Anticytokine autoantibodies in a patient with a heterozygous NFKB2 mutation Kesava A. Ramakrishnan, MD, William Rae, MRCP, Gabriela Barcenas-Morales,

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Anticytokine autoantibodies in a patient with a heterozygous NFKB2 mutation Kesava A. Ramakrishnan, MD, William Rae, MRCP, Gabriela Barcenas-Morales, PhD, Yifang Gao, PhD, Reuben J. Pengelly, PhD, Sanjay V. Patel, MRCPCH, Dinakantha S. Kumararatne, MD, FRCPath, Sarah Ennis, PhD, Rainer Döffinger, FRCPath, PhD, Saul N. Faust, FRCPCH, PhD, Anthony P. Williams, FRCPath, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 4, Pages 1479-1482.e6 (April 2018) DOI: 10.1016/j.jaci.2017.11.014 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Family pedigree consistent with a pattern of autosomal-dominant inheritance. B, Fluorescent traces showing NFKB2 c.2557C>T in I.1 and II.2, and absent in I.2. C, Western blot demonstrating the presence of a truncated NF-κB2 p100 subunit in the patient compared with control. Stimulation with anti-CD3, anti-CD3 and anti-CD70, or PHA shows minimal processing to NF-κB2 p52 in the patient. D, Reduced NF-κB2 p52 processing in an EBV cell line in response to noncanonical NF-κB pathway stimulation with CD40L in patients (I.1 and II.2) compared with unaffected relative (I.2). Graph showing relative NF-κB2 p52 production normalized to GAPDH from EBV cell-line lysates (see this article's Methods section). GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2018 141, 1479-1482.e6DOI: (10.1016/j.jaci.2017.11.014) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, TNF-α production from whole blood and washed PBMCs stimulated with lipotechoic acid (LTA) and LPS from II.2 (patient) was comparable to control. Whole blood from II.2 stimulated with LPS ± IFN-γ or LPS + IL-12 showed reduced IL-12 and IFN-γ production, respectively. Washed PBMCs under similar conditions showed reversal of abnormalities. B, Presence of IL12p40, IL-23, IFN-α, IFN-β, and IFN-ω ACAA in the serum of patient (II.2) and in patients with thymoma (n = 2) and APECED (n = 2) at a titration of 1:100. ACAAs were not present in 150 controls or I.1. C, Whole blood (WB) from II.2 stimulated with LPS ± IFN-α showed reduced TNF-α production in II.2 compared with control. PBMCs washed in either FCS, complete serum (CS), or PBS demonstrate normalized TNF-α production. D, Production of IFN-γ from control PBMCs stimulated with IL-12 + IL-18 in FCS, control serum, or II.2's serum (see this article's Methods section). APECED, Autoimmune polyendocrinopathy-candidasis-ectodermal dysplasia; Med, medium. Journal of Allergy and Clinical Immunology 2018 141, 1479-1482.e6DOI: (10.1016/j.jaci.2017.11.014) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Timeline of clinical course and therapeutic interventions. Illustration of the clinical timeline of events and therapeutic interventions. RTA, renal tubular acidosis; SCIG, subcutaneous immunoglobulin replacement 0.1 g/kg/wk; steroids, tapering course of prednisolone. *Sampling for ACAAs. Journal of Allergy and Clinical Immunology 2018 141, 1479-1482.e6DOI: (10.1016/j.jaci.2017.11.014) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Whole-exome filtering of variants. 1, LRRC8A encodes a protein that functions as a volume-regulated anion channel by forming heteromers with other LRRC8 proteins. A single case of a patient with a de novo balanced t(9;20)(q33.2;q12) that resulted in a dominant negative-acting truncated LRRC8A protein is previously reported with the phenotype of agamaglobulinemia, absent B cells due to pre–B-cell arrest, and minor facial anomalies.E1 The missense variant LRRC8A:NM_001127245:exon2:c.G294T:p.K98N (PolyPhen 0.038:benign, SIFT 0.03:deleterious) present in both I.1 and II.2 is absent in the ExAC database; however, many missense variants in LRRC8A that are located near this variant are present in the ExAC database (http://exac.broadinstitute.org/gene/ENSG00000136802) at a frequency greater than expected for the reported phenotype. I.1 and II.2 do not display a similar phenotype to that reported for LRRC8A-dominant negative variants,E1 because they do not have pre–B-cell arrest, or agammaglobulinemia (Table E1), or facial anomalies. It appears unlikely that this missense variant contributes the phenotype of I.1 or II.2. 2, NFKB2:NM_001077494:exon22:c.C2557T:p.R853X has been reported to cause an autosomal-dominant CVID with autoimmunity.E2 This variant segregated with disease and the clinical phenotype of autoimmunity including alopecia, trachonychia, and bronchiectasis is similar to that reported. Journal of Allergy and Clinical Immunology 2018 141, 1479-1482.e6DOI: (10.1016/j.jaci.2017.11.014) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Western blot of NFKB2 p100 and p52 subunits from I.2 and II.2. Whole-cell lysates showing the expression of the truncated NFKB2 p100 subunit as well as wild-type allele p100 protein in the proband (II.2). I.2 (unaffected) shows only wild-type NFKB2 p100 with only a single band present. Journal of Allergy and Clinical Immunology 2018 141, 1479-1482.e6DOI: (10.1016/j.jaci.2017.11.014) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 ACAA titers pre-RTX and post-RTX and responses to RTX therapy. Means ± SD of titrations of serum antibodies to IL12p40, IFN-α, IFN–ω, and IFN-β. Data show MFI of titrations for patient's sera taken over a period of 6 years before RTX (pre-RTX) (n = 7) and means ± SD of sera taken after RTX (post-RTX) (n = 4). Data normal distribution checked by Shapiro-Wilk test and statistical analysis performed by paired t test. MFI, Mean fluorescent intensity; RTX, rituximab. *P < .05, **P < .01. Journal of Allergy and Clinical Immunology 2018 141, 1479-1482.e6DOI: (10.1016/j.jaci.2017.11.014) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions