A Potential Trigger of Nephritogenic Anti‐DNA Antibodies in Lupus Nephritis

Abstract

Anti-DNA antibodies play an essential role in the pathogenesis of lupus nephritis. Mammalian DNA alone, however, is poorly immunogenic. We speculated that the antigenic trigger for the production of human nephritogenic anti-DNA antibodies is a non-DNA substance. The cDNA library from peripheral blood lymphocytes (PBLs) of a patient with active lupus nephritis was screened using the single-chain Fv of a human monoclonal nephritogenic O-81 anti-DNA antibody in a two-hybrid system. A clone containing the gene of an endoplasmic reticulum (ER) stress-inducible protein, Herp, was obtained: The O-81 antibody bound to recombinant Herp protein synthesized by Escherichia coli. Immunization with Herp elicited both anti-double-stranded DNA (anti-dsDNA) and anti-single-stranded (anti-ssDNA) antibodies in BALB/c mice and formed deposits of IgG in renal glomeruli. Anti-DNA antibodies purified from SLE sera bound to Herp. Moreover, anti-Herp antibodies showed specific binding to DNA. Herp was spontaneously expressed in PBLs of patients with active SLE, but not in PBLs of healthy subjects. These results imply that an inducible intracellular self-protein represents a candidate trigger for human nephritogenic anti-DNA autoantibodies. Any cell stress causing ER stress, such as viral infection, ultraviolet radiation, and chemicals, might be responsible for anti-DNA antibody production via Herp.

Clinical immunology Relationship between hypoalbuminemia, hyperlipidemia and renal severity in patients with lupus nephritis: a prospective study

“…Lupus nephritis (LN) is manifested in about 40-90% of all systemic lupus erythematosus (SLE) patients, and is associated with significant morbidity and a poor prognosis [ 1 , 2 ]. Double-stranded DNA (dsDNA), nucleosome, histone, as well as more complex antigenic structures resulting from the assembly of histone and non-histone proteins with DNA [ 3 ] are recognized by both cellular and humoral constituents of the immune system in SLE patients with and without LN [ 4 – 6 ]. In active lupus renal disease, both the classic and the alternate pathways of the complement cascade are activated, and serum levels of C3 and C4 are often depressed [ 7 , 8 ].…”

Series test of cluster and network analysis for lupus nephritis, before and after IFN‐K‐immunosuppressive therapy

“…DERL3 was an important gene involved in protein processing in endoplasmic reticulum and ER‐associated protein catabolic process. Hirabayashi et al found that viral infection, chemicals, ultraviolet radiation and other cell stress could induce ER stress, and effect nephritogenic anti‐DNA antibodies, which was important in pathogenesis of LN. Collectively, VIMP participated in pathogenesis of lupus nephritis by being involved in inflammation processes and endoplasmic reticulum protein.…”

Anti-dsDNA antibodies induce inflammation via endoplasmic reticulum stress in human mesangial cells

“…The role of ER stress in lupus nephritis (LN) is still not clear. It has been shown that homocysteine-induced ER protein (Herp), an ER stress-inducible protein, was able to bind to anti-dsDNA antibodies [31], and was a potential triggering antigen for anti-DNA response [32], implying that anti-dsDNA antibodies have a functional connection with ER stress in the pathogenesis of LN. In this study, we found that stimulation of HMCs with anti-dsDNA antibodies resulted in significantly increased expression of GRP78 and increased expression of inflammatory cytokines IL-1β, MCP-1 and TNF-α.…”