Mechanisms of splenic control of murine malaria: Reticular cell activation and the development of a blood‐spleen barrier

Abstract By complex stromal responses, the spleen controls the course of nonlethal Plasmodium yoelii murine malaria. The course of disease may be divided into four phases. In the immediate postinfective phase, lasting several days, the filtration beds of the spleen are open. Parasitized and nonparasitized erythrocytes, many plasma cells, lymphocytes, and macrophages are sequestered from the blood; and most or all of the parasitized erythrocytes are phagocytized. In the following precrisis phase, approximately 1 week long, there is increasing parasitemia and anemia. The filtration beds of the spleen support large‐scale erythropoiesis, lymphopoiesis, plasmacytopoiesis, and monocyte‐to‐macrophage differentiation. Reticular cells, the stromal cells which form the splenic filtration beds, become activated, showing signs of intense protein secretion and increased branching and mitosis. The locules of the filtration beds appear sealed off from the blood by branches of activated reticular cells. A blood‐spleen barrier is thereby formed, protecting splenic hematopoiesis from the parasite. Factors are produced, moreover, which damage intraerythrocytic parasites, producing crisis forms. Crisis follows. It may occur over several days, presaged by the appearance of circulating crisis forms. The filtration beds are opened to the blood. Circulating crisis forms are trapped within the locules of the filtration beds and phagocytized while the stores of reticulocytes produced there in the precrisis period are released to the blood. The malaria, as a result, is no longer patent and the anemia is relieved. In the fourth or postcrisis phase, lasting many months, the normal structure of the spleen is approached. We postulate that reticular cells, normal and activated, have the following functions: to fabricate the locules of the filtration beds; to control the migration of free cells through these beds; to trap free cells, including parasitized erythrocytes, by cell‐surface adherence; to open or close the filtration locules, creating a dynamic blood‐spleen barrier; to control the circulation of the spleen—by contraction and alignment in normal spleens and by activation and closing of locules in enlarged spleens; to synthesize collagen III; to synthesize factors which influence marrow release of monocytes; and to secrete antiplasmodial substances.