and on the Clinical Course and of

To the Editor—We read with interest the recent article by Dodoo et al. [1], and we fully agree with them that secretion of proinflammatory cytokines is essentially to clearance of Plasmodium falciparum malaria. This statement is based mainly on several crucial points: (1) early production of interferon (IFN)–g, stimulated by induction of interleukin (IL)-12 or IL-18 from macrophages [2, 3]; (2) the correlation of high levels of production of malaria-specific INF-g and decreased risk of development of fever or of clinical malaria during follow-up [1]; (3) the ability of live parasites—rather than dead parasites—to mount an early INF-g response to malaria antigens, in conjunction with the ability of either g/d T cells or NK cells to respond preferentially to live parasites [4]; and, finally, in severe malaria, (4) suppression of the protective effects of IL-12 and transforming growth factor (TGF)–b [5]. Taken together, these findings show that innate immune response—and, in part, adaptive immune response, through increased production of INF-g—limits the initial reproduction of the parasite and subsequently provokes its elimination [6, 7]. In our opinion, resolution of P. falciparum malaria is strictly dependent on a very early and effective activation of macrophages, stimulated by various malaria antigens, to produce and secrete IL-12 and IL-18. In the early phase of the immune response, innate immunity—that is, prompt production of IL-12 along with IL-18—may be able to directly activate NK cells and CD8 T cells to produce INF-g. In addition, activation of NK cells and T cells by IL-18 and IL-12 is also able to produce tumor necrosis factor (TNF)–a, which cooperates with INF-g to lead to resolution of malarial infection [8]. In a subsequent phase, adaptive immunity, CD8 T cells and g/d T cells are critical in the immune response, in that they produce and secrete INF-g [9, 10]. This adaptive immune response, along with the early immune response, leads to a rapid and effective resolution of malarial infection. In severe and complicated P. falciparum malaria, including cerebral malaria, there is a dramatic increase and persistent production of TNF-a, paralleled by decreased production of IL-10 and TGF-b [8, 11]. In contrast, the early activation of IL-18 and IL-12 may be weakened, since there is suppression of the protective effects of these cytokines by TGF-b [5]. TGF-b seems to be an important cytokine for maintaining the balance between protection against and progression toward P. falciparum malaria. However, the role that this cytokine plays in malaria has not been completely clarified, and several studies have shown contrasting results with respect to proinflammatory or antiinflammatory response during the infection. Dodoo et al. [1] have shown that TGF-b production, induced by phytohemagglutinin, is associated with a significantly reduced risk of fever, and they have concluded that regulation of the proinflammatory cytokine cascade by cytokines such as TGF-b may contribute to protection from malarial pathology. It is conceivable that, in severe P. falciparum malaria, including cerebral malaria, increased production of TGF-b may be associated with anti-inflammatory effects, through inhibition or decrease of proinflammatory cytokines such as IL-18 and IL-12 during the early phase of immune activation. In fact, Omer et al. [12] have reported that TGF-b has proinflammatory activity at low levels, whereas high levels of TGF-b are associated with antiinflammatory activity. Thus, we can postulate that, at low levels, TGF-b stimulates the early proinflammatory cytokine response—such as the production of IL-12, IL-18, and INFg—to lead to a prompt and complete resolution of malarial infection. In contrast, high levels of TGF-b up-regulate the antiinflammatory cytokine response, which provokes reduced production of IL-12, IL18, and INF-g, with increased and persistent production of TNF-a, a series of events that is responsible for severe P. falciparum malaria infection as well as for cerebral malaria. In conclusion, it seems that an early proinflammatory cytokine response, including production of IL-12, IL-18, and TGF-b (at low concentrations), mediates protective immunity, whereas a persistent and late anti-inflammatory cytokine response, including production of TNF-a and TGF-b (at high concentrations), contributes to severe and complicated P. falciparum malaria. However, further studies are needed to confirm the reciprocal and balancing effects that TGF-b, IL-12, and IL-18 have in determining the resolution or persistence and worsening of malaria infection.