Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG.
We have analyzed the properties of anti-factor VIII (FVIII) immunoglobulin (Ig) G recovered by affinity chromatography on FVIII-Sepharose from the IgG fraction of the plasma of healthy individuals and nonresponder patients with hemophilia A. Affinity-purified anti-FVIII antibodies were found to neutralize FVIII activity and to bind to FVIII with an affinity similar to that of anti-FVIII IgG that had been affinity-purified from the plasma of inhibitor-positive hemophilia patients and of patients with anti-FVIII autoimmune disease. The antibodies also exhibited patterns of reactivity with thrombin-digested FVIII similar to those of FVIII inhibitors and preferentially recognized epitopes located in the light chain of FVIII. These observations suggest that FVIII inhibitors occurring in hemophilia A and in patients with anti-FVIII autoimmune disease originate from the expansion of preexisting natural anti-FVIII clones that exhibit FVIII-neutralizing properties.
Moreau
A
A
INSERM U 430 and Université Pierre et Marie Curie, Hôpital Broussais, Paris, France.
Lacroix-Desmazes
S
S
Stieltjes
N
N
Saenko
E
E
Kaveri
S V
SV
D'Oiron
R
R
Sultan
Y
Y
Scandella
D
D
Kazatchkine
M D
MD
D000906:Antibodies / Q000494:pharmacology*; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000097:blood* / Q000276:immunology; D002846:Chromatography, Affinity; D004797:Enzyme-Linked Immunosorbent Assay; D005169:Factor VIII / Q000276:immunology* / Q000378:metabolism*; D006467:Hemophilia A / Q000097:blood*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood* / Q000302:isolation & purification; D016756:Immunoglobulins, Intravenous; D007518:Isoantibodies / Q000494:pharmacology; D007700:Kinetics; D012016:Reference Values
D000906:Antibodies; D001323:Autoantibodies; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D007518:Isoantibodies; D005169:Factor VIII