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Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B- cell dysfunction in patients with Smith-Magenis syndrome  Javier Chinen,

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Presentation on theme: "Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B- cell dysfunction in patients with Smith-Magenis syndrome  Javier Chinen,"— Presentation transcript:

1 Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B- cell dysfunction in patients with Smith-Magenis syndrome  Javier Chinen, MD, PhD, Monica Martinez-Gallo, PhD, Wenli Gu, PhD, Montserrat Cols, PhD, Andrea Cerutti, MD, Lin Radigan, Li Zhang, PhD, Lorraine Potocki, MD, Marjorie Withers, MS, James R. Lupski, MD, PhD, Charlotte Cunningham-Rundles, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 127, Issue 6, Pages (June 2011) DOI: /j.jaci Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Decreased extracellular and intracellular expression of TACI in patients with SMS. EBV-transformed B-cell lines from patients with SMS (n = 29), including 4 patients with SMS with 2 TACI alleles and healthy donor control subjects (n = 4) were analyzed. MFIs of both measurements of each subject are shown (correlation coefficient, r = 0.89; P = .001). Open circles, Patients with SMS with the deletion including TACI; solid circles, patients with SMS with 2 TACI alleles; squares, healthy donors. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Decreased TACI protein levels in cytoplasm of B cells from patients with SMS. Green fluorescent intensity in B cells stained with fluorescein isothiocyanate–labeled anti-human TACI antibody is decreased in the cytoplasm of patients with SMS with 1 TACI allele deleted. DAPI (4′,6-diamidino-2-phenylindole) was used to stain the cell nucleus. HD, Healthy donor control; 1190, patient with SMS with 2 TACI alleles; 1402 and 699, patients with SMS with 1 TACI allele deleted. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 APRIL binding to TACI receptor is associated with extracellular TACI expression. EBV-transformed B-cell lines from patients with SMS and healthy donor control subjects were incubated with FLAG-tagged megaAPRIL, followed by biotinylated anti-FLAG antibody and subsequent streptavidin-PE, and then analyzed by means of flow cytometry. MFIs are plotted against extracellular TACI MFIs, showing significant association between these 2 measurements (P = .007, Pearson correlation test). Open circles, Patients with SMS with the deletion including TACI; solid circles, patients with SMS with 2 TACI alleles; squares, healthy donor control subjects. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 TACI mRNA expression in patients with SMS might be decreased. A, TACI mRNA expression in B cells from 2 patients with SMS with deletion of 1 copy of the TACI gene (patients 1402 and 699) and 1 subject with no deletion of TACI (patient 1615) was decreased compared with that seen in B cells from a healthy donor. TACI sequences corresponding to exons 1 to 3 and exons 3 to 5 were amplified by means of RT-PCR and examined by means of gel electrophoresis. Two bands shown for exons 1 to 3 correspond to the known 2 isoforms. β-Actin mRNA was amplified as the control for mRNA amount. M, 1-Kb Ladder DNA marker; HD, healthy donor control subject. B, Box plot illustrates means ± SEMs of TACI exon 3 to 5 copy number values by using β-actin copies as a reference. HD, Healthy donor control subjects (n = 6); SMS +/+, patients with SMS with 2 TACI alleles (n = 3); SMS +/−, patients with SMS with the common 17p11.2 deletion, with 1 TACI allele deleted (n = 4). ∗∗P = .42. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 TLR9-induced TACI surface expression is impaired in patients with SMS. B cells isolated from fresh blood samples of patients with SMS with loss of 1 TACI allele and from healthy control subjects were incubated with or without the oligonucleotide ODN2006 for 48 hours, and TACI expression was examined by means of flow cytometry. The ratio of MFIs obtained from TACI staining of the TLR9-stimulated cells over unstimulated cells and measured by means of flow cytometry were recorded and are presented on the y-axis with regard to the concentration of the oligonucleotide in the culture media. B cells from patients with SMS have impaired upregulation of B-cell surface expression of TACI over baseline. HD, Healthy donor control subjects (n = 5); SMS, patients with SMS with deletion of 1 TACI allele (n = 4). Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Upregulation of AICD expression by TACI activation is compromised in patients with SMS. AICD mRNA expression was measured by means of quantitative PCR after incubation of B cells with an agonist anti-TACI antibody or with an isotype as control. β-Actin mRNA expression was used as a reference to determine the fold of AICD expression. B-cell lines of patients with SMS with 1 TACI allele deleted (SMS TACI +/−, n = 5) were not able to induce AICD mRNA expression after stimulation with an agonist anti-human TACI antibody. HD, Healthy donor control subject; SMS TACI +/+, patients with SMS with 2 TACI alleles (patients 1106 and 1615) showed comparable AICD mRNA induction. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 Protective serum levels of antibody against pneumococcal serotypes were more likely to be present in patients with SMS with “near-normal” TACI expression. Blood serum titers of 12 anti-pneumococcal serotype antibodies were measured in blood serum samples of 17 patients with SMS, including 2 patients without TACI deletion. The number of these antibodies at protective titers (>1 μg/mL) in each subject is charted with regard to the degree of extracellular TACI expression in B cells. Three categories of TACI expression were established according to the MFI value obtained by means of flow cytometry: low (MFI <30), intermediate (MFI >30 and <70), and near normal (MFI >70). ∗Includes 2 patients with SMS without TACI allele deletion. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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