Zeynep Yesim Kucuk, MD, Louis-Marie Charbonnier, PhD, Richard L

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CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder Zeynep Yesim Kucuk, MD, Louis-Marie Charbonnier, PhD, Richard L. McMasters, MD, Talal Chatila, MD, MSc, Jack J. Bleesing, MD, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 3, Pages 862-864.e4 (September 2017) DOI: 10.1016/j.jaci.2017.02.032 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Histopathology of submandibular gland. A, Low-power view (hematoxylin and eosin [H&E], 11×) shows thick pink bands of collagen fibrosis, destruction of acini, and ectopic (inducible) MALT with secondary lymphoid follicles containing expanded germinal centers. A single secondary lymphoid follicle is highlighted by the box. B, Low-power view (H&E, 11×) of a normal gland from a control patient shows an absence of fibrosis and preserved acini. Arrows point to a few subtle tiny lymphoid aggregates without germinal centers, which are not considered to be ectopic MALT. C, High-power view (H&E, 44×) of the secondary lymphoid follicle, highlighted by the box in A. The center contains an expanded, pale-staining germinal center, which is surrounded by a dark blue outer mantle zone. D-K, Immunohistochemical stains (44×) confirm that the secondary lymphoid follicle has fully developed architecture. Abundant CD20+ B cells are present in both the germinal center and mantle zone, whereas relatively few CD3+ T cells are present in the germinal center. CD4+ T cells outnumber CD8+ T cells and there is no obvious increase in DNTs. The germinal center contains a mixture of BCL6+ follicular center cells, CD21+ follicular dendritic cells, and PD1+ follicular helper/regulatory T cells. BCL2 stains the B cells in the mantle zone and all of the T cells. It does not stain the BCL6+ follicular dendritic cells. Journal of Allergy and Clinical Immunology 2017 140, 862-864.e4DOI: (10.1016/j.jaci.2017.02.032) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 A, Peripheral blood: frequency of FOXP3+ CD4+ T cells and expression of Treg canonical markers. CD25, CD127, CTLA4, and Helios in a healthy control (HC), father, healthy mutant mother, and patient. Right upper numbers, which are included in the quadrants for each marker, represent MFI for each subject. Normal % of FOXP3+ CD4+ T cells with decreased expression of canonical Treg markers for CD25 and CTLA4 in the patient and healthy mutant mother. B, Peripheral blood: frequency of follicular T helper (TFH) and follicular T regulatory (TFR) cells. Frequency of CXCR5+PD1+TFH and CXCR5+PD1+FOXP3+ TFR cells in CD4+ T and TFH cells, respectively, in HC, father, healthy mutant mother and patient PBMCs. Expanded TFH cells with contraction of TFR cells in the patient, but not in healthy mother. Circulating TFH cells in patient express more IL-21, but not IL-2, than TFH cells in healthy controls. C, Treg suppression function. Treg suppression function is impaired in the patient, but normal in healthy mutant mother (right upper figure). ∗P <.05 and ∗∗P <.01 by 2-way ANOVA with posttest analysis. Journal of Allergy and Clinical Immunology 2017 140, 862-864.e4DOI: (10.1016/j.jaci.2017.02.032) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 A, Peripheral blood: frequency of FOXP3+ CD4+ T cells and expression of Treg canonical markers. CD25, CD127, CTLA4, and Helios in a healthy control (HC), father, healthy mutant mother, and patient. Right upper numbers, which are included in the quadrants for each marker, represent MFI for each subject. Normal % of FOXP3+ CD4+ T cells with decreased expression of canonical Treg markers for CD25 and CTLA4 in the patient and healthy mutant mother. B, Peripheral blood: frequency of follicular T helper (TFH) and follicular T regulatory (TFR) cells. Frequency of CXCR5+PD1+TFH and CXCR5+PD1+FOXP3+ TFR cells in CD4+ T and TFH cells, respectively, in HC, father, healthy mutant mother and patient PBMCs. Expanded TFH cells with contraction of TFR cells in the patient, but not in healthy mother. Circulating TFH cells in patient express more IL-21, but not IL-2, than TFH cells in healthy controls. C, Treg suppression function. Treg suppression function is impaired in the patient, but normal in healthy mutant mother (right upper figure). ∗P <.05 and ∗∗P <.01 by 2-way ANOVA with posttest analysis. Journal of Allergy and Clinical Immunology 2017 140, 862-864.e4DOI: (10.1016/j.jaci.2017.02.032) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions