Figure 2

Self-sustaining and amplifying feedback loops of NETosis and subsequent humoral response. Enhanced neutrophil activation and the accumulation of neutrophil extracellular traps (NETs) characterize several autoimmune diseases. NETs are a source of diverse antigens that include myeloperoxidase, proteinase 3, human neutrophil peptide (HNP), the chemotactic peptide LL37, ribonucleoproteins, citrullinated residues, various nuclear proteins as well as DNA itself. Owing to the adjuvant effect of NET-associated signals such as the high mobility group box 1 protein, autoantigens are productively processed by dendritic cells (DC) and presented to T cells that undergo productive activation and favor the production of autoantibodies upon clonal expansion, proliferation and differentiation of antigen-specific B lymphocytes. Recognition of nucleic acids by plasmacytoid dendritic cells (pDC) induces the release of interferon alpha (IFNα), which in turn promotes NET generation. Autoantibodies generated against neutrophil nuclear or cytosolic components such as anti-citrullinated peptides (ACPA), anti-ribonuclear protein (aRNP) or anti-neutrophil cytoplasmic antibody (ANCA) antibodies as well as anti-LL37, anti-HNP, anti-DNA and anti-DNAse antibodies promote neutrophil activation and NETosis: (a) by direct interaction with immunoglobulin receptors (FcγR) on the cell membrane, (b) by recognizing their target antigens on the surface of neutrophils and (c) through inhibition of the clearance of NET by macrophages and hindrance with their enzymatic degradation by enzymes such as DNAse. Locally produced soluble pattern recognition receptors, such as pentraxin (PTX)3, could be implicated at various levels. On the other hand, NET-derived nuclear components recognized by macrophage promote the assembly of inflammasomes with eventual extensive release of cytokines such as interleukin (IL)-1β and IL-18. These in turn promote neutrophil activation and the synthesis of innate humoral mediators such as PTX3, which can further affect NET clearance. AAV, ANCA-associated vasculitides; Ab, antibody; Ag, antigen; N, neutrophil; Mϕ, macrophage; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.