Mechanisms of tissue injury in lupus nephritis

Nephritis is a major cause of morbidity and mortality in patients with lupus. Nephritis occurs in approximately 50% of lupus patients, but rates vary significantly between genders (men more than women) and ethnicities (more common in people of color). Men and minorities with lupus nephritis are also more likely to progress to end-stage renal disease than women or people of European ancestry. The multiple factors underlying these demographic differences are unclear at this time [1].The International Society of Nephrology revised the World Health Organization classification of lupus nephritis recently, although maintaining six classes [2]. The pathologic classes vary from mild mesangial involvement (Class I) to diffuse proliferative disease (Class IV) to membranous disease (Class V) to end-stage fibrosis (Class VI). Although most attention in lupus nephritis is focused on glomerular disease, there is also significant tubular disease that impacts prognosis and renal function [3]. For the purposes of the present review, we will primarily focus on the proliferative forms of lupus nephritis (focal proliferative, Class III disease; and diffuse proliferative, Class IV disease), highlighting several contributors to tissue injury.Much of what is known about pathogenic factors in tissue damage in lupus nephritis was derived from studies of murine models of lupus, with confirmation as possible in humans. These studies utilize multigenic models of lupus (that is, MRL/lpr, NZB/NZW, and NZM congenic strains) as well as single gene mutants (that is, DNAse 1, Nrf2, or Fcγ receptor (FCγR) knockouts) [4,5]. These models share common features of human disease such as anti-double-stranded DNA (anti-dsDNA) antibodies and proliferative nephritis, but differ in their renal cytokine/chemokine profile, cellular infiltration and acuity/chronicity of disease [5]. Thus, as in human disease, there is heterogeneity of pathogenic mechanisms in murine lupus nephritis.The presence of autoantibodies