Schwarzer E, Turrini F, Ulliers D, Giribaldi G, Ginsburg H, Arese P
Dipartimento di Genetica, Biologia e Chimica Medica, University of Torino Medical School, Italy.
J Exp Med. 1992 Oct 1;176(4):1033-41. doi: 10.1084/jem.176.4.1033.
Human monocyte-derived macrophages ingest diamide-treated red blood cells (RBC), anti-D immunoglobulin (Ig)G-opsonized RBC, or Plasmodium falciparum ring-stage parasitized RBC (RPRBC), degrade ingested hemoglobin rapidly, and can repeat the phagocytic cycle. Monocytes fed with trophozoite-parasitized RBC (TPRBC), which contain malarial pigment, or fed with isolated pigment are virtually unable to degrade the ingested material and to repeat the phagocytic cycle. Monocytes fed with pigment display a long-lasting oxidative burst that does not occur when they phagocytose diamide-treated RBC or RPRBC. The phorbol myristate acetate-elicited oxidative burst is irreversibly suppressed in monocytes fed with TPRBC or pigment, but not in monocytes fed with diamide-treated or IgG-opsonized RBC. This pattern of inhibition of phagocytosis and oxidative burst suggests that malarial pigment is responsible for the toxic effects. Pigment iron released in the monocyte phagolysosome may be the responsible element. 3% of total pigment iron is labile and easily detached under conditions simulating the internal environment of the phagolysosome, i.e., pH 5.5 and 10 microM H2O2. Iron liberated from pigment could account for the lipid peroxidation and increased production of malondialdehyde observed in monocytes fed with pigment or in RBC ghosts and liposomes incubated at pH 6.5 in presence of pigment and low amounts of H2O2. Removal of the labile iron fraction from pigment by repeated treatments with 0.1 mM H2O2 at pH 5.5 reduces pigment toxicity. It is suggested that iron released from ingested pigment is responsible for the intoxication of monocytes. In acute and chronic falciparum infections, circulating and tissue-resident phagocytes are seen filled with TPRBC and pigment particles over long periods of time. Moreover, human monocytes previously fed with TPRBC are unable to neutralize pathogenic bacteria, fungi, and tumor cells, and macrophage responses decline during the course of human and animal malaria. The present results may offer a mechanistic explanation for depression of cellular immunity in malaria.
人单核细胞衍生的巨噬细胞摄取经二酰胺处理的红细胞（RBC）、抗D免疫球蛋白（Ig）G调理的RBC或恶性疟原虫环状体寄生的RBC（RPRBC），能迅速降解摄取的血红蛋白，并可重复吞噬循环。用含有疟色素的滋养体寄生的RBC（TPRBC）喂养单核细胞，或用分离出的色素喂养单核细胞，实际上无法降解摄取的物质，也无法重复吞噬循环。用色素喂养的单核细胞会出现持续时间较长的氧化爆发，而当它们吞噬经二酰胺处理的RBC或RPRBC时则不会出现这种情况。在用TPRBC或色素喂养的单核细胞中，佛波酯肉豆蔻酸酯引发的氧化爆发被不可逆地抑制，但在用经二酰胺处理或IgG调理的RBC喂养的单核细胞中则没有被抑制。这种吞噬作用和氧化爆发的抑制模式表明疟色素是造成毒性作用的原因。在单核细胞吞噬溶酶体中释放的色素铁可能是起作用的成分。总色素铁的3%是不稳定的，在模拟吞噬溶酶体内环境的条件下，即pH 5.5和10微摩尔过氧化氢时很容易分离。从色素中释放的铁可以解释在用色素喂养的单核细胞中观察到的脂质过氧化以及在pH 6.5、存在色素和少量过氧化氢的条件下RBC空壳和脂质体中丙二醛产量的增加。通过在pH 5.5下用0.1毫摩尔过氧化氢反复处理从色素中去除不稳定铁部分可降低色素毒性。有人提出，摄取的色素释放的铁是单核细胞中毒的原因。在急性和慢性恶性疟感染中，循环中和组织驻留的吞噬细胞长时间内可见充满TPRBC和色素颗粒。此外，先前用TPRBC喂养的人单核细胞无法中和致病细菌、真菌和肿瘤细胞，并且在人和动物疟疾病程中巨噬细胞反应会下降。目前的结果可能为疟疾中细胞免疫抑制提供一个机制性解释。
