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The acute phase protein caeruloplasmin consistently co-purified with circulating anti-MPO antibodies when plasma from both patients and healthy controls underwent affinity chromatography over either native or recombinant human MPO. Caeruloplasmin inhibited MPO enzymatic activity in both a dose- and time-dependent manner, suggesting an <I>in vivo</I> role as a physiological inhibitor of MPO. Affinity-purified anti-MPO antibodies from patients with active renal vasculitis inhibited the binding between MPO and caeruloplasmin, correlating with a reversal of the caeruloplasmin-mediated inhibition of MPO activity. The affinity of the interaction between MPO and anti-MPO antibodies was shown to be higher than that between MPO and caeruloplasmin, indicating that binding to the autoantibody would be favoured <I>in vivo</I>. Studies using patient sera confirmed preferential binding of MPO to anti-MPO antibodies compared to caeruloplasmin. Compared to healthy controls and patients with active anti-MPO vasculitis, free MPO and MPO-caeruloplasmin complexes were found to be elevated in the sera of patients with an acute inflammatory response, whereas MPO-ANCA complexes were elevated only in the patients with vasculitis. There was a trend for lower relative caeruloplasmin activity in the patients with vasculitis. The results contribute to current understanding of the mechanism of inhibition of MPO activity in neutrophil-mediated inflammation, and how this might be disturbed in the presence of anti-MPO antibodies. The reduction in hydrogen peroxide-mediated cell permeabilisation in the presence of MPO suggests that the mechanism of action of MPO in host inflammation is other than by an immediate increase in cell death.

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