The BLNK adaptor protein has a nonredundant role in human B-cell differentiation Chantal Lagresle-Peyrou, PhD, Michèle Millili, Sonia Luce, Annie Boned,

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Presentation transcript:

The BLNK adaptor protein has a nonredundant role in human B-cell differentiation Chantal Lagresle-Peyrou, PhD, Michèle Millili, Sonia Luce, Annie Boned, Hanem Sadek, Julien Rouiller, Pierre Frange, MD, Guilhem Cros, MD, Marina Cavazzana, MD, PhD, Isabelle André-Schmutz, PhD, Claudine Schiff, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 1, Pages 145-154.e3 (July 2014) DOI: 10.1016/j.jaci.2013.12.1083 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Analysis of bone marrow B-cell development in a patient with agammaglobulinemia. Bone marrow mononuclear cells harvested from the patient (12 years old) and from a control subject (20 years old) were analyzed by flow cytometry for cell surface expression of CD34 and CD19 (A); CD19, CD22, and cytoplasmic IgM (B). Journal of Allergy and Clinical Immunology 2014 134, 145-154.e3DOI: (10.1016/j.jaci.2013.12.1083) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 BLNK mutation in a patient with agammaglobulinemia. Electropherograms of genomic DNA from the patient and his parents by using BLNK-specific oligonucleotides. A homozygous g.844C>T substitution was found in the patient's CD34+ cells (A, top panel). This led to a p.R282X mutation in the BLNK protein (A, bottom panel) affecting levels of BLNK transcripts (B) and BLNK protein expression as assessed by flow cytometry analysis (C). Light gray represents the isotype-matched control for BLNK staining. Journal of Allergy and Clinical Immunology 2014 134, 145-154.e3DOI: (10.1016/j.jaci.2013.12.1083) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 BLNK mutation in a patient with agammaglobulinemia. Electropherograms of genomic DNA from the patient and his parents by using BLNK-specific oligonucleotides. A homozygous g.844C>T substitution was found in the patient's CD34+ cells (A, top panel). This led to a p.R282X mutation in the BLNK protein (A, bottom panel) affecting levels of BLNK transcripts (B) and BLNK protein expression as assessed by flow cytometry analysis (C). Light gray represents the isotype-matched control for BLNK staining. Journal of Allergy and Clinical Immunology 2014 134, 145-154.e3DOI: (10.1016/j.jaci.2013.12.1083) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Normal IgVH repertoire in the patient's pre-BI cells. VH-DH-JH sequences from the patient's (black bars, 106 sequences) and control pre-BI cells (gray bars, 117 sequences) are represented: VH1, VH3, and VH4 gene usage (A). IgVH CDR3 length in amino acids (B). Reading frame usage in the IgVH CDR3s is shown for some D segments (14, 5, and 5 patient's pre-BI sequences analyzed for DH3-22, DH2-15, and DH6-13, respectively (C). Journal of Allergy and Clinical Immunology 2014 134, 145-154.e3DOI: (10.1016/j.jaci.2013.12.1083) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Ectopic expression of BLNK in the patient's CD34+ cells leads to B-cell reconstitution in vivo. Patient's BM CD34+ cells were transduced ex vivo with either a lentiviral vector that contained BLNK cDNA or the empty lentiviral vector (mock) before injection into NSG mice (n = 2, BLNK-TD1 and BLNK-TD2 for BLNK lentiviral vector; n = 1, for the empty vector). Twelve weeks after transplantation, human CD45+ cells from the BM were analyzed for CD19 and IgM expression by flow cytometry. Journal of Allergy and Clinical Immunology 2014 134, 145-154.e3DOI: (10.1016/j.jaci.2013.12.1083) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Reconstitution of the IgVκ repertoire after BLNK expression in the patient's cells. IgVκ repertoires were obtained from sorted CD19+IgM− cells from the mock mouse (top, 6/26 different sequences), sorted CD19+IgM− cells (middle, 14/51 different sequences) and CD19+IgM+ cells (bottom, 44/61 different sequences) from the BLNK-TD2 mouse. Vk usage (left) and Jk usage (right) are indicated. The Vk genes are represented in the 5′-to-3′ direction on the IGk locus. Journal of Allergy and Clinical Immunology 2014 134, 145-154.e3DOI: (10.1016/j.jaci.2013.12.1083) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Detection of BLNK transcripts in the patient's transduced or mock-transduced CD34+ cells. Journal of Allergy and Clinical Immunology 2014 134, 145-154.e3DOI: (10.1016/j.jaci.2013.12.1083) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Ectopic expression of BLNK in the patient's CD34+ cells leads to B-cell reconstitution in vivo. Patient BM CD34+ cells were transduced ex vivo with either a lentiviral vector that contained BLNK cDNA or the empty lentiviral vector (mock) before injection into NSG mice (n = 2, BLNK-TD1 and BLNK-TD2 for BLNK lentiviral vector; n = 1, for the empty vector). Twelve weeks after transplantation, we analyzed by flow cytometry the expression of CD19 and IgM in the human CD45+ spleen population. Journal of Allergy and Clinical Immunology 2014 134, 145-154.e3DOI: (10.1016/j.jaci.2013.12.1083) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions