Modulation of the immune response in pristane-induced lupus by expression of activation and inhibitory Fc receptors

Altered homeostasis in Fc gamma receptor (Fc gamma R) expression has been implicated in the induction of both immune complex-mediated glomerulonephritis and autoantibody production in systemic lupus erythematosus. Fc gamma RI and III are required for immune complexes to activate inflammatory cells, thereby inciting tissue injury. In contrast, Fc gamma RIIB functions as a negative regulator of immune complex-mediated inflammation and autoantibody production. We investigated the role of Fc gamma RI/III versus Fc gamma RIIB on pristane-induced lupus in mice. Fc gamma RI/III and Fc gamma RIIB-deficient ((-/-)) and control ((+/+)) BALB/c mice were injected with either pristane or PBS. Proteinuria and glomerular immune deposits were evaluated 9 months after treatment and serial sera were analysed for total IgG levels and lupus-specific autoantibodies. The incidence of nephritis was higher in pristane-treated Fc gamma RIIB-/- mice than pristane-treated Fc gamma RI/III-/- and (+/+) mice. Hypergammaglobulinaemia and spontaneous anti-DNA/chromatin autoantibody production were associated with interleukin (IL)-6 over-expression in Fc gamma RIIB-/- mice and were augmented further by pristane treatment when compared to both Fc gamma RI/III-/- and (+/+) mice. Lack of either Fc gamma RIIB or Fc gamma RI/III had little effect on both anti-nRNP/Sm and anti-Su production induced by pristane. Our results confirm that spontaneous autoimmunity occurs in the absence of Fc gamma RIIB. Moreover, the lupus-like syndrome induced by pristane in BALB/c mice was regulated by opposing activating and inhibitory Fc gamma Rs. Activating Fc gamma Rs were required for significant proteinuria and unbridled activation in the absence of Fc gamma RIIB dramatically exacerbated glomerular inflammatory responses. Fc gamma RIIB may be a key modulator that suppresses cell activation in the inflammatory immune response in systemic lupus erythematosus in humans.