Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality.

Hawa, MI; Fava, D.; Medici, Francesco; Deng, Yang; Notkins, A L; Mattia, G. De; Leslie, R. David

doi:10.2337/diacare.23.2.228

Cited by 71 publications

(60 citation statements)

References 3 publications

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“…Like GADA, protein tyrosine phosphatase-like protein antibodies (IA-2As) are antigen-specific islet antibodies. IA-2As are detected in a high frequency at diagnosis in type 1 diabetic children [6], whereas the frequency is lower in adultonset type 1 diabetic patients [7,8] and in LADA patients [9]. In addition, it has been suggested that IA-As could be of value for identifying LADA patients [10] It was previously described from our group that low levels of GADA, ICA or IA-2A may indicate a preserved beta cell function [4].…”

Section: Introductionmentioning

confidence: 84%

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

et al. 2011

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Aims Both type 1 (T1D) and type 2 (T2D) diabetes are considered to be associated with different degrees of progressive beta cell damage. However, few long term studies have been made. Our aim was to study the clinical course of 20 years of diabetes disease, including diabetes progression, co-morbidity and mortality in a prospectively studied cohort of consecutively diagnosed diabetic patients.Methods Among all 233 patients diagnosed with diabetes during 1985-1987 in Malmö, Sweden, 50 of 118 surviving patients were followed-up after 20 years. The age at diagnose was 42.323.1 and 57.513.6 yrs for antibody positive and antibody negative patients, respectively. HbA1c and plasma lipids were analysed with regard to metabolic control.Results Islet antibody negative patients at diagnosis had highly preserved C-peptide levels after 20 years in contrast to antibody positive patients (antibody-negative: C-peptide 0yrs 0.780.47 and 20yrs 0.700.46 (nmol/l), p=0.51 and antibody-positive: C-peptide 0yrs 0.330.35 and 20yrs 0.100.18; p<0.001. Islet antibodies but not age, BMI or C-peptide at diagnosis were predictors of C-peptide levels at 20 years when analysed by logistic regression (p<0.05). HbA1c did not differ between the groups after 20 years. The 20-year mortality was higher among antibody-negative patients, dependent on the higher age at diagnosis in this group (number of deaths: antibody-positive: 18 of 56 vs. antibody-negative: 109 of 188, p<0.001). Of the deceased, 79 % had died from diseases or complications that may be associated to diabetes. ConclusionWe found no progressive beta cell damage in autoantibody negative diabetes at a 20 year follow-up of the clinical course of diabetes.

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Section: Introductionmentioning

confidence: 84%

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

et al. 2011

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“…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. The present study is in line with previous findings in that IgG1 subclass IA-2A were most prominent (Fig.…”

Section: Discussionmentioning

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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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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“…Previous reports have indicated that the predominant diabetesassociated autoantibody isotypes in type 1 diabetes are IgG1 and IgG3 (108). Hawa et al (109) noted no significant difference in GAD65Ab or IA-2Ab isotypes when comparing children and young adults with type 1 and adult type 2 diabetic patients. The predominant isotype was IgG1, consistent with antigen-driven B-cell activation, predominantly Th1 activity.…”

Section: Antibody Isotypesmentioning

confidence: 96%

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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Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality.

Cited by 71 publications

References 3 publications

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

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

Autoantibodies in Diabetes

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