B7x modulates the adaptive immune response and diminishes renal injury in murine antibody mediated nephritis (P5168)

Abstract

Abstract B7x (B7-H4, B7S1), a member of the B7/CD28 co-stimulatory superfamily, is an inhibitor of T cell activation and proliferation. B7x is highly expressed in peripheral, non-lymphoid tissues. However, the in vivo function of B7x is largely unknown. We hypothesized that B7x may modulate the pathogenesis of antibody mediated nephritis through its effects on T cells. We induced nephritis in B7x-deficient (B7x-/-) (n=10) and B7x-wild type (WT) B6 mice (n=10) pre-immunized with rabbit IgG by intravenous injection of nephrotoxic sera (rabbit anti-mouse glomerular antibodies). Following nephritis induction we observed a significant increase in the levels of serum IgG, particularly of the IgG2b and IgG1 isotype, in B7x-/- mice as compared to B7x WT mice. At the mRNA level, IL-23, CCL2 and CCR5 were significantly upregulated in B7x-/- kidney tissue. Immunohistochemistry revealed significantly increased glomerular infiltration of CD3+ T cells and CD68+ macrophages in B7x-/- kidneys. Furthermore, kidney histopathology was more severe in B7x-/- mice, in terms of infiltrating polymorphonuclear cells in both glomerular and interstitial compartments, crescent formation, and tubular atrophy/dilatation, as compared to B7x WT mice. In conclusion, B7x plays a protective role in immune mediated nephritis, likely through exerting an inhibitory effect on T cell activation and restricting the migration of immune cells. Our results indicate a potential role for modulation of the B7x pathway for the treatment of nephritis mediated by pathogenic antibodies, including anti-glomerular basement membrane disease (Goodpasture’s syndrome), lupus nephritis, and related conditions.