The serpin secreted by Brugia malayi microfilariae, Bm-SPN-2, elicits strong, but short-lived, immune responses in mice and humans.
Understanding the basic immunology of an infectious disease requires insight into the pattern of T cell reactivity and specificity. Although lymphatic filariasis is a major tropical disease, the predominant T cell Ags of filarial species such as Brugia malayi are still undefined. We have now identified a prominent T cell Ag from B. malayi microfilariae (Mf) as Bm-SPN-2, a serpin secreted exclusively by this stage. Mf-infected mice mounted strong, but short-lived, Bm-SPN-2-specific Th1 responses, measured by in vitro production of IFN-gamma, but not IL-4 or IL-5, 14 days postinfection. By day 35, responsiveness to Bm-SPN-2 was lost despite enhanced reactivity to whole Mf extract. Single immunization with Mf extract also stimulated typical Th1 reactions to Bm-SPN-2, but IgG1 Ab responses dominated after repeated immunizations. Human patients displayed potent humoral responses to Bm-SPN-2 in both IgG1 and IgG4 subclasses. Thus, 100% (20 of 20) of the microfilaremic (MF(+)) patients bore IgG4 responses to Bm-SPN-2, while only 30% of endemic normal subjects were similarly positive. Following chemotherapy, Bm-SPN-2-specific Abs disappeared in 12 of 13 MF(+) patients, although the majority remained seropositive for whole parasite extract. PBMC from most, but not all, endemic subjects were induced to secrete IFN-gamma when stimulated with Bm-SPN-2. These findings demonstrate that Bm-SPN-2 is recognized by both murine and human T and B cells and indicate that their responses are under relatively stringent temporal control. This study also provides the first example of a stage-specific secreted molecule that acts as a major T cell Ag from filarial parasites and is a prime candidate for a serodiagnostic probe.
Zang
X
X
Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh, United Kingdom.
Atmadja
A K
AK
Gray
P
P
Allen
J E
JE
Gray
C A
CA
Lawrence
R A
RA
Yazdanbakhsh
M
M
Maizels
R M
RM
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000302:isolation & purification; D000947:Antigens, Helminth / Q000008:administration & dosage / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism*; D017178:Brugia malayi / Q000201:enzymology / Q000254:growth & development / Q000276:immunology*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005368:Filariasis / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology; D015801:Helminth Proteins; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D015848:Interleukin-5 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008842:Microfilariae / Q000201:enzymology / Q000254:growth & development / Q000276:immunology*; D015843:Serpins / Q000008:administration & dosage / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; D000947:Antigens, Helminth; C120921:Bm-SPN-2 protein, Brugia malayi; D015801:Helminth Proteins; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D015848:Interleukin-5; D015843:Serpins; D007371:Interferon-gamma