Deposition of nucleosomal antigens (histones and DNA) in the epidermal basement membrane in human lupus nephritis

Abstract

Objective. Antinuclear autoantibodies complexed to nucleosomes can bind to heparan sulfate (HS) in the glomerular basement membrane. This binding is due to the binding of the positively charged histones to the strongly anionic HS. Nucleosomes and histones have been identified in glomerular deposits in human lupus nephritis. We investigated whether nucleosomes are present in the basement membrane of nonlesional skin of lupus patients.Methods. Skin biopsy samples from patients with systemic lupus erythematosus (SLE) (30 with active lupus nephritis and 15 with inactive disease) and controls (with parapemphigus or diabetes) were stained for IgG, histones, DNA, and nucleosomes.Results. IgG deposits were found in 87% of the patients with lupus nephritis, in 33% of the patients with inactive disease, and in 71% of the parapemphigus patients. Using polyclonal antihistone antibodies, histones were detected in 87% of lupus nephritis patients, but in none of the other SLE patients or the diabetes controls (P < 0.0001). Among the parapemphigus controls, 14% of samples stained positive in one of the polyclonal antihistone stainings (P < 0.0001). Using monoclonal antibodies, histones and DNA were identified in 21% of the lupus nephritis patients. Although none of the other groups showed positive staining for nucleosomes, 7% of the lupus nephritis biopsy samples were positive using antinucleosome monoclonal antibodies. Colocalization of nucleosomal antigens and IgG was confirmed using confocal laser microscopy.Conclusion. These findings suggest that nucleosome-mediated binding of autoantibodies to basement membranes may also occur at sites in the body other than in the glomerulus.

Nephritogenic Lupus Antibodies Recognize Glomerular Basement Membrane-Associated Chromatin Fragments Released from Apoptotic Intraglomerular Cells

“…Because antibodies eluted from nephritic B/W kidneys 30 and experimental antibodies generated in different species all recognize components of nucleosomes and stain EDDs, the nature of such EDDs is most likely reflecting released chromatin fragments complexed in vivo with autoantibodies. Similar mechanisms may be operational for binding of autoantibodies in other basement membranes, as indicated by Grootscholten et al 44 Early electron microscopy studies on lupus nephritic kidneys revealed the presence of EDDs associated with GBMs, 27 and correlation between EDDs and the clinical course of lupus nephritis has been reported. [27][28][29] These deposits have been assumed to contain chromatin constituents and could therefore represent target structures for pathogenic anti-dsDNA antibodies (Refs.…”

IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: A possible new treatment?

“…It is well established that ICs are involved in many of the disease manifestations of SLE, including nephritis (3,5), pleuritis (6), vasculitis (7), skin and CNS involvement (8)(9)(10), and thrombosis (11,12). Deposited IgG or ICs cause local inflammation by activation of the classical pathway of complement with recruitment of PMNs, which could contribute to tissue destruction.…”

“…ICs may also activate PMNs and induce oxidative burst (4). Many of the disease manifestations of SLE, including nephritis (3,5), pleuritis (6), vasculitis (7), and skin and central nervous system (CNS) involvement (8)(9)(10) are most likely IC mediated. Furthermore, autoantibodies against phospholipids are associated with the development of thrombosis (11,12).…”

Complement C3a, CpG Oligos, and DNA/C3a Complex Stimulate IFN-α Production in a Receptor for Advanced Glycation End Product-Dependent Manner

“…Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, characterized by autoantibodies and systemic clinical manifestations (9). Abnormalities in apoptosis lead to the release of DAMPs and nuclear components that stimulate the immune system to produce autoantibodies including anti-DNA Abs, activate the complement system, and damage tissues (10)(11)(12)(13)(14)(15). This process initiates a pathogenic cycle in which both the adaptive and the innate immune system collaborate to advance the disease.…”