Cell- rather than antibody-mediated immunity leads to the development of profound thrombocytopenia during experimental Plasmodium berghei malaria.
Experimental malarial thrombocytopenia can reach life-threatening levels and is believed to be due to Abs targeting platelets for destruction by the reticuloendothelial system. However, we report that Abs account for at most 15% of platelet destruction as Plasmodium berghei-infected B cell-deficient mice exhibited profound thrombocytopenia (83%) as did C57BL/6 controls (98%). Further, no significant increase in Abs bound to intact platelets was observed during infection. P. berghei infection can enhance the activity of anti-platelet Abs as indicated by a significantly (p < 0.005) increased thrombocytopenia on day 4 of infection in mice that were administered a low dose anti-CD41 mAb compared with rat IgG1-injected controls. RAG1-/- and CD4- plus CD8-deficient mice were markedly protected from thrombocytopenia (p < 0.005) and malarial pathogenesis. CD8- or TCRgammadelta-deficient mice were not protected from thrombocytopenia and CD4-deficient mice were modestly protected. RAG1-/- mice exhibited significantly (p < 0.05) lower levels of plasma TNF, IFN-gamma, and IL-12 during infection. IFNgamma-/- and IL-12-/- mice exhibited increased survival but similar thrombocytopenia to C57BL/6 controls. Collectively, these data indicate that thrombocytopenia is necessary but not sufficient for malarial pathogenesis and Abs are not the major contributors to malarial thrombocytopenia. Rather, we propose that both CD4+ and CD8+ T cell populations play key roles in malarial thrombocytopenia; a complex bidirectional interaction between cell-mediated immunity and platelets exists during experimental severe malaria that regulates both responses.
Gramaglia
Irene
I
La Jolla Bioengineering Institute, La Jolla, CA 92037, USA.
Sahlin
Herman
H
Nolan
John P
JP
Frangos
John A
JA
Intaglietta
Marcos
M
van der Heyde
Henri C
HC
D000818:Animals; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005434:Flow Cytometry; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D008212:Lymphocyte Depletion; D008288:Malaria / Q000150:complications / Q000276:immunology*; D051379:Mice; D010962:Plasmodium berghei / Q000276:immunology*; D040201:Platelet Membrane Glycoprotein IIb / Q000276:immunology; D013921:Thrombocytopenia / Q000209:etiology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
D040201:Platelet Membrane Glycoprotein IIb; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma