title: Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset.
abstract: The immunological mechanisms involved in maintenance of an asymptomatic microfilaremic state (MF) in patients with lymphatic filariasis remain undefined. MF patients have impaired filarial antigen (Ag)-specific lymphocyte proliferation and decreased frequencies (Fo) of Ag-specific T cells, and yet elevated serum IgE and antifilarial IgG4. To investigate the mechanism of Ag-specific anergy in MF patients in contrast to amicrofilaremic individuals with chronic lymphatic obstruction (CP), the Fo of Ag-specific lymphocytes from peripheral blood mononuclear cells secreting either IL-4 or IFN-gamma were assessed by filter spot enzyme-linked immunosorbent assay, and IL-10 and transforming growth factor-beta (TGF-beta) mRNA transcript levels were assessed by a semiquantitative reverse transcriptase polymerase chain reaction technique. The Fo of filaria-specific IL-4-secreting lymphocytes were equivalent in both MF (geometric mean [GM] = 1:11,700) and CP (GM = 1:29,300 P = 0.08), whereas the Fo of IFN-gamma-secreting lymphocytes were lower in MF (GM = 1:39,300) than in CP (GM = 1:4,200, P < 0.01). When the ratio of IL-4/IFN-gamma (T helper type 2 [Th2]/Th1)-secreting cells was examined, MF subjects showed a predominant Th2 response (8:1) compared with a Th1 response in CP individuals (1:4). mRNA transcript levels of IL-10 were also significantly elevated in MF compared with CP individuals (P < 0.01). Further, IL-10 and TGF-beta were shown to have a role in modulating the Ag-specific anergy among MF subjects, in that neutralizing anti-IL-10 or anti-TGF-beta significantly enhanced lymphocyte proliferation response (by 220-1,300%) to filarial Ags in MF individuals. These findings demonstrate that MF subjects respond to parasite antigen by producing a set of suppressive cytokines that may facilitate persistence of the parasite within humans while producing little clinical disease.
authors.affiliation: Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: C L
authors.initials: CL
authors.lastname: King
authors.forename: S
authors.initials: S
authors.lastname: Mahanty
authors.forename: V
authors.initials: V
authors.lastname: Kumaraswami
authors.forename: J S
authors.initials: JS
authors.lastname: Abrams
authors.forename: J
authors.initials: J
authors.lastname: Regunathan
authors.forename: K
authors.initials: K
authors.lastname: Jayaraman
authors.forename: E A
authors.initials: EA
authors.lastname: Ottesen
authors.forename: T B
authors.initials: TB
authors.lastname: Nutman
mesh_terms: D000328:Adult; D000818:Animals; D000909:Antibodies, Helminth / Q000097:blood; D017178:Brugia malayi / Q000276:immunology / Q000302:isolation & purification; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood*; D004605:Elephantiasis, Filarial / Q000097:blood / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D000909:Antibodies, Helminth; D016207:Cytokines; D007074:Immunoglobulin G; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma