Long-lived plasma cells and memory B cells produce pathogenic anti-GAD65 autoantibodies in Stiff Person Syndrome.
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.
Rizzi
Marta
M
Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany.
Knoth
Rolf
R
Hampe
Christiane S
CS
Lorenz
Peter
P
Gougeon
Marie-Lise
ML
Lemercier
Brigitte
B
Venhoff
Nils
N
Ferrera
Francesca
F
Salzer
Ulrich
U
Thiesen
Hans-Jürgen
HJ
Peter
Hans-Hartmut
HH
Walker
Ulrich A
UA
Eibel
Hermann
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D010950:Plasma Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D000069283:Rituximab; D016750:Stiff-Person Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D001323:Autoantibodies; D022801:Complementarity Determining Regions; D000939:Epitopes; D007074:Immunoglobulin G; D011947:Receptors, Antigen, B-Cell; D000069283:Rituximab; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2