The pathogenesis of lupus nephritis

Abstract

Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-α signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies.

Figure 1.

Pathomechanisms of LN outside the kidney. (A) Genetic variants of homeostatic cell death (i.e., Fas variants) and the rapid clearance of dead cell corpses (e.g., C3/4 variants or DNAses variants) result either in secondary necrosis or incomplete chromatin digestion, which both promote the exposure of nuclear particles to the immune system. (B) Nuclear particles resemble viral particles and activate the same viral nucleic acid recognition receptors on antigen-presenting cells. Genetic variants of those signaling elements are recognized to be risk factors for SLE. The activation of antigen-presenting cells changes (by costimulation) the immune interpretation of concomitantly presented antigens of the same particle. (C) Polyclonal lymphocyte expansion has multiple effects on the disease process and genetic variants further affect the differentiation of T helper cells. The complex regulation of lymphocyte activation and expansion is affected by multiple genetic variants. The susceptibility genes and genes/molecules that are involved within each biologic pathway are listed to the right: C1q, C2, C4A/B, C-reactive protein (CRP), α-glucoside transporter 5 (ATG5), three prime repair exonuclease 1 (TREX1), B cell CLL/lymphoma 2 (Bcl-2), IL-2 receptor α (IL-2Rα), tyrosine-protein kinase receptor 3 (TYRO3), mast/stem cell growth factor (MGF), Fcγ receptor (FcGR), HLA IL-1 receptor–associated kinase (HLA IRAK), IFN regulatory factor (IRF), signal transducer and activator of transcription (STAT), integrin αM (ITGAM), TNF α-induced protein 3 (TNFAIP3), zinc finger protein 36 (Zfp-36), IL-4, IFN-γ, MHCI, MHCII, TNF, TLR7, single Ig and Toll-IL 1 receptor (SIGIRR), B cell scaffold protein with ankyrin repeats 1 (BANK1), B lymphoid tyrosine kinase (BLK), IKAROS family zinc finger 1 (IKZF1), protein tyrosine phosphatase, nonreceptor type 22 (PTPN22), pituitary tumor-transforming 1 (PTTG1), RAS guanyl releasing protein 3 (RASGRP3), TNF (ligand) superfamily, member 4 (TNFSF4), TNFAIP3-interacting protein 1 (TNIP1), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), BAFF/BLyS, cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1/PDCD-1), and Gadd45 (activated by the stress-inducible GADD45).

Figure 2.

Therapeutic targets for LN. Aberrant immunity in SLE involves many different cell types and cytokine mediators, which could be suitable therapeutic targets. MCP-1, monocyte chemotactic protein-1; CCR, CC chemokine receptor; CXCR, C-X-C chemokine receptor.