How anti-neutrophil cytoplasmic autoantibodies activate neutrophils

Abstract

Neutrophils are pivotal to host defence during infectious diseases. However, activated neutrophils may also cause undesired tissue damage. Ample examples include small-vessel inflammatory diseases (vasculitis) that are associated with anti-neutrophil cytoplasmic autoantibodies (ANCA) residing in the patients' plasma. In addition to being an important diagnostic tool, convincing evidence shows that ANCA are pathogenic. ANCA-neutrophil interactions induce important cellular responses that result in highly inflammatory necrotizing vascular damage. The interaction begins with ANCA binding to their target antigens on primed neutrophils, proceeds by recruiting transmembrane molecules to initiate intracellular signal transduction and culminates in activation of effector functions that ultimately mediate the tissue damage.

Fig. 1

Anti-neutrophil cytoplasmic autoantibodies (ANCA) antigen expression. Myeloperoxidase (MPO) and proteinase 3 (PR3) are expressed by neutrophils and monocytes only, whereas lysosomal-associated membrane protein 2 (LAMP-2) is also found in endothelial cells. PR3 has a bimodal expression pattern on the neutrophil membrane in that a mPR3^low- and mPR3^high-expressing subset can be distinguished.

Fig. 2

Neutrophil antigen B1 (NB1) is a receptor for proteinase 3 (PR3) presentation on the neutrophil membrane. (a) A mPR3^high/NB1^positive and a mPR3^low/NB1^negative neutrophil subset exist. (b) PR3 and NB1 are part of a larger signalling complex in the lipid rafts. The transmembrane β2-integrin Mac-1 is part of this complex and mediates PR3–anti-neutrophil cytoplasmic autoantibodies (ANCA)-induced neutrophil activation.

Fig. 3

Anti-neutrophil cytoplasmic autoantibodies (ANCA)-induced neutrophil activation is controlled by intracellular signalling pathways. phosphatidylinositol 3-kinase γ (PI3Kγ) is depicted as an example for a signal molecule that was characterized as a key molecule for ANCA-induced neutrophil activation. PI3Kγ can be targeted therapeutically to prevent necrotizing crescentic glomerulonephritis (NCGN).