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Apoptotic Depletion of CD4+ T Cells in Idiopathic CD4+ T Lymphocytopenia

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Apoptotic Depletion of CD4+ T Cells in Idiopathic CD4+ T Lymphocytopenia Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia. J Laurence, … , F P Siegal, L Staiano-Coico J Clin Invest. 1996;97(3):672-680. https://doi.org/10.1172/JCI118464. Research Article Progressive loss of CD4+ T lymphocytes, accompanied by opportunistic infections characteristic of the acquired immune deficiency syndrome, ahs been reported in the absence of any known etiology. The pathogenesis of this syndrome, a subset of idiopathic CD4+ T lymphocytopenia (ICL), is uncertain. We report that CD4+ T cells from seven of eight ICL patients underwent accelerated programmed cell death, a process facilitated by T cell receptor cross-linking. Apoptosis was associated with enhanced expression of Fas and Fas ligand in unstimulated cell populations, and partially inhibited by soluble anti-Fas mAb. In addition, apoptosis was suppressed by aurintricarboxylic acid, an inhibitor of calcium- dependent endonucleases and proteases, in cells from four of seven patients, The in vivo significance of these findings was supported by three factors: the absence of accelerated apoptosis in persons with stable, physiologic CD4 lymphopenia without clinical immune deficiency; detection of serum antihistone H2B autoantibodies, one consequence of DNA fragmentation, in some patients; and its selectivity, with apoptosis limited to the CD4 population in some, and occurring among CD8+ T cells predominantly in those individuals with marked depletion of both CD4+ T lymphocytes linked to clinical immune suppression have evidence for accelerated T cell apoptosis in vitro that may be pathophysiologic and amenable to therapy with apoptosis inhibitors. Find the latest version: https://jci.me/118464/pdf Apoptotic Depletion of CD4؉ T Cells in Idiopathic CD4؉ T Lymphocytopenia Jeffrey Laurence,* Debashis Mitra,* Melissa Steiner,‡ David H. Lynch,§ Frederick P. Siegal,ʈ and Lisa Staiano-Coico‡ *Laboratory for AIDS Virus Research, Division of Hematology-Oncology and ‡Department of Surgery, Cornell University Medical College, New York, New York 10021; §Immunex Corp., Seattle, Washington 98101; and ʈDivision of Hematology, Long Island Jewish Medical Center, New Hyde Park, New York 11042 Abstract (2), and severe unexplained HIV seronegative immune sup- pression (SUHIS) by the World Health Organization (4). It is -Progressive loss of CD4؉ T lymphocytes, accompanied by defined by an absolute CD4 count Ͻ 300/mm3 or Ͻ 14%, ei opportunistic infections characteristic of the acquired im- ther alone (ICL) or accompanied by clinical signs and symp- mune deficiency syndrome, has been reported in the ab- toms of cellular immune deficiency (SUHIS). The etiology of sence of any known etiology. The pathogenesis of this syn- this syndrome is unclear and, given the lack of risk factors for drome, a subset of idiopathic CD4؉ T lymphocytopenia acquisition of HIV infection in most individuals, absence of a -ICL), is uncertain. We report that CD4؉ T cells from clear epidemiologic pattern, diversity of prodromes, and tran) seven of eight ICL patients underwent accelerated pro- sient nature of many cases, almost certainly multifactorial. grammed cell death, a process facilitated by T cell receptor We recently distinguished a subset of ICL patients mimick- cross-linking. Apoptosis was associated with enhanced ex- ing HIV disease: severe, prolonged decrement in peripheral pression of Fas and Fas ligand in unstimulated cell popula- CD4ϩ T cells with progressive decline in such counts docu- tions, and partially inhibited by soluble anti-Fas mAb. In mented in some; CD4/CD8 T cell ratios Յ 1; and a history of addition, apoptosis was suppressed by aurintricarboxylic opportunistic infections (5, 6). This finding served as the impe- acid, an inhibitor of calcium-dependent endonucleases and tus to investigate mechanisms associated with T cell loss in proteases, in cells from four of seven patients. The in vivo HIV infection and other disorders which might also be etio- significance of these findings was supported by three fac- logic in ICL. tors: the absence of accelerated apoptosis in persons with Apoptosis of T lymphocytes in vitro, linked to transient T stable, physiologic CD4 lymphopenia without clinical im- cell loss in vivo, is a consequence of certain viral infections, in- mune deficiency; detection of serum antihistone H2B au- cluding lymphocytic choriomeningitis (7) and vaccinia (8) in toantibodies, one consequence of DNA fragmentation, in mice and EBV (9) in humans. It has also been reported in as- some patients; and its selectivity, with apoptosis limited to sociation with HIV-1 (10, 11) in humans, although whether or the CD4 population in some, and occurring among CD8ϩ T not direct HIV infection is required for this effect, and its spec- cells predominantly in those individuals with marked deple- ificity for CD4ϩ T cells, are subjects of debate (10–12). We tion of both CD4؉ and CD8؉ peripheral T lymphocyte sought to test the hypothesis that apoptosis plays a role in ICL subsets. These data suggest that patients with idiopathic associated with clinical immune deficiency and attempted to loss of CD4؉ T lymphocytes linked to clinical immune sup- relate the accelerated in vitro death of CD4ϩ T cells from pression have evidence for accelerated T cell apoptosis in these individuals with expression of two molecules linked to vitro that may be pathophysiologic and amenable to ther- programmed cell death, Fas and Fas ligand (13). We also eval- apy with apoptosis inhibitors. (J. Clin. Invest. 1996. 97:672– uated the ability of anti-Fas mAb and two drugs, aurintricar- 680.) Key words: aurintricarboxylic acid • cell death, pro- boxylic acid (ATA) and tamoxifen (TMX), known inhibitors grammed • immunologic deficiency syndromes • T lym- of two common pathways to apoptosis, Ca2ϩ-dependent endo- phocyte nuclease activation and cAMP signalling, respectively, to miti- gate this cell death. In vivo correlates were sought by assays Introduction for circulating antihistone H2B autoantibodies, one conse- quence of DNA fragmentation (12), and examination of lym- Marked CD4ϩ T lymphopenia in the absence of HIV infec- phocytes from patients with stable, “physiologic” CD4 lym- tion has been documented by our group (1) and others (2, 3). phopenia. Our results suggest the discrimination of a subset of This syndrome is termed idiopathic CD4ϩ T lymphocytopenia ICL patients with sustained T cell apoptosis that is clinically (ICL)1 by the U.S. Centers for Disease Control and Prevention relevant and may be amenable to therapy with inhibitors of programmed cell death. Address correspondence to Jeffrey Laurence, Cornell University Medical College, 411 East 69th Street, New York, NY 10021. Phone: Methods 212-746-2988; Fax: 212-746-8601. Received for publication 9 August 1995 and accepted in revised Patient selection. PBMC were prepared from heparinized venous form 31 October 1995. blood of eight ICL patients and four controls by density gradient cen- trifugation (14). The clinical data and risk factors for retroviral infec- 1. Abbreviations used in this paper: ATA, aurintricarboxylic acid; tion, if any, are shown in Table I. Only one of the ICL patients, ICL-1, ICL, idiopathic CD4ϩ T lymphocytopenia; PHA, phytohemagglutinin; has been previously reported (1). All subjects were seronegative for PKA, protein kinase A; RT, reverse transcriptase; TMX, tamoxifen. HIV-1,-2, and human T cell lymphotropic virus types I, II by ELISA and, HIV-1, by immunoblotting. No patient had an active infection at J. Clin. Invest. the time of study. All were receiving trimethoprim-sulfamethaxazole © The American Society for Clinical Investigation, Inc. prophylaxis against Pneumocystis carinii pneumonia. ICL-2, ICL-3, 0021-9738/96/02/0672/09 $2.00 and ICL-8 were also taking fluconazole as prophylaxis against crypto- Volume 97, Number 3, February 1996, 672–680 coccosis. Ig isotype levels were normal in all individuals except for 672 Laurence et al. Table I. Summary of Case Histories and DNA Histogram Analysis Lymphocyte phenotype per mm3 Cell cycle Analysis Risk factors for CD4/CD8 CD4ϩ apoptotic peak* Subject Age/sex retroviral infection Clinical findings CD4ϩ CD8ϩ ratio peak (AO) percent ICL-1 44/M Needlestick; Herpes zoster, intractable 124 125 0.99 43.8 bisexual papillomatosis, Bowen’s disease ICL-2 35/F Needlestick Cryptococcal meningitis 100 1200 0.08 39.0 ICL-3 55/M Worker, Cryptococcal 73 350 0.21 3.8 biohazardous meningitis, B cell waste disposal co. lymphoma ICL-4 32/M None Herpes simplex, fever 110 244 0.45 33.8 ICL-5 43/F None Pneumocystis carinii 120 133 0.90 39.9 pneumonia ICL-6 27/M None Cryptococcal meningitis 22 51 0.43 19.4 ICL-7 35/F Needlestick Thrush, progressive, 157 365 0.43 19.2 global dementia ICL-8 34/F None Cryptococcosis 104 100 0.96 30.7 * Determined by DNA histogram analysis of CD4ϩ T lymphocytes in PBMC maintained in culture for 72 h in the absence of exogenous stimuli. ICL-1, who had a monoclonal IgM spike on immunofixation. This 18). All experiments involved at least two patient samples obtained had been noted for the past seven years, without evidence for malig- Ն 2 mo apart, with Ao values usually varying by Յ15%. nancy. No evidence for active EBV or cytomegalovirus infection by Parallel cell aliquots were analyzed for fragmentation of genomic culture or serology was noted in any patient at the time of study. DNA. Low molecular weight DNA was prepared by lysis of 2 ϫ 106 PBMC cocultures with assay for HIV-1,2 p24 Gag antigen, and par- cells per condition in 0.4 ml of lysis buffer, consisting of 10 mM Tris- ticulate reverse transcriptase in culture supernatants, and amplifica- HCl, pH 7.5, 0.2% Triton X-100, and 1 mM EDTA, followed by cen- tion of PBMC DNA for HIV-1,-2 by PCR using gag primers (SK145 trifugation and precipitation of the supernatant with 0.1 ml 5 M NaCl and SK431, Perkin-Elmer, Foster City, CA), performed as previously and 0.5 ml isopropanol overnight at Ϫ20ЊC (10, 19, 20).
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