New insights into immune mechanisms of antiperlecan/LG3 antibody production: Importance of T cells and innate B1 cells.

Abstract

Autoantibodies against perlecan/LG3 (anti‐LG3) have been associated with increased risks of delayed graft function, acute rejection, and reduced long‐term survival. High titers of anti‐LG3 antibodies have been found in de novo renal transplants recipients in the absence of allosensitizing or autoimmune conditions. Here, we seek to understand the pathways controlling anti‐LG3 production prior to transplantation. Mice immunized with recombinant LG3 produce concomitantly IgM and IgG anti‐LG3 antibodies suggesting a memory response. ELISpot confirmed the presence of LG3‐specific memory B cells in nonimmunized mice. Purification of B1 and B2 subtypes identified peritoneal B1 cells as the major source of memory B cells reactive to LG3. Although nonimmunized CD4‐deficient mice were found to express LG3‐specific memory B cells, depletion of CD4+ T cells in wild type mice during immunization significantly decreased anti‐LG3 production. These results demonstrate that B cell memory to LG3 is T cell independent but that production of anti‐LG3 antibodies requires T cell help. Further supporting an important role for T cells in controlling anti‐LG3 levels, we found that human renal transplant recipients show a significant decrease in anti‐LG3 titers upon the initiation of CNI‐based immunosuppression. Collectively, these results identify T cell targeting interventions as a means of reducing anti‐LG3 levels in renal transplant patients.