What is the cause of lymphopenia in malaria?

Abstract

Two recent reports conclude that Fas-induced apoptosis plays an important role in the lymphopenia of Plasmodium falciparum malaria in humans (5) and in Plasmodium coatneyi-infected macaques (6). In both studies, the authors base their conclusion on concomitant findings of increased levels of soluble Fas ligand in serum and lymphopenia. An important element in their arguments is the finding of spontaneous ex vivo T-cell apoptosis in P. falciparum patients from Senegal (1, 7). However, to our knowledge no other reports exist supporting the hypothesis that high levels of apoptotic cells in the peripheral blood are a general feature of P. falciparum malaria. We have never been able to detect significant increases in the proportion of peripheral T cells showing evidence of apoptosis in several studies of many malaria patients in Ghana, except once in a moribund cerebral malaria patient (our unpublished data). Indeed, Matsumoto et al. could detect apoptotic peripheral blood mononuclear cells (not necessarily T cells) in moribund animals only (6), in line with our findings but at variance with the Senegalese data where apoptotic cells were readily detected even in asymptomatic parasite carriers (7). Lymphopenia is a well-established feature of P. falciparum malaria but is replaced by lymphocytosis in a matter of a few days after initiation of drug therapy, before gradually normalizing over the next couple of weeks (4). How this can occur if the lymphopenia is the result of widespread apoptosis is difficult to imagine. Rather, we have proposed that the initial lymphopenia reflects disease-induced reallocation of T cells to sites of inflammation (2), followed by reemergence of such cells upon cure (4). Although apoptosis appears not to be involved in these changes, it can be speculated that the eventual return to predisease homeostasis is mediated by apoptosis of excess “battle-worn” T cells (Fig. ​(Fig.1).1). Whether such postmalaria apoptosis occurs remains uncertain, let alone whether it is detectable in the peripheral circulation and is mediated through Fas. Although the papers by Kern et al. (5) and Matsumoto et al. (6) provide evidence of both lymphopenia and increases in soluble Fas ligand, both fail to demonstrate any evidence that one is the consequence of the other. Until such evidence becomes available, we feel that reallocation/reemergence remains the most plausible explanation of the observed lymphopenia in malaria. FIG. 1 Schematic diagram of perturbations in numbers of peripheral T cells following Plasmodium infection. This hypothesis is supported by a number of independent studies, most recently by an investigation of peripheral and splenic cellular changes in P. chabaudi-infected mice (3).