IgA Triggers Cell Death of Neutrophils When Primed by Inflammatory Mediators

Abstract

IVIG preparations consisting of pooled IgG are increasingly used for the treatment of autoimmune diseases. IVIG is known to regulate the viability of immune cells, including neutrophils. We report that plasma-derived IgA efficiently triggers death of neutrophils primed by cytokines or TLR agonists. IgA-mediated programmed neutrophil death was PI3K-, p38 MAPK–, and JNK-dependent and evoked anti-inflammatory cytokines in macrophage cocultures. Neutrophils from patients with acute Crohn's disease, rheumatoid arthritis, or sepsis were susceptible to both IgA- and IVIG-mediated death. In contrast to IVIG, IgA did not promote cell death of quiescent neutrophils. Our findings suggest that plasma-derived IgA might provide a therapeutic option for the treatment of neutrophil-associated inflammatory disorders.

Antibody diversity in IVIG: Therapeutic opportunities for novel immunotherapeutic drugs

“…Serum monomeric IgA exhibits anti-inflammatory properties ( 86 – 88 ), and IgA ( 89 ), or FcαRI targeting by monoclonal antibodies ( 90 ), has been shown to regulate the lifespan in particular of activated neutrophils. It remains to be shown if plasma-derived polyclonal IgA preparations might have therapeutic use for the treatment of inflammatory or autoimmune disorders.…”

The neutrophil: A key resourceful agent in immune‐mediated vasculitis

“…Because FcαRI‐mediated cross‐linking of neutrophils in vitro induces inflammatory processes such as ROS production and the release of NETs and leukotriene B4, 71,72 it is hypothesized that FcαRI‐mediated activation of neutrophils results in vessel damage and leakage of red blood cells into the skin, causing typical cutaneous hemorrhage. More recently, IgA was shown to trigger neutrophil death when primed with inflammatory mediators in phosphoinositide 3‐kinase (PI3K)‐, p38 mitogen‐activated protein kinase (MAPK)‐, and c‐Jun N‐terminal kinase (JNK)‐dependent pathways 73 …”

“…More recently, IgA was shown to trigger neutrophil death when primed with inflammatory mediators in phosphoinositide 3-kinase (PI3K)-, p38 mitogen-activated protein kinase (MAPK)-, and c-Jun N-terminal kinase (JNK)-dependent pathways. 73 FcαRI (CD89) has been shown to be lower in the urine of children with active IgAV, suggesting that the deposits remain in the kidneys and are not excreted. 74,75 In skin biopsies of patients with IC-SVV such as IgAV, NETs were present in the early stages of the disease and were significantly more abundant than in patients with urticarial vasculitis.…”

IgA and FcαRI: Versatile Players in Homeostasis, Infection, and Autoimmunity

“…33,34 Upregulation of FcαRI on neutrophils occurs rapidly by either transport from an intracellular pool to the cell surface or via de novo synthesis and is induced by N-formylmethionyl-leucyl-phenylalanine (fMLP), interleukin (IL)-8, tumor necrosis factor-alpha (TNF-α), LPS, and granulocyte-macrophage colony-stimulating factor (GM-CSF). [35][36][37][38] On monocytes and monocyte-like cell lines FcαRI expression was enhanced by calcitriol, LPS, TNFα, GM-CSF, and IL-1β. 39,40 Downregulation occurs in the presence of transforming growth factor-β (TGF-β), interferon-γ (IFN-γ), or by ligand binding due to FcαRI aggregation and internalization.…”