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Long-lived plasma cells and memory B cells produce pathogenic anti-GAD65 autoantibodies in Stiff Person Syndrome.

Abstract
Stiff person syndrome (SPS) is a rare, neurological disorder characterized by sudden cramps and spasms. High titers of enzyme-inhibiting IgG autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65) are a hallmark of SPS, implicating an autoimmune component in the pathology of the syndrome. Studying the B cell compartment and the anti-GAD65 B cell response in two monozygotic twins suffering from SPS, who were treated with the B cell-depleting monoclonal anti-CD20 antibody rituximab, we found that the humoral autoimmune response in SPS is composed of a rituximab-sensitive part that is rapidly cleared after treatment, and a rituximab-resistant component, which persists and acts as a reservoir for autoantibodies inhibiting GAD65 enzyme activity. Our data show that these potentially pathogenic anti-GAD65 autoantibodies are secreted by long-lived plasma cells, which may either be persistent or develop from rituximab-resistant memory B lymphocytes. Both subsets represent only a fraction of anti-GAD65 autoantibody secreting cells. Therefore, the identification and targeting of this compartment is a key factor for successful treatment planning of SPS and of similar autoimmune diseases.
AuthorsMarta Rizzi, Rolf Knoth, Christiane S Hampe, Peter Lorenz, Marie-Lise Gougeon, Brigitte Lemercier, Nils Venhoff, Francesca Ferrera, Ulrich Salzer, Hans-Jürgen Thiesen, Hans-Hartmut Peter, Ulrich A Walker, Hermann Eibel
JournalPloS one (PLoS One) Vol. 5 Issue 5 Pg. e10838 (May 26 2010) ISSN: 1932-6203 [Electronic] United States
PMID20520773 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20
  • Autoantibodies
  • Complementarity Determining Regions
  • Epitopes
  • Immunoglobulin G
  • Receptors, Antigen, B-Cell
  • Rituximab
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2
Topics
  • Animals
  • Antibodies, Monoclonal (pharmacology, therapeutic use)
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD20 (immunology)
  • Autoantibodies (immunology)
  • Brain (drug effects, immunology, pathology)
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Clone Cells
  • Complementarity Determining Regions (immunology)
  • Epitopes (immunology)
  • Glutamate Decarboxylase (immunology)
  • Humans
  • Immunoglobulin G (immunology)
  • Immunologic Memory (drug effects, immunology)
  • Lymphocyte Depletion
  • Mice
  • Plasma Cells (drug effects, enzymology, immunology, pathology)
  • Receptors, Antigen, B-Cell (immunology)
  • Rituximab
  • Stiff-Person Syndrome (drug therapy, immunology, pathology)
  • Time Factors

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