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

Mäkinen, Anna; Härkönen, Taina; Ilonen, Jorma; Knip, Mikael

doi:10.1530/eje-07-0853

Cited by 16 publications

(17 citation statements)

References 31 publications

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“…Our observations that the appearance of IAA only tends to be associated with the HLA-DR4 haplotype while GADA only was associated with the HLA-DR3 haplotype is of considerable interest. Similar associations between HLA and islet autoantibodies have previously been observed at the time of clinical diagnosis [15, 16] extended to the observation that IA-2A was associated with HLA-DR4 but negatively associated with HLA-DR3 [15, 17]. The strong association between HLA and the seroconversion to a specific islet autoantibody therefore underscores prior observations that the association between HLA and type 1 diabetes at the time of clinical diagnosis are secondary to a primary association between HLA and an autoimmune response to either IAA only or GADA only.…”

Section: Discussionsupporting

confidence: 79%

The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study

et al. 2015

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Aims/hypothesis Islet autoantibodies, in addition to elevated blood glucose, define type 1 diabetes. These autoantibodies are detectable for a variable period of time before diabetes onset. Thus, the occurrence of islet autoantibodies is associated with the beginning of the disease process. The age at, and order in, which autoantibodies appear may be associated with different genetic backgrounds or environmental exposures, or both. Methods Infants with HLA-DR high-risk genotypes (DR3/4, DR4/4, DR4/8 and DR3/3) were enrolled and prospectively followed with standardised autoantibody assessments quarterly throughout the first 4 years of life and then semi-annually thereafter. Results Autoantibodies appeared in 549/8,503 (6.5%) children during 34,091 person-years of follow-up. Autoantibodies at 3 (0.1%) and 6 (0.2%) months of age were rare. Of the 549, 43.7% had islet autoantibodies to insulin (IAA) only, 37.7% had glutamic acid decarboxylase autoantibodies (GADA) only, 13.8% had both GADA and IAA only, 1.6% had insulinoma antigen-2 only and 3.1% had other combinations. The incidence of IAA only peaked within the first year of life and declined over the following 5 years, but GADA only increased until the second year and remained relatively constant. GADA only were more common than IAA only in HLA-DR3/3 children but less common in HLA-DR4/8 children. Conclusions/interpretation Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype.

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Section: Discussionsupporting

confidence: 79%

The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study

et al. 2015

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“…Multinomial regression analysis revealed a positive association of the haplotype DRB1*040101/DQB1*0302 with altered anti-IA-2 titers in our population. These results are concordant with previous studies on Canadian (24), Japanese (20), German (10), Finnish (27,28), Italian (13), and Belgian (5) populations that showed that the prevalence and level of IA-2 autoantibody are increased in patients with HLA DR4/DQ8. However, IA-2 was negatively associated with DRB1*110101/ DQB1*030101 in titers and in prevalence.…”

Section: Discussionsupporting

confidence: 92%

“…Our study demonstrated that the prevalence and increased titer of anti-GAD antibodies are associated with . This association between IA-2 and the DRB*04 allele was reported in previous studies (11,13,22,24). Multinomial regression analysis revealed a positive association of the haplotype DRB1*040101/DQB1*0302 with altered anti-IA-2 titers in our population.…”

Section: Discussionsupporting

confidence: 91%

Glutamic Acid Decarboxylase 65 and Islet Cell Antigen 512/IA-2 Autoantibodies in Relation to Human Leukocyte Antigen Class II DR and DQ Alleles and Haplotypes in Type 1 Diabetes Mellitus

Stayoussef¹,

Benmansour²,

Al-Jenaidi³

et al. 2011

Clin. Vaccine Immunol.

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The frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age-and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in the DRB1*030101 allele (P < 0.001), together with the DRB1*030101/DQB1*0201 (P < 0.001) and DRB1*040101/DQB1*0302 (P ‫؍‬ 0.002) haplotypes, while lower anti-GAD titers were associated with the DRB1*070101 (P ‫؍‬ 0.001) and DRB1*110101 (P < 0.001) alleles and DRB1*070101/DQB1*0201 (P ‫؍‬ 0.001) and DRB1*110101/DQB1*030101 (P ‫؍‬ 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in the DRB1*040101 allele (P ‫؍‬ 0.007) and DRB1*040101/DQB1*0302 (P ‫؍‬ 0.001) haplotypes but were lower in the DRB1*110101 allele (P ‫؍‬ 0.010) and the DRB1*110101 (P < 0.001) and DRB1*110101/DQB1*030101 (P ‫؍‬ 0.025) haplotypes. Multinomial regression analysis confirmed the positive association of DRB1*030101 and the negative association of DRB1*110101 and DQB1*030101, along with the DRB1*070101/DQB1*0201 and DRB1*110101/DQB1*030101 haplotypes, with anti-GAD levels. In contrast, only the DRB1*040101/DQB1*0302 haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D.Type 1 diabetes mellitus (T1D) is an endocrine disease characterized by autoimmune destruction of pancreatic ␤ islet cells (2, 27). Several autoantigens have been implicated in triggering this process, including insulin; the 65-kDa isoform of glutamic acid decarboxylase (GAD) (2,19,26), an enzyme involved in the synthesis of the inhibitory neurotransmitter ␥-aminobutyric acid in pancreatic ␤ islet cells; and islet cell antigen 2 (IA-2), a tyrosine phosphatase expressed in ␤ islet cells (12). Up to 90% of newly diagnosed T1D cases are positive for anti-IA-2 and/or anti-GAD antibodies, compared to the very low prevalence of these autoantibodies in nondiabetic control populations (ϳ1%) (27, 28). Most peptides derived from GAD and IA-2 autoantigens can bind to T1D-predisposing and -protective HLA molecules, although some exceptions were observed (8). Functionally, T cell-proliferative responses from T1D patients identified GAD65 as a likely candidate in the development of anti-␤ islet cell immunity (16).We and others have confirmed the association of select HLA class II alleles and haplotypes with increased risk of T1D (1, 21, 29) and have identified both susceptible (DRB1*030101, DRB1*030101-DQB1*0201, and DRB1*040101-DQB1*0302) and protective (DRB1*070101, DRB1*110101, DRB1*070101-DQB1*0201, and DRB1*110101-DQB1*030101) alleles and ha...

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“…The nationwide Finnish Pediatric Diabetes Register (27) has covered more than 90% of children diagnosed with T1D since June 2002 (28). By April 2007, the register had covered 1544 children who had T1D-related autoantibodies analyzed and were diagnosed with T1D before the age of 15 years.…”

Section: Study Design and Subjectsmentioning

confidence: 99%

Extended family history of autoimmune diseases and phenotype and genotype of children with newly diagnosed type 1 diabetes

Parkkola

Härkönen

Ryhänen

et al. 2013

European Journal of Endocrinology

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Objective: Based on the concept of clustering autoimmunity, children with a positive family history of autoimmunity could be expected to have a different pathogenetic form of type 1 diabetes (T1D) and thus a stronger autoimmune reactivity against b-cells and an increased prevalence of the HLA-DR3-DQ2 haplotype.Design and methods: We tested this hypothesis in a cross-sectional observational study from the Finnish Pediatric Diabetes Register. HLA class II genotypes and b-cell autoantibodies were analyzed, and data on the extended family history of autoimmunity and clinical markers at diagnosis were collected with a structured questionnaire from 1488 children diagnosed with T1D under the age of 15 years (57% males). Results: Only 23 children (1.5%) had another autoimmune disease (AID) known at diagnosis, and they had a milder metabolic decompensation at diabetes presentation. One-third (31.4%) had at least one relative with an AID other than T1D with affected mothers being overrepresented (8.2%) compared with fathers (2.8%). The children with a positive family history of other AIDs had higher levels of islet cell antibodies (PZ0.003), and the HLA-DR3-DQ2 haplotype in the children was associated with celiac disease in the extended family (P!0.001), but not with an increased frequency of autoimmune disorders, in general.Conclusions: Approximately one-third of children with newly diagnosed T1D have a first-and/or second-degree relative affected by an AID. Our data do not consistently support the hypothesis of differential pathogenetic mechanisms in such children.

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

Cited by 16 publications

References 31 publications

The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study

The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study

Glutamic Acid Decarboxylase 65 and Islet Cell Antigen 512/IA-2 Autoantibodies in Relation to Human Leukocyte Antigen Class II DR and DQ Alleles and Haplotypes in Type 1 Diabetes Mellitus

Extended family history of autoimmune diseases and phenotype and genotype of children with newly diagnosed type 1 diabetes

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