Insulin Autoantibody Isotypes during the Prediabetic Process in Young Children with Increased Genetic Risk of Type 1 Diabetes

Hoppu, Sanna; Ronkainen, Minna; Kimpimäki, Teija; Simell, Satu; Korhonen, Sari; Ilonen, Jorma; Simell, Olli; Knip, Mikael

doi:10.1203/01.pdr.0000100905.41131.3f

Cited by 34 publications

(33 citation statements)

References 31 publications

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“…In fact, the strongest initial IgG3 response to GAD65 was observed in single progressors. Similarly, the frequency of the IgG3 subclass of IAA was observed to be significantly higher in the progressors than the non-progressors among DIPP children in the first IAApositive sample according to our earlier study (18). In addition, high levels of IgG3 subclass IAA were associated with progression to T1D.…”

Section: Discussionsupporting

confidence: 70%

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Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes

Ronkainen

Hoppu²,

Korhonen³

et al. 2006

eur j endocrinol

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Objective: The pattern of the humoral immunity to disease-associated autoantigens may reflect the severity of the autoimmune disease process. The purpose of this study was to delineate the maturation of the humoral immunity to one of the main autoantigens in type 1 diabetes (T1D), glutamic acid decarboxylase (GAD65). Design and methods: Serum samples were obtained for the detection of epitope-and isotype-specific antibodies sequentially with short intervals from 36 young children with HLA-conferred genetic susceptibility to T1D starting from the first appearance of GAD65Ab. During prospective observation, ten children developed T1D. Antibodies were analyzed using biotinylated anti-human immunoglobulin (Ig) antibodies and chimeric GAD molecules in radio-binding assays. Results: The immune response to GAD65 started as reactivity to the middle region and spread rapidly to the C-terminal region. IgG1 antibodies dominated among the isotypes from the first appearance of GAD65Ab, while other IgG subclasses were observed to a lesser extent. IgG4 antibodies emerged clearly as the last IgG subclass. A broad initial response comprising three to four IgG subclasses and the lack of an emerging IgG4 response during follow-up was associated with increased risk for progression to clinical diabetes (P!0.05). Conclusions:The humoral response to GAD65 epitope clusters is relatively uniform in young children, whereas there is conspicuous individual variation in IgG subclass responses except for IgG1. A narrow initial IgG subclass response to GAD65 and the emergence of IgG4 antibodies were characteristic of those who remained non-diabetic over the first few years of GAD65 autoimmunity.European Journal of Endocrinology 155 633-642

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Section: Discussionsupporting

confidence: 70%

“…In the 2002 DASP workshop, the sensitivity and specificity of the IA-2A and IAA assays were 62 and 100%, and 44 and 100% respectively. More detailed information on the assays has been published previously (18).…”

Section: Other Assaysmentioning

confidence: 99%

Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes

Ronkainen

Hoppu²,

Korhonen³

et al. 2006

eur j endocrinol

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“…In T1D, a study investigating Ig isotypes against insulin, assessed insulin autoantibody (IAA) isotypes in children who were at genetic risk of T1D and encompassed IAA-positive children who progressed to T1D as well as nonprogressor infants (Hoppu et al 2004a). In this study, it was found that children who progressed rapidly to T1D showed strong IgG1 and IgG3 immunoreactivity to insulin, in contrast to a weak or absent IgG3 response, which was deemed to confer relative protection.…”

Section: Does Ig Isotype Matter?mentioning

confidence: 99%

Humoral Autoimmunity in Type 1 Diabetes: Prediction, Significance, and Detection of Distinct Disease Subtypes

Pietropaolo

Towns

Eisenbarth

2012

Cold Spring Harbor Perspectives in Medicine

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Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell-mediated destruction of pancreatic b cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process. Solid evidence indicates that autoantibodies against islet targets serve as key markers to enroll newly diagnosed T1D patients and their family members in intervention trials aimed at preventing or halting the disease process. The next challenge is perfecting mechanistic bioassays to be used as end points for disease amelioration following immunomodulatory therapies aimed at blocking immune-mediated b-cell injury and, in turn, preserving b-cell function in type 1 diabetes mellitus.

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“…The predominant isotype was IgG1, consistent with antigen-driven B-cell activation, predominantly Th1 activity. A more recent report exploring IAA isotypes in genetically susceptible (HLA-DQB1) young children reported a higher frequency of IgG3 in progressors compared with nonprogressors and higher integrated levels of IgG1 and IgG3 IAA compared with nonprogressors (110). In LADA adults, a difference in IgG subclasses was observed, with IgG4 found more commonly in LADA patients compared with type 1 diabetic patients; however, IgG1 remained the most common subtype in both LADA and type 1 diabetic patients (96).…”

Section: Antibody Isotypesmentioning

confidence: 99%

Autoantibodies in Diabetes

et al. 2005

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Islet cell autoantibodies are strongly associated with the development of type 1 diabetes. The appearance of autoantibodies to one or several of the autoantigens-GAD65, IA-2, or insulin-signals an autoimmune pathogenesis of ␤-cell killing. A ␤-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity. It is speculated that progression to ␤-cell loss and clinical onset of type 1 diabetes is reflected in a developing pattern of epitopespecific autoantibodies. Although the appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the autoantibody response that may mark time to onset of type 1 diabetes. The complexity of the disease process is exemplified by multiple clinical phenotypes, including autoimmune diabetes masquerading as type 2 diabetes in youth and adults. Autoantibodies may also provide prognostic information in clinically heterogeneous patient populations when examined longitudinally. Diabetes 54 (Suppl. 2):S52-S61, 2005

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Insulin Autoantibody Isotypes during the Prediabetic Process in Young Children with Increased Genetic Risk of Type 1 Diabetes

Cited by 34 publications

References 31 publications

Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes

Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes

Humoral Autoimmunity in Type 1 Diabetes: Prediction, Significance, and Detection of Distinct Disease Subtypes

Autoantibodies in Diabetes

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