Cytokine control of parasite-specific anergy in human lymphatic filariasis : preferential induction of a regulatory T helper type 2 lymphocyte subset

• Published in: The Journal of clinical investigation 1993-10, Vol.92 (4), p.1667-1673
• Main Authors: KING, C. L, MAHANTY, S, KUMARASWAMI, V, ABRAMS, J. S, REGUNATHAN, J, JAYARAMAN, K, OTTESEN, E. A, NUTMAN, T. B
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antibodies, Helminth - blood; Biological and medical sciences; Brugia malayi - immunology; Brugia malayi - isolation & purification; Cytokines - biosynthesis; Cytokines - blood; Diseases caused by nematodes; Elephantiasis, Filarial - blood; Elephantiasis, Filarial - immunology; Enzyme-Linked Immunosorbent Assay; Filariases; Helminthic diseases; Humans; Immunoglobulin E - blood; Immunoglobulin G - blood; Immunoglobulin G - classification; Infectious diseases; Interferon-gamma - blood; Interleukin-10 - biosynthesis; Interleukin-10 - blood; Interleukin-4 - biosynthesis; Lymphatic filariases; Medical sciences; Middle Aged; Parasitic diseases; RNA, Messenger - metabolism; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; Transcription, Genetic; Transforming Growth Factor beta - biosynthesis; Tropical medicine
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI116752

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.