The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

Hermann, Róbert; Laine, A.-P.; Veijola, Riitta; Vahlberg, Tero; Simell, Satu; Lähde, Jyrki; Simell, Olli; Knip, Mikael; Ilonen, Jorma

doi:10.1007/s00125-005-1844-x

Cited by 43 publications

(44 citation statements)

References 49 publications

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“…There was in fact no difference in the frequency of the highest risk associated (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 genotype. This finding is consistent with previous observations according to which children with (DR4)-DQB1*0302 were shown to test more frequently positive for both IAA and IA-2A and to have higher IAA and IA-2A levels (11,12).…”

Section: Discussionsupporting

confidence: 93%

“…In addition to the class II HLA DRB1*0401-DQB1*0302 haplotype, factors controlling the IA-2-restrictive pathogenesis of T1D might include other genetic loci. In previous studies in prediabetic children, the insulin gene INS -(-23)-HphI polymorphism (12), the cytotoxic T-lymphocyte-associated protein 4 (CTLA4)C49 or CT60 polymorphisms (12), or the Arg620Trp variant in the lymphoid tyrosine phosphatase encoding the PTPN22 gene (27) did not affect the production of IA-2A, but the INS and PTPN22 polymorphisms were observed to be associated with the early appearance of IAA and to contribute to the pathogenesis of T1D by initiating/modifying insulinspecific immunity. Further studies are required to unravel the factors influencing the IA-2-restricted response and the possible pathogenetic mechanism behind.…”

Section: Discussionmentioning

confidence: 99%

“…It has been estimated that about 50% of the familial clustering of T1D can be explained by these genes (11). IA-2 antibodies (IA-2A) have been associated with one of the strongest haplotypes predisposing to T1D, namely the (DR4)-DQB1*0302 haplotype (11,12).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the humoral immune response to islet antigen 2 in children with newly diagnosed type 1 diabetes.

Mäkinen

Härkönen²,

Ilonen³

et al. 2008

European Journal of Endocrinology

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Objective: To characterize the humoral immune response to islet antigen 2 (IA-2) in patients with newly diagnosed type 1 diabetes (T1D), we compared the profile of epitope-and isotype-specific IA-2 antibodies (IA-2A) between children with a humoral immune response restricted to IA-2 and children with a broad response including insulin autoantibodies (IAA) and antibodies to glutamic acid decarboxylase (GADA) in addition to IA-2A. Methods: The study subjects (nZ100) were derived from a consecutive series of 1108 patients from the Finnish Pediatric Diabetes Register (investigators listed in the Appendix). Islet cell antibodies, IAA, GADA, total IA-2A levels, IA-2/IA-2b epitopes, and isotypes were measured, and human leukocyte antigen (HLA) genotypes were analyzed. Results: There were no significant differences between the two groups in the frequency or levels of epitope-specific IA-2A. Those with an IA-2-restrictive response tested positive more frequently for IgA-IA-2A (PZ0.001), had higher titers of IgE-IA-2A (PZ0.025), tested positive for more IA-2A isotypes than the broad responders (PZ0.04), and carried the high-risk HLA-(DR4)-DQB1*0302 haplotype more frequently than those with a broad antibody response (PZ0.019). Conclusions: These data show that children with newly diagnosed T1D, who test positive only for IA-2A out of the three molecular antibodies predictive of T1D, have a broader IA-2-specific isotype response and stronger association with the high-risk HLA haplotype than those testing positive for all three molecular antibodies. This may be indicative of a different pathogenetic mechanism in those with their humoral immune response restricted to IA-2 at the time of diagnosis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Characterization of the humoral immune response to islet antigen 2 in children with newly diagnosed type 1 diabetes.

Mäkinen

Härkönen²,

Ilonen³

et al. 2008

European Journal of Endocrinology

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“…We found that insulin antibodies were lower in both the class I/III and class III/III genotypes than in the class I/I genotype, and confirmed previous findings [11,12] that carriers of class III alleles inherited a higher tolerance towards endogenous insulin, thus possibly relieving the immunological attack on the beta cells. We also found that class III alleles are associated with higher residual beta cell function and that this putative beta-cell-protective effect of class III alleles seemed to be most evident in the class III/III genotype group who, although only eight patients, also seemed to benefit from a clinically evident improvement in glycaemic control (1.1% in insulin-dose-adjusted HbA 1 c, p=0.04).…”

Section: Discussionsupporting

confidence: 91%

Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: reduced insulin antibody titres and preserved beta cell function

et al. 2005

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Aims/hypothesis: The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin gene (INS). We investigated the association between INS VNTR class III alleles (-23HphIA/T) and both insulin antibody presentation and residual beta cell function during the first year after diagnosis in 257 children with type 1 diabetes. Materials and methods: To estimate C-peptide levels and autoantibody presentation, patients underwent a mealstimulated C-peptide test 1, 6, and 12 months after diagnosis. The insulin -23HphIA/T variant was used as a marker of class III alleles and genotyped by PCR-RFLP. Results: The insulin antibody titres at 1 and 6 months were significantly lower in the class III/III and class I/III genotype groups than in the class I/I genotype group (p = 0.01). Class III alleles were also associated with residual beta cell function 12 months after diagnosis and independently of age, sex, BMI, insulin antibody titres, and HLA-risk genotype group (p = 0.03). The C-peptide level was twice as high among class III/III genotypes as in class I/I and class I/III genotypes (319 vs 131 and 166 pmol/l, p=0.01). Furthermore, the class III/III genotype had a 1.1% reduction in HbA 1 c after adjustment for insulin dose (p = 0.04). Conclusions/interpretation: These findings suggest a direct connection in vivo between INS VNTR class III alleles, a decreased humoral immune response to insulin, and preservation of beta cell function in recentonset type 1 diabetes.

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“…This may be due to the inclusion criteria used, resulting in a relatively homogeneous study population, but may also reflect the idea that factors contributing to the initiation of the disease process might be different from those driving the process towards overt disease. However, as previously shown (2,3,6,21,22), several of the factors associated with the initiation of b-cell autoimmunity do contribute to the phenomena associated with the progression rate, such as age at initial seroconversion, the pace of progression towards persistent multipositivity and autoantibody levels. The current study confirmed the prior observations that progression to T1D is related to young age at seroconversion, early progression to multipositivity, higher numbers of detectable autoantibodies and to higher levels of ICA, IAA and IA-2A (1, 2, 3).…”

Section: Discussionmentioning

confidence: 80%

Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

Siljander

Hermann

Hekkala

et al. 2013

European Journal of Endocrinology

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Objective: Reduced early insulin response has been shown to predict type 1 diabetes (T1D) in firstdegree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced b-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies. Design and methods: Intravenous glucose tolerance tests (IVGTTs) were carried out in 218 children with HLA-DQB1-conferred disease susceptibility and advanced b-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed. Results: Children developing T1D were younger at seroconversion, progressed more rapidly to advanced b-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D. Conclusions: Young age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children with HLA-DQB1-conferred disease susceptibility and advanced b-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.

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The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

Cited by 43 publications

References 49 publications

Characterization of the humoral immune response to islet antigen 2 in children with newly diagnosed type 1 diabetes.

Characterization of the humoral immune response to islet antigen 2 in children with newly diagnosed type 1 diabetes.

Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: reduced insulin antibody titres and preserved beta cell function

Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

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