BACKGROUND Idiopathic CD4 lymphopenia (ICL) is defined by persistently low CD4+ cell counts (<300 cells/μL) in the absence of a causal infection or immune deficiency and can manifest with opportunistic infections. Approximately 30% of ICL patients develop autoimmune disease. The prevalence and breadth of their autoantibodies, however, and their potential contribution to pathogenesis of ICL remain unclear.METHODS We hybridized 34 and 51 ICL patients’ sera to a 9,000-human-proteome array and to a 128-known-autoantigen array, respectively. Using a flow-based method, we characterized the presence of anti-lymphocyte Abs in the whole cohort of 72 patients, as well as the Ab functional capability of inducing Ab-dependent cell-mediated cytotoxicity (ADCC), complement deposition, and complement-dependent cytotoxicity (CDC). We tested ex vivo the activation of the classical complement pathway on ICL CD4+ T cells.RESULTS All ICL patients had a multitude of autoantibodies mostly directed against private (not shared) targets and unrelated quantitatively or qualitatively to the patients’ autoimmune disease status. The targets included lymphocyte intracellular and membrane antigens, confirmed by the detection by flow of IgM and IgG (mostly IgG1 and IgG4) anti–CD4+ cell Abs in 50% of the patients, with half of these cases triggering lysis of CD4+ T cells. We also detected in vivo classical complement activation on CD4+ T cells in 14% of the whole cohort.CONCLUSION Our data demonstrate that a high prevalence of autoantibodies in ICL, some of which are specific for CD4+ T cells, may contribute to pathogenesis, and may represent a potentially novel therapeutic target.TRIAL REGISTRATION ClinicalTrials.gov NCT00867269.FUNDING NIAID and National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH.


Ainhoa Perez-Diez, Chun-Shu Wong, Xiangdong Liu, Harry Mystakelis, Jian Song, Yong Lu, Virginia Sheikh, Jeffrey S. Bourgeois, Andrea Lisco, Elizabeth Laidlaw, Cornelia Cudrici, Chengsong Zhu, Quan-Zhen Li, Alexandra F. Freeman, Peter R. Williamson, Megan Anderson, Gregg Roby, John S. Tsang, Richard Siegel, Irini Sereti


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