title: Evidence for autoantibody-induced CD4 depletion mediated by apoptotic and non-apoptotic mechanisms in HIV-positive long-term surviving haemophilia patients.
abstract: It is believed that autoimmune phenomena and apoptosis contribute to CD4 depletion. We investigated 11 long-term (>20 years) HIV-infected haemophilia patients and 10 healthy controls. Using four-colour-fluorescence flow cytometry, we studied the proportions of CD3+CD4+ and CD3+CD4- blood lymphocytes that were CD95+, CD95L+, immune complex+ (IC+, consisting of IgM, IgG, C3d and/or gp120), and were viable or non-viable (propidium iodide+ = PI+). In addition, we studied viability of CD4+IgG+ patient lymphocytes using the apoptosis marker annexin and the permeability indicator 7-amino actinomycin D (7-AAD). HIV+ patients had a higher proportion of CD3+CD4+IgG+PI+ lymphocytes than healthy controls (median: 3.7%versus 0.3%; P = 0.00001). These non-viable IgG-coated lymphocytes might have been killed in vivo by ADCC or complement lysis; 9.1% of the circulating CD3+CD4+ blood lymphocytes were IgG+PI- (controls: 2.5%; P = 0.001). These viable IgG-coated lymphocytes might be targets for phagocytosis or anti-CD95 autoantibody-mediated apoptosis. Because HIV+ patients and healthy controls had similar proportions of PI+ or PI- CD3+CD4+ lymphocytes that carried CD95L on the surface, and because CD3+CD4+CD95L+ cells that were IgG+, C3d+ and/or gp120- were increased in HIV+ patients, the role of CD95L-induced apoptosis in long-term HIV-infected haemophilia patients remains unclear. The findings that HIV+ patients had higher proportions of CD3+CD4+CD95+ (PI+: 6.5%versus 1.4%; P = 0.00002; PI-: 55.8%versus 44.4%; P = 0.04) blood lymphocytes and that the proportion of CD4+IgG+Annexin+7-AAD- blood lymphocytes was associated inversely with peripheral CD4 counts (r = -0.636; P < 0.05) suggest that attachment of IgG to CD4+ blood lymphocytes (anti-CD95?) induces in some lymphocytes apoptosis with subsequent depletion of these IgG-coated apoptotic CD4+ lymphocytes from the circulation. We found supporting evidence for the contention that autoantibody-induced apoptotic and non-apoptotic mechanisms contribute to CD4 depletion in long-term HIV-infected haemophilia patients.
authors.affiliation: Department of Transplantation Immunology, University of Heidelberg, and Kurpfalz Hospital, Heidelberg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Daniel
authors.forename: M
authors.initials: M
authors.lastname: Sadeghi
authors.forename: C
authors.initials: C
authors.lastname: Naujokat
authors.forename: R
authors.initials: R
authors.lastname: Weimer
authors.forename: A
authors.initials: A
authors.lastname: Huth-Kühne
authors.forename: R
authors.initials: R
authors.lastname: Zimmermann
authors.forename: G
authors.initials: G
authors.lastname: Opelz
mesh_terms: D000293:Adolescent; D000328:Adult; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006467:Hemophilia A / Q000150:complications / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D016130:Immunophenotyping; D008137:Longitudinal Studies; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010587:Phagocytosis / Q000276:immunology; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D012367:RNA, Viral