Schistosome-infected IL-4 receptor knockout (KO) mice, in contrast to IL-4 KO mice, fail to develop granulomatous pathology while maintaining the same lymphokine expression profile.
Th2 lymphocytes have been postulated to play a major role in the immunopathology induced by Schistosoma mansoni infection. Nevertheless, infected IL-4 knockout (KO) and wild-type (wt) mice develop egg granulomas comparable in size. To further investigate the function of the Th2 response in egg pathology we studied IL-4Ralpha-deficient mice, which are nonresponsive to both IL-4 and IL-13. In striking contrast to IL-4 KO animals, infected IL-4Ralpha KO mice developed only minimal hepatic granulomas and fibrosis despite the presence of CD3+ T cells in the residual egg lesions. Moreover, liver lymphokine mRNA levels in these animals and IL-4 KO mice were equivalent. In addition, infected IL-4Ralpha-deficient, IL-4-deficient, and wt animals developed similar egg Ag-specific IgG Ab titers, arguing that CD4-dependent Th activity is intact in KO mice. As expected, IFN-gamma secretion was strongly up-regulated in mesenteric lymph node cultures from both groups of deficient animals, a change reflected in increased serum IgG2a and IgG2b Ab levels. Surprisingly, Th2 cytokine production in infected IL-4Ralpha KO mice was not abolished but was only reduced and resembled that previously documented in IL-4 KO animals. This residual Th2 response is likely to explain the ability of IL-4 KO mice to generate egg granulomas, which cannot be formed in IL-4Ralpha-deficient animals because of their lack of responsiveness to the same cytokine ligands. Taken together, these findings argue that tissue pathology in schistosomiasis requires, in addition to egg-specific CD4+ lymphocytes, a previously unrecognized IL-4Ralpha+ non-T cell effector population.
Jankovic
D
D
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. djankovic@atlas.niaid.nih.gov
Kullberg
M C
MC
Noben-Trauth
N
N
Caspar
P
P
Ward
J M
JM
Cheever
A W
AW
Paul
W E
WE
Sher
A
A
D000818:Animals; D000909:Antibodies, Helminth / Q000096:biosynthesis; D002465:Cell Movement / Q000276:immunology; D006099:Granuloma / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008109:Liver Diseases, Parasitic / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010063:Ovum / Q000276:immunology / Q000473:pathology; D019948:Receptors, Interleukin-4 / Q000172:deficiency / Q000235:genetics*; D012555:Schistosomiasis mansoni / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology / Q000469:parasitology / Q000473:pathology
D000909:Antibodies, Helminth; D007074:Immunoglobulin G; D008222:Lymphokines; D019948:Receptors, Interleukin-4; D015847:Interleukin-4