Disruption of T cell tolerance by directing a self antigen to macrophage-specific scavenger receptors

Breakdown of immune self tolerance is speculated to cause autoimmune diseases, but most studies on tolerance use foreign molecules as targets. In this study, we show another approach using delivery of a maleylated self protein to macrophage-specific scavenger receptors. Mice generate Abs against the maleylated form of a ubiquitous self Ag, mouse serum albumin (MSA), although native MSA is nonimmunogenic. This generation of anti-maleyl MSA Abs depends on binding of maleyl MSA to scavenger receptors in vivo, since coinjection of a serologically unrelated scavenger receptor ligand inhibits it, suggesting that the Ab response is T cell dependent. Spleen cells as well as nylon adherence-purified splenic T cells from maleyl MSA-immune mice proliferate in response to both maleyl MSA and MSA; this response is blocked by anti-MHC class II mAbs, and the autoimmune cells can recognize at least five 15-mer peptides from the MSA sequence, establishing that T cell tolerance to MSA has been broken in these mice. Maleyl MSA and MSA are recognized equally well, provided the scavenger receptor-specific delivery of maleyl MSA is blocked during stimulation in vitro, indicating that maleyl MSA-specific non-self peptides are unlikely to play a major role in the observed disruption of T cell tolerance. Thus, delivery of some self molecules to scavenger receptors may lead to disruption of immune tolerance. These results are relevant to mechanisms of immune tolerance and the etiopathogenesis of autoimmunity.