A novel LPS-responsive beige-like anchor protein (LRBA) mutation presents with normal cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and overactive.

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Presentation transcript:

A novel LPS-responsive beige-like anchor protein (LRBA) mutation presents with normal cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and overactive TH17 immunity Marieke De Bruyne, MSc, Delfien J. Bogaert, MD, PhD, Koen Venken, PhD, Lien Van den Bossche, PhD, Carolien Bonroy, MPharm, PhD, Lisa Roels, BSc, Simon J. Tavernier, MD, PhD, Els van de Vijver, MD, Ann Driessen, MD, PhD, Marielle van Gijn, PhD, Laura Gámez-Diaz, PhD, Dirk Elewaut, MD, PhD, Bodo Grimbacher, MD, Filomeen Haerynck, MD, PhD, Nicolette Moes, MD, PhD, Melissa Dullaers, PhD Journal of Allergy and Clinical Immunology Volume 142, Issue 6, Pages 1968-1971 (December 2018) DOI: 10.1016/j.jaci.2018.08.026 Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A novel LRBA splice site mutation causes skipping of exon 21 and abolishes LRBA protein expression. A, Pedigree. B, Intestinal histology of duodenum and colon. At diagnosis (age 3 months), there is complete mucosal destruction, villous atrophy, infiltration with immune cells, and apoptosis. Under immunosuppressive treatment, we see restructuring of intestinal mucosa, disappearance of inflammatory cells, and return of villi in the small intestine. C, Schematic representation of the LRBA protein structure. The here-reported mutation is indicated with an arrow. D, Expression of LRBA mRNA relative to GPI and PSMB2, as determined by real-time quantitative PCR on PHA blasts of the patient and 3 HCs. E, Western blot for LRBA protein on PBMCs of the patient and 3 HCs. Beta-actin was used as a loading control. F, Detection of LRBA by intracellular flow cytometry in unstimulated (rest) and PHA-activated PBMC. LRBA is shown as a univariate histogram in alive lymphocytes. Numbers in the upper right corners represent the fold increase in LRBA fluorescence in response to activation. HC, Healthy control. Journal of Allergy and Clinical Immunology 2018 142, 1968-1971DOI: (10.1016/j.jaci.2018.08.026) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Patient presents normal CTLA-4 expression, normal Treg-cell function, and overactive TH17 function. A, Treg-cell CTLA-4 expression was measured intracellularly and on the surface (mobilized) in resting state and upon activation with PMA-ionomycin for 30 minutes. Patient cells taken at different ages were tested in 3 independent experiments; age is marked (mo = months old). HCs were 27 to 35 years old. B, Patient's (2 years old) and pediatric HC's (12 years old) Treg cells were sorted as CD25highCD127low CD4+ T cells and cultured with CFSE-labeled conventional CD4+ T cells (CD25lowCD127high, Tcon) at indicated Treg:Tcon ratios and stimulated with anti-CD3/CD28 dynabeads for 4 days. Proliferation was measured by CFSE dilution using flow cytometry (left panel) and proliferation indexes were calculated for the different Treg:Tcon ratios (right panel). Results shown are mean ± SD of 3 replicates. C, Intracellular flow cytometry staining for IL-17A and IFN-γ upon activation of PBMCs with PMA-ionomycin for 18 hours. Results are shown in memory CD45RO+CD4+ T cells. Adult (n = 10) and age-matched (n = 8, aged 18 months-8 years) HCs are shown in comparison. D, Cytokine secretion by PBMC upon activation with SEB for 48 hours as measured by ELISA. Cells were first allowed to metabolize sirolimus ex vivo for 6 hours. Rapamycin and abatacept were supplemented to the cultures as indicated. Results are Tukey plots of 2 replicates of 2 HCs each, or of 2 different patient samplings. CFSE, Carboxyfluorescein diacetate succinimidyl Ester; HC, healthy control; MFI, mean fluorescence intensity; SEB, staphylococcal enterotoxin B. Journal of Allergy and Clinical Immunology 2018 142, 1968-1971DOI: (10.1016/j.jaci.2018.08.026) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions