Abstract
Anti-double stranded DNA antibodies (anti-dsDNA) are a hallmark of SLE but their role in disease pathogenesis is not fully resolved. Anti-dsDNA in serum are highly heterogeneous therefore in this study, we aimed to dissect the functional specificities of anti-dsDNA using a panel of human monoclonal antibodies (humAbs) generated from patients with active lupus nephritis. A total of 46 ANA reactive humAbs were isolated and divided into four broad classes based on their reactivity to histones, DNA and Crithidia. Functional analysis indicated that one subclass of antibodies bound strongly to decondensed DNA areas in neutrophil extracellular traps (NETs) and protected NETs from nuclease digestion, similar to the sera from active SLE patients. In addition, these anti-dsDNA antibodies could stimulate type I interferon responses in mononuclear phagocytic cells, or NF-kB activity in endothelial cells, by uptake of NETs-anti-NETs immune complexes and subsequently trigging inflammatory responses in an Fc-gamma receptor (Fcg-R)-dependant manner. Together our data suggest that only a subset of anti-dsDNA antibodies is capable to amplify inflammatory responses by deposit in the nephritic kidney in vivo, protecting NETs digestion as well as uptake of NETs immune complexes into Fcg-R-expressing cells in vitro.
Highlights
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease of varying severity, which commonly affects the skin and joints, but can affect a variety of other organ systems
We measured neutrophil extracellular traps (NETs) nuclease-protection activity in polyclonal sera (10% neat serum is diluted in PBS) from a cohort of SLE patient
SLE patient serum (10% serum diluted in PBS) displayed significantly lower NETs digestion than control antinuclear antibodies (ANA)−ve serum in the presence of DNase (Fig. 1a)
Summary
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease of varying severity, which commonly affects the skin and joints, but can affect a variety of other organ systems. Most patients with SLE develop antinuclear antibodies (ANA) directed to a variety of nuclear components. Anti-dsDNA antibodies are highly specific, being found in 68–83% of SLE patients at some time during their illness[1,2,3]. Anti-dsDNA antibodies are associated with active SLE disease and deposit in the kidney of some lupus nephritis (LN) patients, which may contribute to the development of lupus nephritis (LN)[4,5,6,7,8,9,10,11]. NETs are composed of decondensed chromatin and a range of neutrophil granular antimicrobial proteins including myeloperoxidase (MPO), neutrophil elastase (NE), LL37, etc. NETs have an important role during infection as they capture and neutralise pathogens[13,14]. Impairment in the clearance of apoptotic cells and NETosis are believed to be a potential source of autoantigens in SLE, which are proposed to Official journal of the Cell Death Differentiation Association
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