Transmission intensity determines lymphocyte responsiveness and cytokine bias in human lymphatic filariasis.
Humans living in areas where filariasis is endemic vary greatly in their exposure to mosquito-borne infective third-stage larvae (L3) of these parasitic helminths. Because the intensity of exposure to Ags affects T cell differentiation and susceptibility to parasitic infections in murine models, we compared T cell and cytokine responses in 97 residents of two villages in Papua New Guinea, where transmission intensity of Wuchereria bancrofti differed by 63-fold (37 vs 2355 L3 per person per year). Residents of the high transmission village had 4- to 11-fold lower proliferation and IFN-gamma responses to filarial Ags, nonparasite Ag, and PHA by PBMC compared with the low transmission village (p < 0.01) even when subjects were matched for intensity of infection. In contrast, filarial Ag-driven IL-5 production was 5.5-fold greater (p < 0.001), and plasma IL-4 and TGF-beta levels were 4-fold and 34% higher, respectively, in residents of the high transmission village. IL-4 and IL-10 responses by PBMC differed little according to village, and increased production of the counterregulatory cytokines IL-10 or TGF-beta by PBMC did not correlate with weak proliferation and IFN-gamma responses. Plasma IL-5, IFN-gamma, and IL-10 levels were similar in the two villages. These data demonstrate that the intensity of exposure to L3 affects lymphocyte responsiveness and cytokine bias possibly by a mechanism that alters APC function.
King
C L
CL
Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. cxk21@po.cwru.edu
Connelly
M
M
Alpers
M P
MP
Bockarie
M
M
Kazura
J W
JW
D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004605:Elephantiasis, Filarial / Q000453:epidemiology / Q000276:immunology* / Q000469:parasitology / Q000635:transmission*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D015847:Interleukin-4 / Q000097:blood; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010219:Papua New Guinea / Q000453:epidemiology; D010835:Phytohemagglutinins / Q000494:pharmacology; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014958:Wuchereria bancrofti / Q000276:immunology
D016207:Cytokines; D010835:Phytohemagglutinins; D015847:Interleukin-4; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate