Role of Immune Response in Severe Malarial Anemia

Mahidol University, Nakhon Pathom

Investigators

Abstract

The proposed research is designed to determine if excessive activity of the T helper lymphocyte type 1 (Th-1) immune response and decreased activity of the Th-2 immune response are involved in the pathogenesis of severe anemia in children and adults with Plasmodium falciparum malaria. Severe malarial anemia (hemoglobin <g/dL in a patients with a positive malaria smear) is an important manifestation of complicated malaria among children and adults in Thailand. Th-1 cytokines suppress erythroid precursors, diver iron from hemoglobin synthesis to stores, and lead to moderate to severe anemia. Macrophage migration inhibitory factor (MIF), produced by macrophages upon ingestion of P. falciparum- infected erythrocytes, is an immune modulator that has a suppressive effect on erythropoiesis. This study hypothesizes that severe malarial anemia develops in a patient with an abnormal immune regulatory pattern characterized by (1) the persistence or resurgence of a prominent Th-1 response in the presence of falciparum malaria and (2) excessive release of MIF. The proposed research will examine the Th-1 and Th-2 responses and MIF production in Thai children and adults with severe malarial anemia and in three control groups: similar numbers of normal children and adults or those with cerebral malaria or uncomplicated malaria. The specific aims are: Aim 1. Determine if the production of neopterin, a marker of the Th-1 pathway, and MIF is increased in Thai children and adults with severe malarial anemia compared to normal children and adults or children and adults with cerebral malaria or uncomplicated malaria. Aim 2. Determine if the production of the Th-2 related cytokines, IL-4 and IL-10, are reduced in children and adults with severe malarial anemia compared to normal children and adults or children and adults with cerebral malaria or uncomplicated malaria. Aim 3. Determine how often anemia lingers four weeks after starting effective therapy for complicated or uncomplicated P. falciparum malaria to Thai children and adults, and whether this persistent anemia is associated with sustained elevations in the production of neopterin and MIF. The proposed research program will provide insights into the underlying pathophysiologic mechanisms of severe malaria anemia by characterizing the immune response patterns in severe malarial anemia, cerebral malaria and uncomplicated malaria in Thai children and adults.