Idiotypic spreading promotes the production of pathogenic autoantibodies.
We propose that a major immunoregulatory abnormality in murine and human autoantibody-mediated disease is idiotypic spreading. By this mechanism, B cells with the genetic information to produce immunoglobulin (Ig) bearing certain public idiotypes (Ids) are selectively upregulated, probably by Id-recognizing helper T cells. The model in which we are testing the hypothesis is systemic lupus erythematosus (SLE) in humans and NZB/NZW F1 (BW) female mice. Recent experiments have shown that the number of public Ids expressed on the Ig of nephritic BW mice is quite restricted. IdX is the dominant Id on serum Ig; IdGN1 and IdGN2 are also common. All three Ids were initially derived from spontaneous antibodies to DNA. Together the three are present on 85% of the total Ig repertoire. Such restriction suggests idiotypic spreading. In glomerular Ig deposits from nephritic BW mice, IdGN1 and IdGN2 are found on 45% of the total Ig: IdX is present in minute amounts. Furthermore, suppression of IdGNs by administration of anti-IdGN1 to BW mice resulted in significant delay in the onset of nephritis, but the IdGNs escaped from control and eventually caused a fatal nephritis. Finally, studies of glomerular Ig deposits in renal biopsies of patients with SLE have shown that IdGN2 dominates such Ig, being present in 76% of renal biopsies from SLE patients and in 6% from patients with non-lupus immune nephritis. Therefore, we have concluded that IdGN1 and IdGN2 are markers of nephritogenic subsets of autoantibodies and are probably the products of idiotypic spreading most likely to cause disease. Finally, after a review of recent experiments suggesting the dominance of autoreactive, Mossman Type 2 T helper cells in nephritic BW mice, it is hypothesized that autoreactive, IdGN-recognizing helper T cells may be central to the sustained upregulation of pathogenic autoantibodies in murine and human SLE.
Ebling
F M
FM
Department of Medicine, University of California, Los Angeles 90024-1670.
Ando
D G
DG
Panosian-Sahakian
N
N
Kalunian
K C
KC
Hahn
B H
BH
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001327:Autoimmune Diseases / Q000276:immunology; D003429:Cross Reactions; D006801:Humans; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D007130:Immunoglobulin Idiotypes