Unique epitopes of glutamic acid decarboxylase autoantibodies in slowly progressive type 1 diabetes

J Clin Endocrinol Metab. 2003 Oct;88(10):4768-75. doi: 10.1210/jc.2002-021529.

Abstract

Disease-specific epitope profiles of glutamic acid decarboxylase (GAD)65 autoantibodies (GAD65Ab) were studied in slowly progressive type 1 (insulin-dependent) diabetes mellitus (SPIDDM) and acute onset type 1 (insulin-dependent) diabetes mellitus (AIDDM) using seven kinds of GAD65/67 chimeric molecules. Sera obtained from Japanese SPIDDM (n = 17) and AIDDM (n = 46) patients followed prospectively were analyzed by immunoprecipitation, ELISA, and Western blotting. GAD65Ab in all SPIDDM samples reacted specifically with an N-terminal linear epitope located on the membrane anchoring domain between amino acids 17-51 and C-terminal conformational epitope between amino acids 443-585 of GAD65. The binding of GAD65Ab with N-terminal 83 residues in SPIDDM inversely correlated with the period in which insulin was not required. GAD65Ab in AIDDM did not react with N-terminal epitope located between amino acids 1-83, irrespective of the titer of GAD65Ab. A novel epitope of GAD65Ab in AIDDM residing between amino acids 244-360 was identified in 17% (8 of 46) of patients whose age of onset was younger than other AIDDM patients. In conclusion, GADAb in SPIDDM has unique N-terminal linear epitopes that are located on the anchoring domain of GAD65 molecules. Association is suggested between GAD65Ab targeted to this region and slowly progressive beta-cell failure in SPIDDM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / blood
  • Autoantibodies / immunology*
  • Binding Sites
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / immunology*
  • Glutamate Decarboxylase / chemistry
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / immunology*
  • HLA-DQ Antigens / genetics
  • HLA-DQ alpha-Chains
  • HLA-DQ beta-Chains
  • Haplotypes
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Insulin / therapeutic use
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / immunology*
  • Longitudinal Studies
  • Protein Structure, Tertiary
  • Pyridoxal Phosphate / metabolism
  • Recombinant Fusion Proteins

Substances

  • Autoantibodies
  • Epitopes
  • HLA-DQ Antigens
  • HLA-DQ alpha-Chains
  • HLA-DQ beta-Chains
  • HLA-DQA1 antigen
  • HLA-DQB1 antigen
  • Hypoglycemic Agents
  • Insulin
  • Isoenzymes
  • Recombinant Fusion Proteins
  • Pyridoxal Phosphate
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • glutamate decarboxylase 2