Identification of major plasma PAF acetylhydrolase and study on its gene mutation as a risk factor in allergic diseases.

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Platelet-activation factor (RAF) acetylhydrolase (PAF-AH) catalyzes the hydrolysis of the acetyl ester bond at the sn-2 position of PAF to yield biologically inactive lyso-PAF. Serum/plasma PAF-AH is considered to be indispensable for control of the level of circulating PAF, which exhibits a wide spectrum of biological activity at very low concentrations (in the range of 10ィイD1-10ィエD1 to 10ィイD1-11ィエD1 M) in diverse pathophysiological processes. We have found Japanese subjects with PAF-AH deficiency, and have reported that the deficiency or low activity of serum PAF-AH appears to cause more severe symptoms. Whereas Tjoelker et al. have cloned the plasma PAF-AH (46 kDa) cDNA, we purified major plasma PAF-AH enzyme consisting of a 34 kDa protein and about 9 kDa asparagine-conjugated sugar chain(s) from 301 human plasma (Ref. 2). We are in the process of determining the NHィイD22ィエD2 terminus of major PAFA-AH purified from 501 human plasma. Furthermore, we elucidated that the PAF-AH (46 kDa) gene mutation is likely to have a disease relapse in Japanese childhood steroid-responsive nephrotic syndrome (Ref. 3) and cause more severe symptoms in Japanese childhood IgA nephropathy (Ref. 5). Additional experiments, that isolated LDL from the PAF-AH-deficient subjects was more susceptible to oxidation and stimulated adhesion molecule synthesis in endothelial cells (Refs. 4, 6 and 9), indicated that the PAF-AH gene mutation is considered to be become a risk factor in the development of atherosclerotic disease in Japan.