Decipher the Immunopathological Mechanisms and Set Up Potential Therapeutic Strategies for Patients with Lupus Nephritis

Abstract

Lupus nephritis (LN) is one of the most severe complications in patients with systemic lupus erythematosus (SLE). Traditionally, LN is regarded as an immune complex (IC) deposition disease led by dsDNA–anti-dsDNA-complement interactions in the subendothelial and/or subepithelial basement membrane of glomeruli to cause inflammation. The activated complements in the IC act as chemoattractants to chemically attract both innate and adaptive immune cells to the kidney tissues, causing inflammatory reactions. However, recent investigations have unveiled that not only the infiltrating immune-related cells, but resident kidney cells, including glomerular mesangial cells, podocytes, macrophage-like cells, tubular epithelial cells and endothelial cells, may also actively participate in the inflammatory and immunological reactions in the kidney. Furthermore, the adaptive immune cells that are infiltrated are genetically restricted to autoimmune predilection. The autoantibodies commonly found in SLE, including anti-dsDNA, are cross-reacting with not only a broad spectrum of chromatin substances, but also extracellular matrix components, including α-actinin, annexin II, laminin, collagen III and IV, and heparan sulfate proteoglycan. Besides, the glycosylation on the Fab portion of IgG anti-dsDNA antibodies can also affect the pathogenic properties of the autoantibodies in that α-2,6-sialylation alleviates, whereas fucosylation aggravates their nephritogenic activity. Some of the coexisting autoantibodies, including anti-cardiolipin, anti-C1q, anti-ribosomal P autoantibodies, may also enhance the pathogenic role of anti-dsDNA antibodies. In clinical practice, the identification of useful biomarkers for diagnosing, monitoring, and following up on LN is quite important for its treatments. The development of a more specific therapeutic strategy to target the pathogenic factors of LN is also critical. We will discuss these issues in detail in the present article.

Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy

“…The pathogenesis of LN is not completely understood, but the prevailing view is that LN is characterized by the deposition of immune complexes (IC) formed by various autoantibodies, such as anti-double-stranded DNA (ds-DNA) antibodies and antigens. Infiltration of inflammatory cells occurs, with podocytes being one of the primary targets of IC attacks (121). Anti-dsDNA antibodies can recognize various DNA structures and also crossreact with various non-DNA molecules present in the renal matrix or on the surfaces of endogenous renal cells, such as a-actinin, annexin II, collagen III/IV, and others (122)(123)(124).…”

Lupus Nephritis Risk Factors and Biomarkers: An Update

“…Glomerular deposition of extra-renal immune complexes containing RNA/DNA nucleic acids and activation of the complement system was initially proposed as the main mechanism leading to LN [94,95]. In this process, activation of the classical complement pathway leads to the release of anaphylatoxin (C3a, C5a) that act as chemoattractants to innate and acquired immune cells causing inflammatory mediator release, such as type I IFN, which amplify glomerular lesions.…”