Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders Tomonori Kadowaki, MD, Hidenori Ohnishi, MD, PhD, Norio Kawamoto, MD, PhD,

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Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders Tomonori Kadowaki, MD, Hidenori Ohnishi, MD, PhD, Norio Kawamoto, MD, PhD, Tomohiro Hori, MD, PhD, Kenichi Nishimura, MD, Chie Kobayashi, MD, PhD, Tomonari Shigemura, MD, PhD, Shohei Ogata, MD, PhD, Yuzaburo Inoue, MD, PhD, Tomoki Kawai, MD, PhD, Eitaro Hiejima, MD, PhD, Masatoshi Takagi, MD, PhD, Kohsuke Imai, MD, PhD, Ryuta Nishikomori, MD, PhD, Shuichi Ito, MD, PhD, Toshio Heike, MD, PhD, Osamu Ohara, PhD, Tomohiro Morio, MD, PhD, Toshiyuki Fukao, MD, PhD, Hirokazu Kanegane, MD, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 4, Pages 1485-1488.e11 (April 2018) DOI: 10.1016/j.jaci.2017.10.039 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Pedigree of the families with heterozygous TNFAIP3 mutations. An asterisk (*) shows nonanalyzed genetically possible patients. B, Cytokine analysis of sera of patients with HA20. The number of controls, patients at the time of nonflare, and patients at the time of flare were 20, 15, and 6, respectively. C, Cytokine production levels by PBMCs. The number of controls and patients were 8 and 16, respectively. NS, Not significant. Journal of Allergy and Clinical Immunology 2018 141, 1485-1488.e11DOI: (10.1016/j.jaci.2017.10.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Western blot analysis of the PHA blasts of patients with HA20. The protein expression levels of A20 were reduced except for C243Y. Journal of Allergy and Clinical Immunology 2018 141, 1485-1488.e11DOI: (10.1016/j.jaci.2017.10.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Analyses of the splice site mutations of TNFAIP3. A, Genomic DNA analysis of P3 and P10. B and C, Complementary DNA analysis of the splice site mutations. The regions of TNFAIP3 in which the mutations c.1906+1G>A and c.2088+5G>C are located were amplified by PCR using the forward primer 5′-GAAGTGGACTTCAGTACAAC-3′ and the reverse primer 5′-GGTTACCAAACCTGAGCATC-3′, and then, Sanger DNA sequencing was performed. c.2088+5G>C showed an additional lower band of the predicted size (1998bp), and c.1906+1G>A also showed 1 more upper band. The direct sequencing of these PCR products showed that P3 had a heterozygous exon 8 skipping mutation and P10 had a heterozygous intron 7 insertion mutation. D, The western blot analysis of the PHA blasts of P3 and P10 using anti-A20 antibody. The protein expression levels of P3 and P10 were reduced. Journal of Allergy and Clinical Immunology 2018 141, 1485-1488.e11DOI: (10.1016/j.jaci.2017.10.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Western blot analysis of the HEK293T cells transfected with pcDNA3.1+ myc-A20 (WT or variants). The control subject showed the protein expression of myc-A20 corresponding to the predicted molecular weight size of 89.5 kDa. The protein expressions of R45X (5.2 kDa) and W85GfsX11 (11.2 kDa) could not be detected because of the detection limit of the gel. The expression level of C243Y was reduced. The other variants were detected as corresponding to the predicted molecular weight. Journal of Allergy and Clinical Immunology 2018 141, 1485-1488.e11DOI: (10.1016/j.jaci.2017.10.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 NF-κB reporter gene activity assay. The suppression of TNF-α–induced NF-κB activity by the variants of TNFAIP3 was significantly lower than that of WT, except for C243Y. NF- κB, Nuclear factor-κB. Journal of Allergy and Clinical Immunology 2018 141, 1485-1488.e11DOI: (10.1016/j.jaci.2017.10.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Sanger sequencing of genomic DNA of Families 2 and 9. A, P3 had a heterozygous c.2088+5G>C mutation. In addition, the mother of P3 had a low-frequency mutation of TNFAIP3 in her DNA derived from peripheral blood. B, P21 had a heterozygous c.1245_1248del4 mutation. In addition, the father of P21 had a low-frequency mutation of TNFAIP3 in his DNA derived from peripheral blood. Journal of Allergy and Clinical Immunology 2018 141, 1485-1488.e11DOI: (10.1016/j.jaci.2017.10.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Flow cytometric analysis of TH17 cells. Upper panels (A) are representative flow cytometry plots of IL-4 and IL-17A expression by intracellular cytokine staining. Lower panels (B) are flow cytometry plots of IL-17A expression in patients with HA20 (n = 16) as compared with control subjects (n = 40). The cases are grouped into 3 categories: younger than 2 years, 2 years old to 15 years old, and older than 15 years. The proportion of TH17 cells in patients with HA20 (3.3% ± 3.5%) was significantly higher than that of control subjects (1.4% ± 0.7%; P = .0006). TH9 cells were hardly detected in this study, in any condition. Journal of Allergy and Clinical Immunology 2018 141, 1485-1488.e11DOI: (10.1016/j.jaci.2017.10.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Clinical manifestations of P3, P4, P9, and P22. A, P3 had swelling of the left middle finger from age 6 months. The fingers' X-ray findings showed bone thickening at the proximal phalanx of the left middle finger (red arrow). B, Gadolinium-enhanced T1 imaging of the lower limbs of P3 showed polyarthritis including the enthesitis of his left Achilles tendon (red arrows). The left and right of the figure show an axial section and a coronal section, respectively. C, Psoriatic skin rash of P3 at the age of 2 years and 5 months. The skin biopsy of his psoriatic skin lesion. The epidermis with scabbing and neutrophil infiltration, and swelling of dermal papillae with lymphocyte infiltration were observed. D, Abdominal contrast-enhanced computed tomography during flare of P4. Abdominal lymphedema (red arrow) and mild intestinal edema (white arrows) were observed. E, Excess impetigo crustose on the inoculation site of BCG vaccine of P9 after a febrile episode at the age of 9 months. F, Colonoscopy findings of P22. Ulceration at the ileum side (black arrow) of Bauhin's valve was observed. Journal of Allergy and Clinical Immunology 2018 141, 1485-1488.e11DOI: (10.1016/j.jaci.2017.10.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions