ASSOCIATION OF T-CELL DYSFUNCTION WITH THE PRESENCE OF IGG AUTOANTIBODIES ON CD4(- RESULTS OF A 10-YEAR STUDY() LYMPHOCYTES IN HEMOPHILIA PATIENTS )

HIV induces progressive dysfunction followed by numerical depletion of CD4(+) lymphocytes. IgG autoantibodies and gp 120-containing immune c omplexes have been implicated in the pathogenesis of AIDS. We carried out a longitudinal study in 19 HIV- and 72 HIV+ haemophilia patients o ver a 10-year period in order to investigate a possible relationship b etween the occurrence of autoantibodies and CD4(+) lymphocyte changes. IgM, IgG, C3d and gp120 on the surface of CD4(+) lymphocytes were det ermined in heparinized whole blood with flow cytometry and double-fluo rescence. The in vitro response of autoantibody-coated cells was teste d in cell cultures with concanavalin A (Con A); phytohaemagglutinin (P HA), pokeweed mitogen (PWM), anti-CD3 MoAb or pooled allogeneic stimul ator cells (MLC). After a 10-year follow up, 12 of 71 HIV+ and 16 of 1 9 HIV- haemophilia patients showed no evidence of immunoglobulins on c irculating CD4(+) lymphocytes. HIV- haemophilia patients without autoa ntibodies 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 contra st, 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 vitr o (mean RR greater than or equal to 0.7). HIV+ patients with complemen t-fixing IgM on CD4(+) lymphocytes had somewhat lower CD4(+) (255 +/- 246/mu l, P = NS) and CD8(+) (706 +/- 468/mu l, P = NS) lymphocyte num bers, and also normal T lymphocyte stimulation (mean RR greater than o r 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 impa ired 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 fo r 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 demonstra ted 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 im paired 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 form ation against CD4(+) lymphocytes is an important mechanism in the path ogenesis of AIDS. We hypothesize that autoantibodies against circulati ng CD4(+) lymphocytes inhibit CD4(+) cell function, especially the rel ease of cytokines, and induce CD4(+) cell depletion. The reduction and dysfunction of CD4(+) lymphocytes may be responsible for the CD8(+) c ell depletion observed in HIV+ patients.