Shared idiotypy among patients with myeloperoxidase-anti-neutrophil cytoplasmic autoantibody associated glomerulonephritis and vasculitis

Anti-neutrophil cytoplasmic autoantibodies (ANCA) have been hypothesized to participate in the pathogenesis of necrotizing vasculitis based on their association with small vessel vasculitides and the in vitro ability of such antibodies to activate cytokine-primed neutrophils. Much remains to be elucidated about the factors responsible for the generation and perpetuation of these autoantibodies and the shaping of the ANCA immune response. This study evaluated the clonal diversity of the ANCA immune response in patients with myeloperoxidase-ANCA associated disease. Isoelectric focusing was used to investigate the clonality of myeloperoxidase-ANCA from 34 patients with pauci-immune necrotizing glomerulonephritis. Sixty-nine percent of the patients had two or less clonotypes to myeloperoxidase, whereas 31% had more than two clonotypes. Clonality was stable over the course of the disease and shared among some unrelated patients. Shared idiotypy was specifically investigated using a murine monoclonal anti-idiotype (7F2C11) to the anti- myeloperoxidase antibodies of one patient with ANCA associated vasculitis. This monoclonal antibody was selected by demonstrating: (1) binding to the proband's affinity purified anti-myeloperoxidase antibodies; (2) an inhibitory effect on the binding of the proband's anti-myeloperoxidase to myeloperoxidase; and (3) lack of binding to control human antibody preparations, or to the proband's crude immunoglobulin preparation, thus excluding an anti-allotype antibody. Purified 7F2C11 was immobilized on Sepharose, and this monoclonal anti-idiotype affinity column was used to search for a shared anti-myeloperoxidase idiotype in the plasma of four other patients with myeloperoxidase-ANCA associated disease. Using this column, we were able to extract anti myeloperoxidase antibodies from plasma of the other patients but not from control antibody preparations. We concluded that most myeloperoxidase-ANCA patients have a restricted response to myeloperoxidase and that some patients share a common idiotype. The demonstration of shared idiotypy suggests a restricted number of autoreactive epitopes of the myeloperoxidase molecule, or that some anti-myeloperoxidase autoantibodies are encoded by germ line genes, or both.