Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia
Ainhoa Perez-Diez, … , Richard Siegel, Irini Sereti
Ainhoa Perez-Diez, … , Richard Siegel, Irini Sereti
Published July 7, 2020
Citation Information: J Clin Invest. 2020;130(10):5326-5337. https://doi.org/10.1172/JCI136254.
View: Text | PDF
Clinical Research and Public Health Autoimmunity Immunology Article has an altmetric score of 6

Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia

Abstract

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.

Authors

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

×

Figure 5

Abs against CD4+ T cells from ICL plasma or sera cause complement deposition on, and complement-dependent cytotoxicity (CDC) of, CD4+ T cells.

Options: View larger image (or click on image) Download as PowerPoint
Abs against CD4+ T cells from ICL plasma or sera cause complement deposi...
(A) Representative staining of C3b deposition induced by ICL-9 plasma (solid magenta), ICL-9 Ig-depleted plasma (dotted magenta), or pooled plasma from 10 HC donors (solid black). (B) C3b deposition induced by ICL sera on HC CD4+ T cells, normalized to the deposition induced by HC sera. We considered a ratio ≥2 (dotted line) positive for complement deposition. Sera samples were categorized into 3 groups based on their anti-CD4 Abs: gray circles, patients with no Abs; blue circles, patients with IgG (and not IgM) Abs; and orange circles, patients with IgM Abs. Number in upper left corner represents the number of patients capable of inducing complement deposition out of the total. Numbers with arrows identify the ICL patients whose sera induced CDC of HC CD4+ T cells shown in C. Data pooled from 17 independent experiments. **P < 0.01 by 2 tailed Kruskal-Wallis test with Dunn’s multiple-comparisons test. (C) CDC induced by ICL sera (blue and orange circles) paired by dashed lines with the CDC obtained by the HC sera (open circles) in the same experiment and with the CDC obtained after Ig depletion (crossed circles). Data were pooled from 3 independent experiments where each of the 10 patients that tested positive for complement deposition shown in B was tested 2 to 3 times. Medians for both ICL and HC are shown. Same color code as in B with bigger and darker circles corresponding to patients with positive CDC, determined when the subtraction of percentage ICL killing minus percentage HC killing was greater than 20. In gray diamonds, a mouse IgG2a anti–human CD4 Ab was used as positive control, with and without Ig depletion.