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Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment  Federica Cattaneo, MD, Mike.

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Presentation on theme: "Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment  Federica Cattaneo, MD, Mike."— Presentation transcript:

1 Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment  Federica Cattaneo, MD, Mike Recher, MD, Stefania Masneri, MS, Sachin N. Baxi, MD, Claudia Fiorini, PhD, Francesca Antonelli, BS, Christian A. Wysocki, MD, PhD, Jose G. Calderon, MD, Hermann Eibel, PhD, Angela R. Smith, MD, MS, Francisco A. Bonilla, MD, PhD, Erdyni Tsitsikov, PhD, Silvia Giliani, PhD, Luigi D. Notarangelo, MD, Sung-Yun Pai, MD  Journal of Allergy and Clinical Immunology  Volume 131, Issue 4, Pages (April 2013) DOI: /j.jaci Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Analysis of patients with JAK3 mutations. A, Pedigrees of patient 1 (P1), patient 2 (P2) and patient 3 (P3). B, Schematic representation of the JAK3 gene with the location of primers used to amplify cDNA and of mutations (*patients 1 and 2; #patient 3). C, Expression of JAK3 protein by Western blotting on B-LCLs of a null JAK3 patient, a positive control subject (C), and patient 1 (Pt). D, Phosphorylated STAT5 by Western blotting with or without stimulation with IL-2 of B-LCLs from patient 1 (Pt), a JAK3 null patient (JAK3−/−), and a healthy control subject (C). E, Quantification of JAK3 message by means of real-time PCR in B-LCLs from patient 1 (Pt) and a control subject (C). F, RT-PCR analysis of JAK3 RNA spanning exons 9 to 13 and 9 to 15, showing a lower-sized band in the patient. G, Direct sequencing of the lower-sized band obtained by using RT-PCR in patient 1 revealed the complete skipping of exons 12 and 13 of the JAK3 cDNA. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Phenotypic and functional studies of peripheral B cells. A, Percentages of transitional (CD24hiCD38hi) and marginal zone–like (CD24hiCD38low) B cells for adult control subjects, patient 1 (P1), and patient 3 (P3). B, Percentage of CD19+ B cells from an adult control subject (mother of patient 1) or patient 1 that diluted CFSE in response to the stimuli indicated. C, Percentage of plasmablasts (CD19+CD27+CD38++) from an adult control subject, patient 1 (P1; left panel), and patient 3 (P3; right panel) expressing high levels of CD27 and CD38 after culture with the indicated stimuli. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 TCR Vβ repertoire in peripheral T cells from patient 1 (P1) and patient 3 (P3). The percentages of CD3+, CD3+CD4+, or CD3+CD8+ T cells expressing the indicated TCR Vβ families are depicted compared with published norms for adults. Vβ families were expressed at less than (open circles), within (solid squares), or greater than (open triangles) the normal range. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Phenotypic characteristics of maternally engrafted and host-derived autologous peripheral T cells in patient 1 (P1) and patient 2 (P2). A, The left 2 panels show that CD3+ cells from patients 1 and 2 contain both HLA-A2+ (maternally derived) and HLA-A2− (autologous) populations. The proportion of maternally derived and autologous CD4+, CD8+, and CD19+ cells in patients 1 and 2 is shown in the right 8 panels. B, HLA-A2+ and HLA-A2− cells from patient 1 were electronically gated, and expression of CD45RA is shown (left panel). Control cells from an HLA-A2+ adult is shown for comparison (right panel). C, CD45RA and CD31 expression in CD4 cells from patient 1 and an adult control subject are shown. D, CD3+ T cells from patient 1 were electronically gated according to HLA-A2 expression, and Vβ repertoire is depicted as in Fig 3. E, CD4+CD45RA− T cells and CD8+CD45RA− T cells from patient 1 (left panel) were analyzed for expression of HLA-A2, HLA-DR, and CD62L. Control cells from an HLA-A2+ adult are shown in the right panel. F, CD3+ T cells from patient 1 were analyzed for expression of HLA-A2 and Ki67. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Analysis of apoptosis and proliferation of maternally engrafted and autologous peripheral T cells in patient 1 (P1). A, Staining with Annexin V reagent in freshly isolated CD4+ and CD8+ T cells from patient 1. B, Staining of CD4+ and CD8+ T cells with Annexin V reagent after 3 days of culture in the indicated stimuli for an adult control subject (red), HLA-A2− autologous cells from patient 1 (blue), and HLA-A2+ maternally engrafted cells from patient 1 (green). C, Cells from an adult control subject, patient 1 cultured in bulk, or patient 1 magnetically separated into HLA-A2–expressing and nonexpressing fractions were cultured for 3 days after CFSE labeling. HLA-A2 expression profile after culture (left) and CFSE and HLA-DR expression (right). D, Proliferation of T cells from patient 1 and her mother to irradiated allogeneic targets from the indicated donors in mixed lymphocyte culture. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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