title: Association of T cell dysfunction with the presence of IgG autoantibodies on CD4+ lymphocytes in haemophilia patients; results of a 10-year study.
abstract: HIV induces progressive dysfunction followed by numerical depletion of CD4+ lymphocytes. IgG autoantibodies and gp 120-containing immune complexes have been implicated in the pathogenesis of AIDS. We carried out a longitudinal study in 19 HIV- and 72 HIV+ haemophilia patients over a 10-year period in order to investigate a possible relationship between the occurrence of autoantibodies and CD4+ lymphocyte changes. IgM, IgG, C3d and gp120 on the surface of CD4+ lymphocytes were determined in heparinized whole blood with flow cytometry and double-fluorescence. The in vitro response of autoantibody-coated cells was tested in cell cultures with concanavalin A (Con A), phytohaemagglutinin (PHA), pokeweed mitogen (PWM) anti-CD3 MoAb or pooled allogeneic stimulator cells (MLC). After a 10-year follow up, 12 of 71 HIV+ and 16 of 19 HIV- haemophilia patients showed no evidence of immunoglobulins on circulating CD4+ lymphocytes. HIV- haemophilia patients without autoantibodies had CD4+ and CD8+ cell counts in the normal range (957+/-642/microliters and 636+/-405/microliters) and normal T cell responses in vitro (mean relative response (RR) > or = 0.7). In contrast, HIV+ haemophilia patients showed immunological abnormalities which were associated with the autoantibody and immune complex load of CD4+ blood lymphocytes. HIV+ patients without autoantibodies had a mean CD4+ lymphocyte count of 372+/-274/microliter, a mean CD8+ lymphocyte count of 737+/-435 microliter, and normal T lymphocyte stimulation in vitro (mean RR > or = 0.7). HIV+ patients with complement-fixing IgM on CD4+ lymphocytes had somewhat lower CD4+ (255+/-246/microliters, P = NS) and CD8+ (706 +/- 468/microliters, P = NS) lymphocyte numbers, and also normal T lymphocyte stimulation (mean RR > or = 0.7) in vitro. However, patients with complement-fixing IgG autoantibodies showed a strong decrease of CD4+ (150 +/- 146/microliters, P< 0.02) and CD8+ (360 +/- 300 microliters, (P<0.02) lymphocytes and impaired CD4+ lymphocyte stimulation in vitro with a mean RR of 0.5+/-0.5 for Con A (P = NS), 0.7 +/- 0.8 for PHA (P<0.03), 0.4 +/- 0.4 for PWM (P = NS), 0.8 +/- 1.2 for anti-CD3 MoAb (P<0.04) and 0.7 +/- 1.0 for pooled allogeneic stimulator cells (P=0.05). Patients with gp120-containing immune complexes on CD4+ blood lymphocytes demonstrated strongly decreased CD4+ (25+/-35/microliters, P<0.0001) and CD8+ (213+/-212/microliters, P<0.006) lymphocyte counts as well as strongly impaired T lymphocyte responses in vitro upon stimulation with PHA (RR 0.2+/-0.1, P<0.02), PWM (RR 0.2+/_0.2, P=0.05), anti-CD3 MoAb(RR 0.1+/-0.1, P<0.04), and allogeneic stimulator cells (RR 0.2+/-0.1, P<0.02). These data led us to speculate that autoantibody formation against CD4+ lymphocytes is an important mechanism in the pathogenesis of AIDS. We hypothesize that autoantibodies against circulating CD4+ lymphocytes inhibit CD4+ cell function, especially the release of cytokines, and induce CD4+ cell depletion. The reduction and dysfunction of CD4+ lymphocytes may be responsible for the CD8+ cell depletion observed in HIV+ patients.
authors.affiliation: Department of Transplantation Immunology, Institute of Immunology, Umiversity of Heidelberg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Daniel
authors.forename: C
authors.initials: C
authors.lastname: Süsal
authors.forename: R
authors.initials: R
authors.lastname: Weimer
authors.forename: S
authors.initials: S
authors.lastname: Zipperle
authors.forename: M
authors.initials: M
authors.lastname: Kröpelin
authors.forename: R
authors.initials: R
authors.lastname: Zimmermann
authors.forename: A
authors.initials: A
authors.lastname: Huth-Kühne
authors.forename: G
authors.initials: G
authors.lastname: Opelz
mesh_terms: D000936:Antigen-Antibody Complex; D001323:Autoantibodies / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000150:complications*; D006467:Hemophilia A / Q000150:complications / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G