Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: The German BABYDIAB study

Schenker, M; Hummel, Michael; Ferber, Karin M.; Walter, Melanie; Keller, E.; Albert, E. D.; Janka, Heidrun; Kastendiek, C.; Sorger, M.; Louwen, Frank; Ziegler, Anette‐G.

doi:10.1007/s001250051214

Cited by 78 publications

(66 citation statements)

References 18 publications

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“…Results from the BABYDIAB study, the DIPP study, and the DAISY study consistently show that children carrying high-risk HLA genotypes have a higher risk for early and more frequent development of islet autoantibodies in infancy (13,36,37). Among BABYDIAB offspring, the risk of developing islet autoantibodies by age 2 years is 20% in individuals who have the high-risk DR3-DQ2/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotypes compared with 2.7% in offspring without these genotypes, and, overall, 50% of islet autoantibody-positive offspring have at least one of these genotypes (36) (Fig. 2).…”

Section: Factors Influencing the Development Of Islet Autoimmunitymentioning

confidence: 94%

“…Islet autoantibodies differ in their association with HLA haplotypes. GADAs are more frequent in patients with HLA DR3-DQ2 (27,35), whereas IAAs and IA-2As are more frequent in patients with HLA DR4-DQ8 (27,(35)(36)(37). Patients without these haplotypes are more frequently islet autoantibody negative (13,27,36,37).…”

Section: Factors Influencing the Development Of Islet Autoimmunitymentioning

confidence: 99%

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Natural History of Type 1 Diabetes

Achenbach

Bonifacio²,

Koczwara³

et al. 2005

Diabetes

218

142

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The natural history of autoimmune type 1 diabetes in children is associated with the appearance of islet autoantibodies early in life, which is influenced by genetic and environmental factors. Once islet autoantibodies have developed, the progression to diabetes in antibody-positive individuals is determined by the age of antibody appearance and by the magnitude of the autoimmunity, in turn related to the age of the subject. Characteristics that describe the magnitude of the autoimmunity can stage progression to type 1 diabetes in islet autoantibody-positive subjects regardless of genetic background or age. Diabetes 54 (Suppl. 2):S25-S31, 2005

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Section: Factors Influencing the Development Of Islet Autoimmunitymentioning

confidence: 94%

Section: Factors Influencing the Development Of Islet Autoimmunitymentioning

confidence: 99%

Natural History of Type 1 Diabetes

Achenbach

Bonifacio²,

Koczwara³

et al. 2005

Diabetes

218

142

View full text Add to dashboard Cite

show abstract

“…HLA-DRB1, HLA-DQA1 and HLA-DQB1 genotyping in the BABYDIAB and BABYDIET studies has been described elsewhere [13].…”

Section: Methodsmentioning

confidence: 99%

Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes

et al. 2015

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Aims/hypothesis Autoantibodies that precede type 1 diabetes frequently develop in early childhood and target distinct beta cell proteins. The aim of this study was to determine the heterogeneity of islet autoantibody development and fate. Methods The ages of development of insulin autoantibodies (IAA) and GAD autoantibodies (GADA), followed by multiple islet autoantibodies and progression to diabetes were examined in 2,441 children participating in two German birth cohorts. Results In 218 children who developed islet autoantibodies, the first islet autoantibody-positive sample was characterised by single IAA in 80 (37%), multiple islet autoantibodies in 68 (31%) and single GADA in 63 (29%) children. Of the children who were single antibody positive at seroconversion, 35 (44%) IAA-positive and 15 (24%) GADA-positive children developed multiple islet autoantibodies. Single persistent antibodies had heterogeneous affinities; GADA were also heterogeneous in their binding to N-terminally truncated GAD65 and in an ELISA. Progression to diabetes occurred in >50% of children within 10 years in all groups that developed multiple islet autoantibodies and in 44% of children with persistent single high-affinity IAA or persistent single GADA that were positive in both a radiobinding assay and ELISA. The earliest autoantibody development was seen in children with single IAA that progressed to multiple islet autoantibodies or in those with persistent high-affinity single IAA, with a sharp peak in incidence observed at age 9 months. The peak incidence occurred at age 2 years for children who underwent seroconversion directly to multiple islet autoantibodies and at 5 years for children who first seroconverted to GADA and subsequently developed other autoantibodies. Seroconversion to low-affinity IAA or persistent single GADA occurred at a low incidence after the age of 9 months. Conclusions/interpretation Children of different ages have differing susceptibilities to autoimmunisation against specific beta cell autoantigens.

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“…Foxp3 ͉ HLA-DRB1*0401 ͉ type 1 diabetes P roinsulin (P-Ins) is considered an important autoantigen in type 1 diabetes (T1D), because it is the only truly ␤-cellspecific target, and because autoreactivity to P-Ins is very common in T1D patients with the HLA-DRB1*0401 (DR4) DQ8 haplotype (1)(2)(3)(4)(5)(6). The differences distinguishing autoreactive from foreign antigen reactive T cell responses to the same immunogenic epitope are still largely unknown (7).…”

mentioning

confidence: 99%

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

Durinovic‐Belló

Rosinger

Ja³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Recently, we have identified proinsulin (P-Ins)73-90 as an immunodominant T cell epitope of HLA-DRB1*0401 (DR4) subjects with ␤-islet cell autoimmunity and of HLA-DR4͞CD4 double-transgenic mice immunized with human P-Ins. We have compared the fine specificities of one human CD4 T cell clone and two mouse T cell hybridoma clones recognizing this epitope, and, although these three clones all recognized the same core region (LALEGSLQK), there were major differences in how they interacted with the peptide (p)͞HLA complex, reflecting the fact that human P-Ins is a foreign antigen in the mouse and an autoantigen in the type 1 diabetes patient. The human T cell clone was forkhead transcription factor 3 (Foxp3)-positive, a marker for regulatory T cell lineages, and secreted predominantly IL-5, IL-10, and low levels of IFN␥ in response to P-Ins73-90. This finding is compatible with the previously detected regulatory cytokine pattern in subjects with ␤-cell autoimmunity. However, added N-or C-terminal amino acids drastically changed HLA and tetramer binding capacity as well as T cell reactivity and the cytokine phenotype of the P-Ins 73-90-specific human CD4 T cell clone, suggesting a potential for this P-Ins epitope as a target for therapeutic intervention in HLA-DR4-positive humans with ␤-islet cell autoimmunity or recent-onset type 1 diabetes.Foxp3 ͉ HLA-DRB1*0401 ͉ type 1 diabetes P roinsulin (P-Ins) is considered an important autoantigen in type 1 diabetes (T1D), because it is the only truly ␤-cellspecific target, and because autoreactivity to P-Ins is very common in T1D patients with the HLA-DRB1*0401 (DR4) DQ8 haplotype (1-6). The differences distinguishing autoreactive from foreign antigen reactive T cell responses to the same immunogenic epitope are still largely unknown (7). To understand the structural requirements for activation of self-reactive P-Ins 73-90 -specific T cells in T1D autoimmunity, we have isolated a Foxp3-positive CD4 ϩ T cell clone from a DR4-homozygous T1D patient and compared the fine specificity of this T cell receptor to those of two murine T cell hybridoma clones derived from HLA-DR4 transgenic mice, in which this epitope is a foreign antigen (8). P-Ins 73-90 is situated at the C terminus of the C peptide and also covers the enzymatic cleavage site of the insulin A chain (8). This site is proteolytically destroyed during the maturation of insulin before secretion and is, therefore, an indication that Proinsulin and not Insulin may be the actual autoantigenic target in T1D.In human studies using purified CD4 ϩ T cells from HLA-DR4-positive subjects with islet autoimmunity, P-Ins 73-90 was also identified as an immunodominant epitope. This epitope was recognized by approximately two thirds of autoantibody-positive subjects, one third of recently diagnosed T1D patients, and a few control subjects (5, 9). The cytokines seen in response to P-Ins 73-90 were predominantly IL-4 and IL-10 in subjects with ␤-cell autoimmunity (9). Moreover, in a consecutive follow up of three high-risk individuals, ...

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Early expression and high prevalence of islet autoantibodies for DR3/4 heterozygous and DR4/4 homozygous offspring of parents with Type I diabetes: The German BABYDIAB study

Cited by 78 publications

References 18 publications

Natural History of Type 1 Diabetes

Natural History of Type 1 Diabetes

Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes

DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype

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