Humoral autoimmune responses to glutamic acid decarboxylase have similar target epitopes and subclass that show titer-dependent disease association

Piquer, Sandra; Belloni, Cristina; Lampasona, Vito; Bazzigaluppi, Elena; Vianello, Marika; Giometto, Bruno; Bosi, Emanuele; Bottazzo, Gian Franco; Bonifacio, Ezio

doi:10.1016/j.clim.2005.06.009

Cited by 22 publications

(23 citation statements)

References 23 publications

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“…In these studies, antibodies to the NH 2 -terminal epitopes occur together with antibodies to the more common middle and/or COOH-terminal epitopes. Moreover, NH 2 -terminal reactivity was usually associated with high-titer GADAs (25,28). It is possible, therefore, that the epitopes bound by antibodies in our NH 2 -terminal only reactive to GADAs are not the same as the NH 2 -terminal epitopes bound by GADAs in disease.…”

Section: Diabetes Vol 56 June 2007mentioning

confidence: 88%

GAD Autoantibody Affinity and Epitope Specificity Identify Distinct Immunization Profiles in Children at Risk for Type 1 Diabetes

et al. 2007

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OBJECTIVE—Autoantibodies to insulin and GAD are features of preclinical type 1 diabetes in children. For insulin autoantibodies, the antibody affinity and epitope specificity predict which children progress to diabetes. We asked whether autoantibodies to GAD (GADAs) are heterogeneous in affinity and epitope recognition and whether diabetes-related GADA are restricted to high-affinity responses. RESEARCH DESIGN AND METHODS—GADA affinity was measured by competitive binding experiments with [125I]-labeled and -unlabeled recombinant human GAD65 in the first GADA-positive sample from 95 children with a type 1 diabetes family history who were prospectively followed from birth and in follow-up samples from 65 of these children. RESULTS—At first GADA appearance, affinity ranged from 107 to 1010 l/mol. Affinity was higher in multiple islet autoantibody-positive children (P < 0.0001) and in HLA DR3–positive children (P = 0.006). GADA affinities were >109 l/mol in 52 of 53 multiple autoantibody-positive children. In contrast, children who were single GADA positive often had lower affinity GADA and/or GADA with specificities that were restricted to minor NH2-terminal GAD65 epitopes. At follow-up, affinity increased from low to high in 3 of 65 children. All 24 children who developed diabetes had high-affinity GADAs before diabetes onset. CONCLUSIONS—Children develop discrete, heterogeneous antibody responses to GAD that could arise from distinct immunization events, only some of which are diabetes relevant. Subtyping the GADA responses using affinity measurement will improve type 1 diabetes risk assessment.

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Section: Diabetes Vol 56 June 2007mentioning

confidence: 88%

GAD Autoantibody Affinity and Epitope Specificity Identify Distinct Immunization Profiles in Children at Risk for Type 1 Diabetes

et al. 2007

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“…GAD65 epitope recognition Recognition of conformational epitopes of GAD65 has been proposed as a marker for maturation of the humoral response in preclinical phases of type 1 diabetes [10,31] and suggested as a method for differentiation of disease and/or progression in adult-onset diabetes [12,[31][32][33]. In our cohort, the C-terminal and middle regions of GAD65 contained the most frequently targeted epitopes (in more than 50% of patients) for samples taken at all time points after diagnosis, whereas N-terminal reactivity was uncommon (<9%).…”

Section: Discussionmentioning

confidence: 99%

“…The fusion proteins comprised GAD65 epitopes: (1) at the N-terminal (GAD65 1-95 /GAD67 102-593 ); (2) in the middle region (GAD67 1-243 /GAD65 235-442 /GAD67 443-593 ); or (3) at the C-terminal (GAD67 1-452 /GAD65 445-585 ) [10,12]. Reactivities to GAD65 epitopes and GAD67 were expressed as arbitrary units relative to a standard prepared from samples from patients with type 1 diabetes or Stiff-Person syndrome.…”

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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“…Although sera from patients with SPS or other anti-GAD-positive neurological diseases, and sera from type 1 diabetics recognise epitopes across the catalytic domain of GAD65, an additional linear epitope in the N-terminal membrane-binding domain is present in SPS but not in type I diabetes [210,224,246].…”

Section: Type 1 Diabetes Spsmentioning

confidence: 98%

The Role of Pathogenic Autoantibodies in Autoimmunity

Rowley

Whittingham

2015

Antibodies

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Abstract:The serological presence of autoantibodies is diagnostic of autoimmunity, and these autoantibodies may be present for many years before the presentation of autoimmune disease (AID). Although a pathogenic role has been demonstrated for various autoantibodies reactive with cell surface and extracellular autoantigens, studies using monoclonal antibodies (mAb) show not all antibodies in the polyclonal response are pathogenic. Differences depend on Fab-mediated diversity in epitope specificity, Fc-mediated effects based on immunoglobulin (Ig) class and subclass, activation of complement, and the milieu in which the reaction occurs. These autoantibodies often occur in organ-specific AID and this review illustrates their pathogenic and highly specific effects. The role of autoantibodies associated with intracellular antigens is less clear. In vitro they may inhibit or adversely affect well-defined intracellular biochemical pathways, yet, in vivo they are separated from their autoantigens by multiple cellular barriers. Recent evidence that Ig can traverse cell membranes, interact with intracellular proteins, and induce apoptosis has provided new evidence for a pathogenic role for such autoantibodies. An understanding of how autoantibodies behave in the polyclonal response and their role in pathogenesis of AID may help identify populations of culprit B-cells and selection of treatments that suppress or eliminate them.

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Humoral autoimmune responses to glutamic acid decarboxylase have similar target epitopes and subclass that show titer-dependent disease association

Cited by 22 publications

References 23 publications

GAD Autoantibody Affinity and Epitope Specificity Identify Distinct Immunization Profiles in Children at Risk for Type 1 Diabetes

GAD Autoantibody Affinity and Epitope Specificity Identify Distinct Immunization Profiles in Children at Risk for 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

The Role of Pathogenic Autoantibodies in Autoimmunity

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