Association of Amino-Terminal-Specific Antiglutamate Decarboxylase (GAD65) Autoantibodies with β-Cell Functional Reserve and a Milder Clinical Phenotype in Patients with GAD65 Antibodies and Ketosis-Prone Diabetes Mellitus

Hampe, Christiane S.; Nalini, Ramaswami; Maldonado, Mario; Hall, Tyler R.; Garza, Gilberto; Iyer, Dinakar; Balasubramanyam, Ashok

doi:10.1210/jc.2006-1719

Cited by 24 publications

(21 citation statements)

References 37 publications

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“…Thus, anti-GAD65 reactive with ctc1, as defined by blocking by rFab from mAbs b78, DPD, and DPC, was associated with enzyme inhibitory antibodies, whether from patients with Stiff Person Syndrome (22) or a subset of ketosis-prone type 1 diabetes with a higher ␤-cell functional reserve and a more benign clinical course (23). Also, anti-GAD65 reactive with ctc1/NH 2 -terminal epitopes was associated with slowly progressive type 1 diabetes, i.e., latent autoimmune diabetes of adults (24,25).…”

Section: Discussionmentioning

confidence: 99%

COOH-Terminal Clustering of Autoantibody and T-Cell Determinants on the Structure of GAD65 Provide Insights Into the Molecular Basis of Autoreactivity

et al. 2008

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OBJECTIVE-To gain structural insights into the autoantigenic properties of GAD65 in type 1 diabetes, we analyzed experimental epitope mapping data in the context of the recently determined crystal structures of GAD65 and GAD67, to allow "molecular positioning" of epitope sites for B-and T-cell reactivity. RESEARCH DESIGN AND METHODS-Datawere assembled from analysis of reported effects of mutagenesis of GAD65 on its reactivity with a panel of 11 human monoclonal antibodies (mAbs), supplemented by use of recombinant Fab to crossinhibit reactivity with GAD65 by radioimmunoprecipitation of the same mAbs. RESULTS-The COOH-terminal region on GAD65 was the major autoantigenic site. B-cell epitopes were distributed within two separate clusters around different faces of the COOHterminal domain. Inclusion of epitope sites in the pyridoxal phosphate-and NH 2 -terminal domains was attributed to the juxtaposition of all three domains in the crystal structure. Epitope preferences of different mAbs to GAD65 aligned with different clinical expressions of type 1 diabetes. Epitopes for four of five known reactive T-cell sequences restricted by HLA DRB1*0401 were aligned to solvent-exposed regions of the GAD65 structure and colocalized within the two B-cell epitope clusters. The continuous COOH-terminal epitope region of GAD65 was structurally highly flexible and therefore differed markedly from the equivalent region of GAD67.CONCLUSIONS-Structural features could explain the differing antigenicity, and perhaps immunogenicity, of GAD65 versus GAD67. The proximity of B-and T-cell epitopes within the GAD65 structure suggests that antigen-antibody complexes may influence antigen processing by accessory cells and thereby T-cell reactivity. Diabetes 57:1293-1301, 2008 T ype 1 diabetes is characterized by autoimmune reactivity to islet cell antigens that include the 65-kDa isoform of GAD (GAD65). Of the two isoforms of GAD, GAD67 and GAD65, only GAD65 is autoantigenic, in diseases that include particularly type 1 diabetes (1,2). Importantly, the specificity of antibodies for particular epitopes on GAD65 rather than their actual levels may be a better indicator of impending or actual destruction of islet ␤-cells. Thus in genetically prone individuals, changes in the focus of autoantibody responses to epitopes of GAD65, i.e., intramolecular epitope shifts during the period of pre-diabetic insulitis, herald the onset of overt type 1 diabetes (3).B-cell/autoantibody epitopes on GAD65 engage conformational determinants that are widely distributed over the linear sequence of the three domains, NH 2 -terminal (amino acids 1-234), pyridoxal phosphate (PLP)-binding (235-442), and COOH-terminal (443-585) domains (4). Presently, unanswered questions include the precise location of epitope sites and critical binding residues for autoantibody recognition, the differing immune reactivity of the GAD65 versus the GAD67 isoform, and the failure of natural immune tolerance to GAD65 in the first place. These questions prompted the recent crystallographic s...

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Section: Discussionmentioning

confidence: 99%

COOH-Terminal Clustering of Autoantibody and T-Cell Determinants on the Structure of GAD65 Provide Insights Into the Molecular Basis of Autoreactivity

et al. 2008

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“…We have previously reported the rationale underlying this classification and nomenclature for KPD (3,8); briefly, they specify important differences in phenotype and natural history that are obscured in the current American Diabetes Association classification scheme, wherein both ␤Ϫ subgroups would be termed type 1 diabetes and both ␤ϩ groups would be termed type 2 diabetes. With the exception of the strong autoimmune basis for ␤-cell functional loss in Aϩ␤Ϫ KPD (11,12), the factors underlying irreversible or reversible severe ␤-cell dysfunction in the KPD subgroups remain unclear and may be complex, even for the other subgroup with an apparent autoimmune basis (Aϩ␤ϩ KPD) (13).…”

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confidence: 99%

HLA Class II Alleles Specify Phenotypes of Ketosis-Prone Diabetes

et al. 2008

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OBJECTIVE -Ketosis-prone diabetes (KPD) comprises four subgroups based on the presence or absence of ␤-cell autoantibodies (Aϩ or AϪ) and ␤-cell functional reserve (␤ϩ or ␤Ϫ). Genetic factors could contribute to their distinctive phenotypes. Our aim was to specify the role of HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes in determining KPD phenotypes.RESEARCH DESIGN AND METHODS -A total of 185 adults presenting with diabetic ketoacidosis were followed longitudinally for a mean of 5.5 years, with measurements of autoantibodies, ␤-cell functional reserve, insulin sensitivity, and insulin requirement. Frequencies of susceptibility and resistance alleles at HLA DQA1, DQB1, and DRB1 loci were correlated with clinical and phenotypic features of KPD subgroups and compared with those of ethnic-specific population control subjects.RESULTS -Susceptibility alleles were more frequent (P Ͻ 0.0001) in the two Aϩ than the two AϪ KPD subgroups; in the latter, the frequency was no greater than in population control subjects (except for DQB1*0302). Susceptibility alleles differentiated the two clinically similar ␤Ϫ subgroups (more frequent in Aϩ␤Ϫ than AϪ␤Ϫ KPD; P Ͻ 0.01). Resistance alleles were more frequent in the two ␤ϩ than the two ␤Ϫ KPD subgroups (P Ͻ 0.01). The frequencies of certain susceptibility (e.g., DQB1*02) and resistance (DQB1*0602) alleles were higher in African-American AϪ␤ϩ KPD patients than in African-American control subjects. DQB1*0302 was more frequent in all KPD subgroups compared with control subjects.CONCLUSIONS -HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes help specify the four subgroups of KPD. Inheritance of these alleles may influence long-term ␤-cell functional reserve.

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“…By contrast, rFab from the mAb b78 that mapped to the C-terminal domain blocked anti-GAD65 in sera that contained GAD enzyme inhibitory activity, whether from patients with Stiff Person Syndrome [20], or a subset of patients with ketosis-prone type 1 diabetes [28]. Also, reactivity that mapped to the N-and C-terminal domain inhibitable by rFab from mAb DPD was associated with a higher b-cell functional reserve and a more benign clinical course [28]. Taken together, these epitope mapping studies have suggested that there are differences in the epitopes recognized by different populations of patients.…”

Section: B Cell Responses To Gad65mentioning

confidence: 89%

“…Moreover, progressively increasing levels of b96.11-inhibitable reactivity correlated with high risk HLA-DQ alleles in a longitudinal study on the progression to overt diabetes in anti-GAD65-positive children [29]. By contrast, rFab from the mAb b78 that mapped to the C-terminal domain blocked anti-GAD65 in sera that contained GAD enzyme inhibitory activity, whether from patients with Stiff Person Syndrome [20], or a subset of patients with ketosis-prone type 1 diabetes [28]. Also, reactivity that mapped to the N-and C-terminal domain inhibitable by rFab from mAb DPD was associated with a higher b-cell functional reserve and a more benign clinical course [28].…”

Section: B Cell Responses To Gad65mentioning

confidence: 96%

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GAD65 as a prototypic autoantigen

Fenalti

Rowley

2008

Journal of Autoimmunity

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Association of Amino-Terminal-Specific Antiglutamate Decarboxylase (GAD65) Autoantibodies with β-Cell Functional Reserve and a Milder Clinical Phenotype in Patients with GAD65 Antibodies and Ketosis-Prone Diabetes Mellitus

Abstract: DPD-defined epitope specificity is correlated directly with preserved beta-cell functional reserve in GAD65Ab-positive patients and is associated with the milder clinical phenotype of A+B+ KPDM.

Cited by 24 publications

References 37 publications

COOH-Terminal Clustering of Autoantibody and T-Cell Determinants on the Structure of GAD65 Provide Insights Into the Molecular Basis of Autoreactivity

COOH-Terminal Clustering of Autoantibody and T-Cell Determinants on the Structure of GAD65 Provide Insights Into the Molecular Basis of Autoreactivity

HLA Class II Alleles Specify Phenotypes of Ketosis-Prone Diabetes

GAD65 as a prototypic autoantigen

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