Association of T cell dysfunction with the presence of IgG autoantibodies on CD4(+) lymphocytes in haemophilia patients; Results of a 10-year study

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/mu l and 636 +/- 405/mu l) and normal T cell responses in vitro (mean relative response (RR) greater than or equal to 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/mu l, a mean CD8(+) lymphocyte count of 737 +/- 435/mu l, and normal T lymphocyte stimulation in vitro (mean RR greater than or equal to 0.7). HIV+ patients with complement-fixing IgM on CD4(+) lymphocytes had somewhat lower CD4(+) (255 +/- 246/mu l, P = NS) and CD8(+) (706 +/- 468/mu l, P = NS) lymphocyte numbers, and also normal T lymphocyte stimulation (mean RR greater than or equal to 0.7) in vitro. However, patients with complement-fixing IgG autoantibodies showed a strong decrease of CD4(+) (150 +/- 146/mu l, P < 0.02) and CD8(+) (360 +/- 300/mu l, 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 gp 120-containing immune complexes on CD4(+) blood lymphocytes demonstrated strongly decreased CD4(+) (25 +/- 35/mu l, P < 0.0001) and CD8(+) (213 +/- 212/mu l, 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.