Huie Jing, PhD, Qian Zhang, MD, Yu Zhang, PhD, Brenna J

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Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype Huie Jing, PhD, Qian Zhang, MD, Yu Zhang, PhD, Brenna J. Hill, PhD, Christopher G. Dove, BS, Erwin W. Gelfand, MD, T. Prescott Atkinson, MD, PhD, Gulbu Uzel, MD, Helen F. Matthews, RN, Peter J. Mustillo, MD, David B. Lewis, MD, Fotini D. Kavadas, MD, I. Celine Hanson, MD, Ashish R. Kumar, MD, PhD, Raif S. Geha, MD, Daniel C. Douek, MD, PhD, Steven M. Holland, MD, Alexandra F. Freeman, MD, Helen C. Su, MD, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 6, Pages 1667-1675 (June 2014) DOI: 10.1016/j.jaci.2014.03.025 Copyright © 2014 Terms and Conditions

Fig 1 Mechanisms underlying somatic repair of DOCK8 mutations: representative examples. A, Left, second-site mutation in patient 3. Right, Original-site reversion in patient 4. Black and red arrows designate germline and somatic mutations identified from DNA of neutrophils and primary T cells, respectively. B, Gene conversion in patients 10 or 11. C, Intragenic single crossover in patient 9. Red and blue designate maternally and paternally derived alleles, respectively, as inferred by the genotyped SNPs and mutations. Hatching indicates mRNA. Additional details are provided in Figs E3 and E4. Journal of Allergy and Clinical Immunology 2014 133, 1667-1675DOI: (10.1016/j.jaci.2014.03.025) Copyright © 2014 Terms and Conditions

Fig 2 DOCK8-immunodeficient patients having T-cell reversions. A, Immunoblotting for DOCK8 or β-actin proteins in primary T cells, B cells, or monocytes. Patient 20 has a homozygous large deletion. Patients 12 and 10 have somatic repair. NC, Healthy control subject. B, Representative flow cytometric histograms showing intracellular DOCK8 expression in gated subsets from a healthy control subject (black), a DOCK8 heterozygous carrier (gray), patient 19 with a large homozygous deletion (red), or isotype control staining (blue). C, Histograms are from patient 12, who has somatic repair. Journal of Allergy and Clinical Immunology 2014 133, 1667-1675DOI: (10.1016/j.jaci.2014.03.025) Copyright © 2014 Terms and Conditions

Fig 3 Reversions in multiple T-cell clonotypes. TCRVβ repertoire analyses performed on purified T cells. A, Patient 12's cells also stained for intracellular DOCK8. Healthy control cells are shown in Fig E9. B, Patient 10's cells also stained for the indicated cell-surface markers. Vβ subsets are expressed as a percentage of each T-cell subset, as indicated in the key. Insets indicate the CDR3-sequenced clonotypes contained within the sorted cell subsets, with DOCK8-repaired clonotypes shown in boldface. Journal of Allergy and Clinical Immunology 2014 133, 1667-1675DOI: (10.1016/j.jaci.2014.03.025) Copyright © 2014 Terms and Conditions

Fig 4 Clinical scoring in patients with reversions. Patients with reversions (solid circles) were compared with those without (open circles). A, Age (median ± quartiles). B, Total clinical score. C, Clinical score stratified by age group. D, Atopic score. Scoring criteria are provided in Table E1. Fig 4, B and D, show means ± 95% CIs. P values were calculated by using the Mann-Whitney test. NS, Not significant. Journal of Allergy and Clinical Immunology 2014 133, 1667-1675DOI: (10.1016/j.jaci.2014.03.025) Copyright © 2014 Terms and Conditions