A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency Haifa H. Jabara, BSc, Toshiro Ohsumi, PhD,

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A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency Haifa H. Jabara, BSc, Toshiro Ohsumi, PhD, Janet Chou, MD, Michel J. Massaad, PhD, Halli Benson, BSc, Andre Megarbane, MD, PhD, Eliane Chouery, PhD, Raymond Mikhael, MD, Oliver Gorka, MD, Andreas Gewies, PhD, Pierre Portales, MD, Toshinori Nakayama, MD, PhD, Hiroyuki Hosokawa, PhD, Patrick Revy, PhD, Henry Herrod, MD, Francoise Le Deist, MD, PhD, Gerard Lefranc, PhD, Jürgen Ruland, MD, Raif S. Geha, MD Journal of Allergy and Clinical Immunology Volume 132, Issue 1, Pages 151-158 (July 2013) DOI: 10.1016/j.jaci.2013.04.047 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Schematic representation of the NF-κB activation after ligation of the TCR. TCR ligation causes SRC/Syk kinase and Zap-70–dependent activation of protein kinase C θ (PKCθ), which phosphorylates CARMA1/CARD11. This enables recruitment of BCL-10 and MALT1, followed by oligomerization of the CBM complex. The CBM complex activates TNF receptor-associated factor 6 (TRAF6), which results in the K63 ubiquitinylation (Ub) of NEMO (NF-κB essential modulator) and activation and the IκB kinase (IKK) complex. Activated IKK2 phosphorylates the inhibitor IκBα, resulting in its K48 ubiquitination and degradation by the proteasome. This frees the p50 and p65/RelA subunits of NF-κB from IκBα, permitting NF-κB to undergo nuclear translocation and to initiate gene transcription necessary for cellular activation, including IL-2. Syk, Spleen tyrosine kinase. Journal of Allergy and Clinical Immunology 2013 132, 151-158DOI: (10.1016/j.jaci.2013.04.047) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Family pedigree of the patients and T-cell proliferation to mitogens and antigens. A, Family pedigree. Numbers refer to members studied. B and C, Response of PBMCs from the patients (Pt) to mitogens (B) and antigens (C) expressed as percentage of the proliferation of PBMCs from 2 healthy adult controls (C). Values represent mean ± SE of 2 independent determinations. *P < .05 and ***P < .001. Con A, Concanavalin A; DT, diphtheria toxin; PWM, pokeweed mitogen; TT, tetanus toxoid. Journal of Allergy and Clinical Immunology 2013 132, 151-158DOI: (10.1016/j.jaci.2013.04.047) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 MALT1 mutation in the patients. A, Electrophoregram depicts the c.266G>T mutation in patient (Pt) 1 and her father. B, Genomic organization of MALT1 (top) and protein structure (bottom) of MALT1. Blue boxes represent exons. The mutation in exon 2 is shown. C, Alignment of MALT1 homologues. D, RT-PCR analysis of MALT1 mRNA in PHA T blasts. E, Immunoblot analysis of MALT1 in lysates of PHA T-cell blasts. Data are representative of 2 experiments. GAPDH, Glyceraldehyde phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2013 132, 151-158DOI: (10.1016/j.jaci.2013.04.047) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Impaired IκBα degradation and IL-2 expression in the patient's T cells. Intracellular FACS analysis of IκBα degradation (left panels) and intracellular IL-2 expression (right panels) in gated CD3+ T cells after stimulation of PHA T-cell blasts from patient 1 and a control with PMA + IO. Data are representative of 2 experiments. Journal of Allergy and Clinical Immunology 2013 132, 151-158DOI: (10.1016/j.jaci.2013.04.047) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Failure of the MALT1 mutant to reconstitute IκBα degradation and IL-2 expression in T cells from Malt1−/− mice. A, Intracellular FACS analysis of IκBα and IL-2 in PMA + IO–stimulated CD4+ T cells from Malt1−/− mice that were uninfected or transduced with human WT or mutant MALT1 and Thy1.1. Gated CD4+Thy1.1high and CD4+Thy1.1low cells were analyzed. The fluorescence intensity of Thy1.1high cells was comparable in cells transduced with mutant and WT MALT1. Data are representative of 2 experiments. B, Kinetic analysis of IκBα degradation after stimulation with PMA + IO. Journal of Allergy and Clinical Immunology 2013 132, 151-158DOI: (10.1016/j.jaci.2013.04.047) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions