, correlated with reduced sRAGE. Prediabetic children had higher sRAGE than autoantibody-negative controls. A reduction in sRAGE coincides with the appearance of autoantibodies in children progressing to overt type 1 diabetes, but not in healthy controls, or in children seroconverting to autoantibody positivity later in childhood. After the seroconversion, the sRAGE concentrations remained stable. The RAGE/AGE ratio was higher in the cases than in the controls. To conclude, sRAGE, which has been considered cytoprotective in previous studies, is positively associated with older age at disease onset, protection from metabolic decompensation at diagnosis and AGER genotypes with a lower risk for type 1 diabetes. Children, who seroconvert to humoral islet cell autoimmunity early in childhood, experience a drop in sRAGE coinciding with the appearance of the first autoantibodies. They have higher sRAGE and sRAGE/AGE-ratio than the controls before seroconversion. These observed associations might be a result of an intrinsic protective mechanism, which fails at seroconversion.

KW - Adolescent

KW - Advanced Glycosylation End Product-Specific Receptor

KW - Age Factors

KW - Autoimmune Diseases

KW - +diagnosis

KW - +immunology

KW - Autoantibodies

KW - +blood

KW - Cation Transport Proteins

KW - Child

KW - Child, Preschool

KW - Disease Progression

KW - Diabetes Mellitus, Type 1

KW - +genetics

KW - Glycosylation End Products, Advanced

KW - HLA-DR Antigens

KW - Immunity, Humoral

KW - Infant

KW - Prediabetic State

KW - +pathology

KW - Receptors, Immunologic

KW - 3123 Gynaecology and paediatrics

KW - 3121 Internal medicine

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-2287-2

PB - [K. M. Salonen]

CY - Helsinki

ER -