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

Ronkainen, Minna; Hoppu, Sanna; Korhonen, Sari; Simell, Satu; Veijola, Riitta; Ilonen, Jorma; Simell, Olli; Knip, Mikael

doi:10.1530/eje.1.02271

Cited by 20 publications

(22 citation statements)

References 35 publications

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“…Since the humoral immune system was already attacking multiple autoantigens, namely GAD, insulin, and IA-2 in the broad responders, we expected this phenomenon to be reflected by a broad activation also at the level of epitope and isotype specificity to a single antigen. Such a hypothesis is in line with the epitope spreading seen in prediabetes and the isotype switching/spreading reported for both GAD (19) and IA-2 (9, 20) in preclinical T1D. To our surprise, the isotype-specific response to IA-2 turned out to be broader among the IA-2-restrictive responders.…”

Section: Discussionsupporting

confidence: 88%

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: 88%

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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“…These changes were evident at the same time point where the highest levels of GADA induced by the treatment were observed [15]. In the Prediction and Prevention study in Finland, emergence of GADA of the IgG4 subclass was observed in genetically susceptible children who remained non-diabetic [32]. Moreover, higher GADA of the IgG4 subclass were observed in LADA as compared to type 1 diabetes patients, which was interpreted as an indication of a more balanced immune response in the pancreatic tissue [33].…”

Section: Discussionmentioning

confidence: 84%

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Chéramy

Skoglund

Johansson

et al. 2010

Clinical Immunology

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, GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD (65) AbstractWe have previously shown that two injections of 20 μg GAD-alum to recent onset type 1 diabetic children induced GADA levels in parallel to preservation of insulin secretion. Here we investigated if boosted GADA induced changes in IgG1, 2, 3 and 4 subclass distributions or affected GAD 65 enzyme activity. We further studied the specific effect of GAD-alum through analyses of IA-2A, tetanus toxoid and total IgE antibodies. Serum from children receiving GAD-alum or placebo was collected pre-treatment and after 3, 9, 15 and 21 months.At 3 month a reduced percentage of IgG1 and increased IgG3/IgG4 were detected in GADalum treated. Further, IA-2A, IgE and tetanus toxoid antibodies, as well as GAD 65 enzyme activity, were unaffected confirming the specific effect of treatment. In the GAD-alum group, higher pre-treatment GADA were associated to more pronounced C-peptide preservation. The induced IgG3/IgG4 and reduced IgG1 suggest a Th2 deviation of the immune response.

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“…In addition, GADA IgG1–4 subclass distribution remained similar in all groups until 9 months, when the proportion of IgG4 in the 4D group drastically increased in parallel to a decrease of IgG1, supporting the notion of an enhanced humoral Th2-like response by additional GAD-alum doses. Previous studies have shown that higher levels of GADA IgG4 were associated with slower progression to clinical onset of disease in at-risk individuals (24,25). Furthermore, immunization with insulin promoted IgG4 in type 1 diabetic patients, an event interpreted to be associated with a Th2-like response (26).…”

Section: Discussionmentioning

confidence: 96%

Cellular and Humoral Immune Responses in Type 1 Diabetic Patients Participating in a Phase III GAD-alum Intervention Trial

et al. 2013

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OBJECTIVEGAD formulated in aluminum hydroxide (GAD-alum) has previously been shown to induce preservation of residual insulin secretion in recent-onset type 1 diabetes, but recent phase II and III GAD-alum trials failed to reach primary outcomes. The European phase III study was therefore closed after 15 months, and only a minority of patients completed the 30 months of follow-up.RESEARCH DESIGN AND METHODSThis study aimed to characterize cellular and humoral responses in the Swedish patients (n = 148) participating in the phase III trial, receiving four (4D) or two (2D) GAD-alum doses or placebo. Serum GAD65 antibody (GADA) levels, GADA IgG1–4 subclass distribution, cytokine secretion, and proliferative responses in peripheral blood mononuclear cells (PBMCs) were analyzed.RESULTSThe GAD65-induced cytokine profile tended to switch toward a predominant Th2-associated profile over time both in the 2D and 4D group. The groups also displayed increased GADA levels and PBMC proliferation compared with placebo, whereas GADA IgG subclass distribution changed in 4D patients.CONCLUSIONSBoth 2D and 4D patients displayed GAD65-specifc cellular and humoral effects after GAD-alum treatment, but at different time points and magnitudes. No specific immune markers could be associated with treatment efficacy.

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

Cited by 20 publications

References 35 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.

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Cellular and Humoral Immune Responses in Type 1 Diabetic Patients Participating in a Phase III GAD-alum Intervention Trial

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