Taco W. Kuijpers, MD, PhD, Anton T. J

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Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency Taco W. Kuijpers, MD, PhD, Anton T.J. Tool, PhD, Ivo van der Bijl, Martin de Boer, Michel van Houdt, Iris M. de Cuyper, Dirk Roos, PhD, Floris van Alphen, Karin van Leeuwen, Emma L. Cambridge, Mark J. Arends, MBChB(Hons), PhD, MRCPath, Gordon Dougan, PhD, Simon Clare, PhD, Ramiro Ramirez-Solis, PhD, Steven T. Pals, MD, PhD, David J. Adams, PhD, Alexander B. Meijer, PhD, Timo K. van den Berg, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 1, Pages 273-277.e10 (July 2017) DOI: 10.1016/j.jaci.2016.09.061 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Clinical, histological, and in vitro findings in the patient. A-C, Remarkable clinical features of the affected index case, with skin manifestations appearing superficially, rather similar to vasculitic purpura-like lesions with poor wound repair under certain conditions. Skin biopsy showing small-vessel vasculitis with leukocytoclasia and thrombosis (D,arrow), and colon biopsy with severe active inflammation and crypt abscesses (E, arrows) (Hematoxylin and eosin, 200×). Defective chemotaxis over 3-μm pore-size filters (F), and F-actin polymerization in suspension after stimulation with C5a and fMLP (G, mean ± SEM, n = 7-9). fMLP, N-formylmethionine-leucyl-phenylalanine; MFI, mean fluorescence intensity; PAF, platelet-activation factor; RFU, relative fluorescence unit. Journal of Allergy and Clinical Immunology 2017 140, 273-277.e10DOI: (10.1016/j.jaci.2016.09.061) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 ARPC1B deficiency and Arpc1b-knock-out mouse model. A-C, Mass spectrometry analysis showing the significant difference in protein levels between the neutrophils of healthy controls and the patient (n = 3; Volcano plot in C); ARPC1A is absent in proteomics analysis in control platelets and neutrophils (data not shown). D, Absence of ARPC1B was confirmed by Western blotting with anti-ARPC1B antibody of PMN and platelet lysates. Anti–glyceraldehyde-3-phosphate dehydrogenase antibody was used as loading control (n = 3). WASP was present by Western blotting (data not shown). E, Vasculitis and renal glomerulonephritis in Arpc1b−/− mice with aortic vasculitis (200×; left panel), cardiac subendocardial vasculitis (200×; middle panel), and proliferative glomerulonephritis (400×; right panel). F, Kaplan-Meier curve for survival following infection of Arpc1b−/− and wild-type (WT) mice with S typhimurium M525. The results shown are pooled from 2 independent experiments of 8 mice each (4 males, 4 females; 16 mice total). In both experiments half of the Arpc1b−/− animals reach the severity limit (see Methods). PSM, peptide spectral matches. Journal of Allergy and Clinical Immunology 2017 140, 273-277.e10DOI: (10.1016/j.jaci.2016.09.061) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Actin localization on neutrophil activation. A, Polymerized F-actin was stained in control and patient PMNs. Polymerized actin staining on glass cover slide (red = actin, blue = nucleus). Control cells were activated by fMLP (upper panel) and compared with patient cells (lower panel) at the indicated time points. On activation with fMLP, the normal lamellipodia are not observed with the patient cells and instead the formation of filopodia are the major effect induced in the patient cells, which is in line with expected role of a dysfunctional Arp2/3 complex, resulting in lack of actin polymerization by branching. B, Polymerized F-actin was stained in control and patient platelets activated by collagen and showed defective spreading behavior similar to what was observed with neutrophils. These are representative for 3 independent experiments (see the Methods in the Online Repository). Journal of Allergy and Clinical Immunology 2017 140, 273-277.e10DOI: (10.1016/j.jaci.2016.09.061) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Neutrophil function tests. A, Protease release of control and patient PMNs after stimulation with fMLP, PAF/fMLP, cytochalasin B (CytoB)/fMLP, and TX-100 (maximal slope in relative fluorescence units [RFU]/min; mean ± SEM, n = 3). B, CD63 expression on control and patient PMNs after stimulation with fMLP, PAF/fMLP, and CytoB/fMLP (mean of 2 independent experiments). C, Nicotinamide adenine dinucleotide phosphate–oxidase activity was quantified as H2O2 release after stimulation with zymosan, serum-treated zymosan (STZ), PMA, or PAF/fMLP (nmol/L H2O2/min/106 PMNs; mean ± SEM, n = 4). (D) Killing of S aureus by control and patient PMNs. Killing was quantified by determining colony-forming units after incubation with PMNs at different time points, t = 0 was defined as 100% (mean ± SEM, n = 4). See the Methods in the Online Repository. Journal of Allergy and Clinical Immunology 2017 140, 273-277.e10DOI: (10.1016/j.jaci.2016.09.061) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Mild defect in patient platelet aggregation and activation to multiple ligands. A, Platelet aggregation was determined as double-colored events (see the Methods in the Online Repository). PMA (100 ng/mL), TRAP (20 μmol/L) and background levels without stimulation are shown (mean ± SEM, n = 4; *P < .05). B, Platelet expression of CD62P, CD63, and PAC-1 compared with CD61 upregulation (expressed as a ratio) on activation by TRAP (CD62P and CD63, platelet-rich plasma), or by collagen and PMA (PAC-1–CD61 ratio, washed platelets) (mean ± SEM; n = 3). Journal of Allergy and Clinical Immunology 2017 140, 273-277.e10DOI: (10.1016/j.jaci.2016.09.061) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Identification of ARPC1B c.191_195 TCAAGdelCCTGCCCins mutation. A, Screenshot from the Integrative Genome Viewer (Broad Institute, Cambridge, Mass) shows the exon 5 sequence reads from the ARPC1B gene of the patient obtained with the Ion Torrent PGM system. All reads show the c.191_195 TCAAGdelCCTGCCCins mutation. B, Electrophorograms are shown from the Sanger sequencing results obtained with the exon-5 forward primer. The pink shading indicates the start of the homozygous c.191_195 TCAAGdelCCTGCCCins mutation in the genomic DNA of the patient in exon 5 of ARPC1 gene (second row). The mother and father of the patient (third and fourth rows) show a heterozygous pattern. The healthy control (upper row) shows the wild-type sequence. Journal of Allergy and Clinical Immunology 2017 140, 273-277.e10DOI: (10.1016/j.jaci.2016.09.061) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Fibroblast migration and ARPC1A/ARPC1B expression. Comparison of fibroblast migration in a scratch assay showed no difference between patient and control cells in response to PDGF and FCS. A, Still images of patient and control cells after stimulation with 10% (vol/vol) FCS. B, Quantification of the wound area after 0, 15, 30, and 45 hours after stimulation (mean ± SD of 12 different areas). The wound area at t = 0 was defined as 100%. C, Western blot of patient and control fibroblast lysates (upper panel) and control fibroblasts and blood cell lysates (lower panel) with anti-ARPC1A antibody and actin as a loading control. Journal of Allergy and Clinical Immunology 2017 140, 273-277.e10DOI: (10.1016/j.jaci.2016.09.061) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions