IFN‐γ mediates early B‐cell loss in experimental African trypanosomosis

Abstract

SUMMARYAfrican trypanosomes infect humans and animals throughout the African continent. These parasites maintain chronic infections by various immune evasion strategies. While antigenic variation of their surface coat is the most studied strategy linked to evading the host humoral response, African trypanosomes also induce impaired B-cell lymphopoiesis, the destruction of the splenic B-cell compartment and abrogation of protective memory responses. Here we investigate the mechanism of follicular B-cell destruction. We show that during infection follicular B cells undergo apoptosis, correlating to enhanced Fas death receptor surface expression. Investigation of various type 1 cytokine knockout mice indicates a crucial role of IFN-c in the early onset of FoB cell destruction. Indeed, both IFN-c À/À and IFN-cR À/À mice are protected from trypanosomosis-associated FoB cell depletion, exhibiting an inhibition of B-cell apoptosis as well as a reduced activation of FoB cells during the first week post-infection. The data presented herein offer new insights into B-cell dysfunctioning during experimental African trypanosome infections.

Trypanosoma brucei brucei causes a rapid and persistent influx of neutrophils in the spleen of infected mice

“…Single-cell spleen suspensions were prepared at 0, 4,5,6,7,8,9,10,14,17,21,24 and 28 days post-infection (dpi) as previously described. 13 Unless otherwise stated, cell suspensions were re-suspended in 0.05% FBS BD FACSFlow Sheath Fluid. Cell washings were carried out by centrifugation at 314 g for 7 minutes.…”

Experimental African trypanosome infection suppresses the development of multiple myeloma in mice by inducing intrinsic apoptosis of malignant plasma cells

“…brucei infection in 5T33MM mice was accompanied by an increase in IFNy levels in serum up to 25 ng/ml at day 20 (Figure 4A ). Recently, our group has underscored the detrimental role of IFNɣ in mediating the early loss of B cells by apoptosis during experimental African trypanosomiasis [ 14 ]. Therefore its potential role in the apoptosis of myeloma cells was investigated by treating T .…”

“…Indeed, IFNɣ has been shown to play a major role in anti-tumor responses as well as in the control of trypanosomiasis. T. brucei infections promote the development of a Th1-mediated immune response [ 31 ] and IFNɣ was recently implicated in the early B cell loss in a mouse model of African trypanosomiasis [ 14 ]. Our results showed that trypanosome infected mice treated with anti-IFNɣ blocking antibodies display statistically higher M-protein levels compared to untreated and infected mice, but no clear impact on BM plasmacytosis was seen.…”

Infections With Extracellular Trypanosomes Require Control by Efficient Innate Immune Mechanisms and Can Result in the Destruction of the Mammalian Humoral Immune System

“…When it comes to immune destruction of the B cell compartment, this has also been documented in detail for T. vivax (82) and in more detail for T. brucei (83). In the latter model it has been shown that the early loss of B cells is linked to an excessive inflammatory IFNγ response (84), can involve the NK cell mediated killing activity (85), is observed both at the level of the bone marrow and spleen (86) and takes several weeks to be restored after drug treatment of experimentally infected mice (87). Also here, infection-induced B cell destruction seems to be associated to parasite virulence as mice that are infected with very chronic T. b. gambiense parasites do not seem to suffer the same B cell depletion problem as those infected with a much more acute T. b. brucei strain (88).…”