Determinants of the fate of B cells producing pathogenic autoantibodies

Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterized by the production of autoantibodies directed against components of the cell nucleus or cytoplasma. A normal, functioning immune system has the ability to distinguish between foreign and self antigens. This process of immune tolerance is developed during B cell differentiation and is breached in autoimmune diseases such as lupus. The nature of abnormalities in B cell function that predispose to the production of autoantibodies are still undefined. To study the possible molecular mechanisms that are directly involved in the process of self-tolerance, the fate of B cells expressing targeted rearranged heavy (H) and light (L) chain genes that encode a pathogenic autoantibody from a hybridoma (564) from the autoimmune (SWRxNZB)F1 mouse (SNF1) was examined in normal and lupus-prone mice. The SNF1 mouse produces a select population of cationic immunoglobulin G (IgG) autoantibodies that share a recurrent crossreactive idiotype called Id564 and these autoantibodies recognize ssRNA, ssDNA, and nucleosomes. These knock-in, antibody-encoding genes were introduced into the Sle congenic strains that contain individual Sle susceptibility loci (Sle1 or Sle2). The effects of these Sle susceptibility loci on the fate of aberrant B cells were examined to determine whether the genes that allow B cells to escape tolerance are associated with these regions of susceptibility and whether these genes are associated with specific mechanisms of tolerance. B cells of 564Igi.Sle1 mice showed a relatively high expression of the 564 idiotype on the surface compared to normal mice, while B cells of 564Igi.Sle2 mice showed less expression of the idiotype. The 564 idiotype and antibodies against ssDNA and histone DNA were detected in the sera of 564Igi.Sle1 mice. Also, surface staining using CD5 and lambda as markers for anergy and receptor editing, respectively, showed low expression of these markers in 564Igi.Sle1 mice, whereas normal mice and 564Igi.Sle2 mice had relatively higher expressions of these markers. These results suggest that central tolerance is compromised in 564Igi.Sle1 mice and intact in the 564Igi.Sle2 mice, supporting that the Sle1 locus is involved in the breakdown of tolerance.