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.
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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

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Figure 1

ICL patients have increased prevalence of IgG and IgM autoantibodies compared with healthy controls.

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ICL patients have increased prevalence of IgG and IgM autoantibodies com...
Sera from 51 ICL patients and 25 HCs were screened for autoantibodies using a high-throughput 124 autoantigen microarray platform. (A) Volcano plots of the IgG and IgM autoantibodies, on the left and the right, respectively, displaying –log10(P value) on the y axis versus log2 (average Ab score in ICL samples/average Ab score in HC samples) on the x axis. Each circle represents an autoantibody, highlighting in blue (IgG) or green (IgM) the statistically significant positive autoantibodies between the HC and ICL groups, calculated with the nonparametric Mann-Whitney test with Bonferroni’s correction. Only targets having P < 0.05/122 (with 122 being the number of comparisons) were considered significant and are highlighted. (B) Venn diagram showing antigens recognized by both IgG and IgM (pink) vs. by only IgG (blue) or only IgM (green) autoantibodies. (C) Number of autoantibody targets with Z ≥ 4 for HCs and each subgroup of ICL patients. Z scores for each target were calculated as the number of standard deviations the Ab score was above the mean of the HC Ab score for of each target. Group 1 (open circles, n = 22) corresponds to ICL patients without a diagnosed autoimmune disease and without a positive test for a set of clinical autoantibodies. Group 2 (cyan circles, n = 15) corresponds to patients who tested positive for clinical autoantibodies but did not meet clinical criteria for any specific autoimmune diagnosis. Group 3 (blue circles, n = 14) corresponds to patients who had been diagnosed with 1 or more autoimmune disease. Data were pooled from 2 independent experiments. **P < 0.01; ***P < 0.001; ****P < 0.0001 by Kruskal-Wallis test and Dunn’s correction for multiple comparisons.