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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
immunology and microbiology
Analysis of GAD65 autoantibodies in Stiff-Person syndrome patients
Journal of Immunology, Volume 175, No. 11, Year 2005
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Description
Autoantibodies to the 65-kDa isoform of glutamate decarboxylase GAD65 (GAD65Ab) are strong candidates for a pathological role in Stiff-Person syndrome (SPS). We have analyzed the binding specificity of the GAD65Ab in serum and cerebrospinal fluid (CSF) of 12 patients with SPS by competitive displacement studies with GAD65-specific rFab-derived from a number of human and mouse mAbs specific for different determinants on the Ag. We demonstrate considerable differences in the epitope specificity when comparing paired serum and CSF samples, suggesting local stimulation of B cells in the CSF compartment of these patients. Moreover, these autoantibodies strongly inhibit the enzymatic activity of GAD65, thus blocking the formation of the neurotransmitter γ-aminobutyric acid. The capacity of the sera to inhibit the enzymatic activity of GAD65 correlated with their binding to a conformational C-terminal Ab epitope. Investigation of the inhibitory mechanism revealed that the inhibition could not be overcome by high concentrations of glutamate or the cofactor pyridoxal phosphate, suggesting a noncompetitive inhibitory mechanism. Finally, we identified a linear epitope on amino acids residues 4-22 of GAD65 that was recognized solely by autoantibodies from patients with SPS but not by serum from type 1 diabetes patients. A mAb (N-GAD65 mAb) recognizing this N-terminal epitope was successfully humanized to enhance its potential therapeutic value by reducing its overall immunogenicity. Copyright © 2005 by The American Association of Immunologists, Inc.
Authors & Co-Authors
Raghavan, Raju
Unknown Affiliation
Foote, Jefferson
Unknown Affiliation
Banga, Jasvinder Paul
Unknown Affiliation
Hall, Tyler R.
Unknown Affiliation
Padoa, Carolyn J.
Unknown Affiliation
Dalakas, M. C.
Unknown Affiliation
Örtqvist, Eva
Unknown Affiliation
Hampe, Christiane Susanne
Unknown Affiliation
Statistics
Citations: 137
Authors: 8
Affiliations: 7
Identifiers
Doi:
10.4049/jimmunol.175.11.7755
ISSN:
00221767
Research Areas
Noncommunicable Diseases