Hattar Katja, Bickenbach Annette, Csernok Elena, Rosseau Simone, Grandel Ulrich, Seeger Werner, Grimminger Friedrich, Sibelius Ulf
Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
J Leukoc Biol. 2002 Jun;71(6):996-1004.
Antineutrophil cytoplasmic antibodies (ANCA) targeting proteinase 3 [PR3; cytoplasmic ANCA (c-ANCA)], a leukocyte serine protease, are highly specific for Wegener's Granulomatosis (WG). A pathogenetic role for c-ANCA has been proposed as a result of their ability of activating neutrophils, whereas their interaction with monocytes is less well characterized. We investigated the influence of monoclonal anti-PR3 antibodies (anti-PR3) and c-ANCA from WG sera on monocyte cytokine and prostanoid release. We found that PR3 was expressed on the surface of isolated monocytes. Anti-PR3 challenge provoked a pronounced release of cytokines with early appearance of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta and delayed release of IL-6, IL-8, and thromboxane A2 (TxA2). The secretory response was reproduced by c-ANCA but not by human and murine control IgG and anti-CD14 antibodies. Because F(ab)2 fragments of anti-PR3 were ineffective, coligation of Fc gamma receptors (FcgammaR) was apparently mandatory for monocyte activation. Using soluble receptors for TNF-alpha and IL-1beta and a Tx receptor antagonist, we noted that the "early" cytokines functioned as inducers of TxA2, which then activated IL-8 release. In contrast, IL-6 formation was an independent event. We concluded that anti-PR3 antibodies are potent inducers of monocyte cytokine and prostanoid release, and TNF-alpha, IL-1beta, and TxA2 function as facilitators of the secretory response. These mechanisms may contribute to inflammatory tissue injury in WG.
靶向蛋白酶3（PR3；胞浆型抗中性粒细胞胞浆抗体[c-ANCA]）的抗中性粒细胞胞浆抗体是一种白细胞丝氨酸蛋白酶，对韦格纳肉芽肿病（WG）具有高度特异性。由于其激活中性粒细胞的能力，有人提出c-ANCA具有致病作用，而它们与单核细胞的相互作用则了解较少。我们研究了单克隆抗PR3抗体（抗PR3）和来自WG血清的c-ANCA对单核细胞细胞因子和前列腺素释放的影响。我们发现PR3在分离的单核细胞表面表达。抗PR3刺激引发细胞因子的显著释放，肿瘤坏死因子α（TNF-α）和白细胞介素（IL）-1β早期出现，IL-6、IL-8和血栓素A2（TxA2）延迟释放。c-ANCA可重现分泌反应，但人和鼠对照IgG及抗CD14抗体则不能。由于抗PR3的F(ab)2片段无效，Fcγ受体（FcgammaR）的共结合显然是单核细胞激活所必需的。使用TNF-α和IL-1β的可溶性受体以及Tx受体拮抗剂，我们注意到“早期”细胞因子作为TxA2的诱导剂，然后激活IL-8释放。相比之下，IL-6的形成是一个独立事件。我们得出结论，抗PR3抗体是单核细胞细胞因子和前列腺素释放的有效诱导剂，TNF-α、IL-1β和TxA2作为分泌反应的促进剂发挥作用。这些机制可能导致WG中的炎症组织损伤。
