Anti-P autoantibody production requires P1/P2 as immunogens but is not driven by exogenous self-antigen in MRL mice

Considerable evidence supports the idea that autoantibody production in human and murine SLE is Ag driven. To determine whether Ag (the ribosomal P proteins) could initiate autoantibody production in lupus mice, 34 MRL/lpr mice were immunized with mouse riboosomal proteins in Freund's adjuvant. Neither intact ribosomes, denatured total mouse ribosomal proteins, nor the purified mouse ribosomal proteins, P1 and P2, induced the production of anti-P autoantibodies in the MRL/lpr mice. In contrast to these negative findings, MRL/lpr mice immunized with Artemia salina ribosomes produced anti-P antibodies as well as anti-P autoantibodies. Although the induced anti-P autoantibodies bound exclusively to the carboxyl terminus, these anti-P antibodies differed from spontaneously occurring anti-P autoantibodies in their predominant binding to mouse P0 on immunoblots and their preferential reactivity against A. salina synthetic peptides by ELISA. Induction of anti-P antibodies required the presence of P1 and P2 on the ribosome because ribosomal cores devoid of P1 and P2 dimers did not induce anti-P. Despite the presence of approximately 80 ribosomal proteins, autoantibodies to other mouse ribosomal proteins were rarely observed. Immunization of MRL/+ mice and a normal H-2-matched strain of mice, C3H, also resulted in anti-P antibodies reactive with the A. salina P proteins and mouse P0. Whereas anti-P levels gradually declined in C3H mice, anti-P levels either remained elevated (MRL/lpr) or showed a secondary rise (MRL/+) at the onset of autoimmunity. These observations indicate that: i) high levels of autologous Ag are not sufficient to drive antiribosomal autoantibody production in MRL mice, ii) multivalency of the P proteins may explain their potent immunogenicity and ability to break tolerance, and iii) immunized MRL mice show an abnormal persistence of high level anti-P production presumably reflecting T cell activation of presensitized B cells.