Abstract
Circulating autoantibodies of IgG2 isotype predominate in Systemic Lupus Erythematosus (SLE) and concur to the development of the renal lesions characteristic of Lupus Nephritis (LN). Anti-dsDNA and anti-histones IgG2, together with anti-podocyte proteins (i.e., α-enolase) are the major autoantibodies in serum and renal glomeruli of LN patients. The mechanisms underlying autoantibody formation and isotype switching in SLE and LN are unknown. A major issue is how DNA/histones are externalized from cell nucleus, driving the autoimmune response. Neutrophil Extracellular Traps (NETs) have been recently identified as crucial players in this context, representing the main source of DNA and nucleosome proteins. A second key point is what regulates IgG2 isotype switching: in mouse models, T-bet transcription factor has been described as essential for IgG2a class switch. We hypothesized that, in SLE, NET formation is the key mechanism responsible for externalization of autoantigens (i.e., dsDNA, histones 2,3, and α-enolase) and that T-bet is upregulated by NETs, driving, in this way, immunoglobulin class switch recombination (CSR), with production of IgG2 autoantibodies. The data here presented show that NETs, purified from SLE patients, stimulate ex vivo IgG2 isotype class switch possibly through the induction of T-bet. Of note, we observed a prominent effect of NETs on the release of soluble IgG2 in SLE patients', but not in healthy donors' B cells. Our results add important knowledge on the mechanisms of IgG2 class switch in SLE and contribute to further elucidate the role of NETs in LN pathogenesis.
Highlights
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by heterogeneous clinical manifestations, varying from minimal symptoms, such as fever and small joint pain, to severe organ lesions [1]
We did not detect a significant increase in IgG2 production by normal naïve B cells, following Neutrophil Extracellular Traps (NETs) exposition: the ability of Lupus Nephritis (LN)-NET to raise soluble IgG2 levels appears to be specific for SLE B cells, By analyzing the responsiveness of individual patients, we did not observe a significant correlation with disease severity on IgG2 induction by LN-NET (Supplementary Table 1): for this reason, it is conceivable that LN-NETs exert a pathogenic function in the early phases of autoimmunity, irrespectively of the disease evolution
The first finding of this study is the significant increase in IgG2 production, observed in enriched naïve B cells, stimulated with NETs: this effect is selective for IgG2, since other immunoglobulin isotypes are not significantly altered in the same experimental conditions; it is specific for SLE, as B cells, isolated from normal donors, are unresponsive to NET stimulation
Summary
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by heterogeneous clinical manifestations, varying from minimal symptoms, such as fever and small joint pain, to severe organ lesions [1]. The analysis of potentially pathogenic antibodies, micro-eluted from glomeruli, has been completed; beside confirming the glomerular localization of anti-dsDNA, anti-histones (H2A, H3, H4) and anti-C1q antibodies [11], the presence of antibodies against two cytoplasmic proteins, i.e., anti-α enolase and antiAnnexinA1 [12], characterized by the prevalence of IgG2 isotype [13, 14], was shown. For their predominance, IgG2 autoantibodies have been defined as “nephritogenic”
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