Cross reactivity between IA-2 and phogrin/IA-2β in binding of autoantibodies in IDDM

Hatfield, Emma; Hawkes, C. J.; Payton, Mark; Christie, Michael R.

doi:10.1007/s001250050828

Cited by 34 publications

(35 citation statements)

References 23 publications

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“…There are, however, fewer studies measuring the same parameters among patients with newly diagnosed T1D. Our findings on the frequencies of the different epitope-specific IA-2A are in line with these previous studies, where IA-2A binding specifically to the PTP epitope or cross-reacting with the IA-2/IA-2b PTP epitopes were detected most frequently, while responses targeting the PTP epitope of IA-2b were rare (4)(5)(6)8). In studies where isotype-specific IA-2A have been measured in patients with newly diagnosed T1D, IgG1 subclass antibodies have been observed to be the dominant isotype-specific antibody reactivity, although they have not been detected in all the subjects (21)(22)(23) (23) or analyzed at all (21,22) in those studies.…”

Section: Discussionsupporting

confidence: 91%

“…Several autoantigenic domains have been identified, including the juxtamembrane region (JM) of the IA-2 protein (amino acids (aa) 601-682), the PTP domain of the IA-2 protein (aa 687-979), and the PTP domain of the IA-2b protein (aa 741-1033). Autoantibodies that cross-react between the IA-2 and IA-2b PTP domains (crPTP) are also common (4)(5)(6)(7)(8). Antibodies to the IA-2b-specific epitopes are less frequent than those specific for the IA-2 epitopes, and have therefore been implicated to arise by epitope spreading secondary to the IA-2-specific humoral response (5,(7)(8)(9).…”

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: 91%

Section: Introductionmentioning

confidence: 99%

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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“…In this group of 242 patients, comparisons were made of GADA levels determined previously in samples taken at diagnosis with those taken at 0.5 years in this study and at 3 and 6 years post-diagnosis (see ESM Fig. 2) Plasma GADA levels were determined with a radiobinding assay using 35 S-labelled human GAD65 as antigen which was validated in the 2003 Diabetes Antibody Standardization Program (DASP 2003) [10,11]. GAD65 was produced by in vitro transcription/translation of human GAD65 (also known as GAD2) cDNA using a rabbit reticulocyte lysate (Promega, Madison, WI, USA) and L-[…”

Section: Methodsmentioning

confidence: 99%

GAD autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77

et al. 2007

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Aims/hypothesis Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes, with autoantibodies to islet proteins developing in older patients who have no immediate requirement for insulin therapy. Markers of its clinical course are uncharacterised. The aim of this study was to determine whether persistence of, or changes in, GAD65 autoantibodies (GADAs) in the LADA patients who participated in the United Kingdom Prospective Diabetes Study (UKPDS) were associated with disease progression or insulin requirement. Methods GADA levels and their relative epitope reactivities to N-terminal, middle and C-terminal regions of human GAD65 were determined in 242 UKPDS patients who were GADA-positive at diagnosis; samples taken after 0.5, 3 and 6 years of follow-up were tested using a radiobinding assay. Comparisons were made of GADA status with clinical details and disease progression assessed by the requirement for intensified glucose-lowering therapy. Results GADA levels fluctuated between 0.5 and 6 years but persisted in 225 of 242 patients. No association of GADA levels with disease progression or insulin requirement was observed. Antibody reactivity was directed to Cterminal and middle epitopes of GAD65 in >70% patients, and the N-terminal in <9%. There were no changes in epitope reactivity pattern over the 6 year follow-up period, nor any association between epitope reactivity and insulin requirement.

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“…Taking into consideration log-transformed levels of IAA, ICA, GADA, and IA-2A instead of antibody prevalence, multivariate analysis revealed only an association between GLIMA antibody positivity and IA-2A levels (P Ͻ 0.001). Incubation of GLIMA antibodypositive sera with 5 g recombinant human IA-2ic, conditions that effectively block antibody binding to IA-2 and-in many sera-IA-2␤ (15,16), failed to block antibody binding to GLIMA (Fig. 3) in the immunoprecipitation test, indicating that the association between antibodies to IA-2 and GLIMA is not the result of shared antigenic epitopes.…”

Section: Discussionmentioning

confidence: 96%

Autoantibodies to a 38-kDa Glycosylated Islet Cell Membrane–Associated Antigen in (Pre)type 1 Diabetes

et al. 2001

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THE BELGIAN DIABETES REGISTRY 6OBJECTIVE -To study the association of autoantibodies against a 38-kDa glycated islet cell membrane-associated (GLIMA) protein with (pre)type 1 diabetes, patient characteristics, and other immune and genetic markers of the disease and to evaluate the possible added value of GLIMA antibody determinations for disease prediction and classification.RESEARCH DESIGN AND METHODS -Recent-onset type 1 diabetic patients (n ϭ 100), prediabetic siblings (n ϭ 23), and nondiabetic control subjects (n ϭ 100) were consecutively recruited by the Belgian Diabetes Registry. GLIMA antibodies were determined by immunoprecipitation of radiolabeled islet cell proteins; islet cell antibodies (ICAs) were determined by indirect immunofluorescence; and insulin autoantibodies (IAAs), insulinoma-associated protein-2 antibodies (IA-2As), and GAD antibodies (GADAs) were determined by radioligand assays.RESULTS -GLIMA antibodies were detected in 38% of type 1 diabetic patients and 35% of prediabetic siblings (during follow-up) vs. 0% in control subjects (P Ͻ 0.001). Their prevalence was lower than that of other antibodies and was significantly associated with high levels of IA-2A and ICA (P Ͻ 0.0001). In (pre)diabetes, GLIMA antibodies could only be demonstrated in sera positive for Ն1 other autoantibody.CONCLUSIONS -GLIMA antibodies are strongly associated with type 1 diabetes and antibody markers of rapid progression to clinical onset but have a lower diagnostic sensitivity for the disease than IAA, ICA, IA-2A, or GADA. In its present form, the GLIMA antibody assay does not provide much additional information for prediction or classification of diabetes, compared with that obtained from the measurement of IA-2As alone or in combination with IAAs, ICAs, and GADAs.

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Cross reactivity between IA-2 and phogrin/IA-2β in binding of autoantibodies in IDDM

Cited by 34 publications

References 23 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 autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77

Autoantibodies to a 38-kDa Glycosylated Islet Cell Membrane–Associated Antigen in (Pre)type 1 Diabetes

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