Infection with Brugia microfilariae induces apoptosis of CD4(+) T lymphocytes: a mechanism of immune unresponsiveness in filariasis.
In humans infected with lymphatic filariasis, microfilaraemia [the presence of microfilariae (Mf) in the blood] is generally associated with both poor antigen (Ag)-specific proliferative responses and with protection from severe disease. Clonal deletion has been suggested as one possible mechanism by which parasite-reactive lymphocytes, that may be capable of mediating resistance and/or immunopathology, are silenced in asymptomatic carriers. In this study we demonstrate that splenic lymphocytes from mice infected with microfilariae of Brugia pahangi display an Ag-specific proliferative defect. However, these cells were not completely unresponsive since they produced high levels of Ag-specific IFN-gamma. Using TdT-mediated dUTP-biotin nick end labeling for flow cytometry, CD4(+) lymphocytes from Mf-infected mice cultured with Ag showed high levels of apoptosis when compared to those from L3-infected mice which proliferated well in response to Ag. Treatment of Ag-stimulated cultures with aminoguanidine (AMG), an inhibitor of inducible nitric oxide synthase, rescued the CD4(+) T cells from apoptosis and reversed the proliferative defect. Furthermore, carboxyfluorescein diacetate succinimidyl ester labeling allowed the visualization of dividing CD4(+) T cells in cultures from Mf-infected animals only in the presence of AMG. We hypothesize that CD4(+) T cells indirectly trigger their own apoptosis by secreting significant quantities of IFN-gamma resulting in the induction of high levels of nitric oxide, and the subsequent elimination of effector T cells. Our findings are the first direct evidence that infection with Brugia Mf can selectively induce lymphocyte apoptosis, a phenomenon that could contribute to the proliferative defect and parasite persistence associated with the microfilaraemic state in the infected human.
Jenson
Jessica S
JS
Department of Veterinary Parasitology, University of Glasgow, Glasgow, GB.
O'Connor
Richard
R
Osborne
Julie
J
Devaney
Eileen
E
D000330:Aedes / Q000469:parasitology; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D017209:Apoptosis; D017179:Brugia pahangi / Q000254:growth & development / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005368:Filariasis / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D005452:Fluoresceins / Q000032:analysis; D005456:Fluorescent Dyes / Q000032:analysis; D005849:Gerbillinae; D006146:Guanidines / Q000494:pharmacology; D007153:Immunologic Deficiency Syndromes / Q000209:etiology / Q000469:parasitology; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008842:Microfilariae / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D018512:Parasitemia / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000473:pathology; D013388:Succinimides / Q000032:analysis; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000947:Antigens, Helminth; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006146:Guanidines; D013388:Succinimides; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine