Ζ Chain–associated protein of 70 kDa (ZAP70) deficiency in human subjects is associated with abnormalities of thymic stromal cells: Implications for T-cell.

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Presentation transcript:

ζ Chain–associated protein of 70 kDa (ZAP70) deficiency in human subjects is associated with abnormalities of thymic stromal cells: Implications for T-cell tolerance Pietro Luigi Poliani, MD, PhD, Elena Fontana, PhD, Chaim M. Roifman, MD, Luigi D. Notarangelo, MD Journal of Allergy and Clinical Immunology Volume 131, Issue 2, Pages 597-600.e2 (February 2013) DOI: 10.1016/j.jaci.2012.11.002 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Analysis of the thymic stromal compartment and nTreg cells from biopsy specimens of healthy subjects and ZAP70−/− patients. A, Morphometric analysis of normal and ZAP70−/− thymic sections (hematoxylin and eosin staining, ×4 original magnification) by using the Scanscope CS Aperio Scanner (Aperio Technologies, Vista, Calif) and a custom-provided script from Definiens Architect XD 2.0 image analysis software (Definiens, Wilmington, Del) that automatically discriminates cortical (green), medullary (light blue), and connective (yellow) areas. Quantification of corticomedullary ratio is shown in the plot on the right. c, Cortex; m, medulla. B, mTECs expressing UEA-1 and CLD4 are present in both normal and ZAP70−/− thymic biopsy specimens (brown staining, left panels, ×40 original magnification). Double staining for AIRE (nuclear brown staining) and IVL (cytoplasmic blue staining) highlights the presence of AIRE-expressing mTECs around the Hassall corpuscles (central panels, ×4 and ×60 original magnifications), although in ZAP70−/− thymuses AIRE+ cell numbers are significantly reduced (graph on the right). Hassall corpuscles in ZAP70−/− thymuses appear smaller and express only minimal amounts of IVL (central panels, blue staining) and thymic stromal lymphopoietin (TSLP; right panel, brown staining, ×60 original magnification). C, ZAP70−/− thymuses show a preserved expression of FOXP3+ thymocytes within the medullary region (brown nuclear signal, ×10 and ×40 original magnification in the left and right panels, respectively), although in a significantly reduced number compared with control thymus (right graph). Scale bars correspond to 500, 200, 50, and 20 μm, respectively, for ×4, ×10, ×40, and ×60 original magnification. In the graphs in Fig 1, B and C, for each of the indicated markers, the mean ± SD of positive cells per square millimeter measured in 10 different high-power fields for each thymus are shown. Journal of Allergy and Clinical Immunology 2013 131, 597-600.e2DOI: (10.1016/j.jaci.2012.11.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Distribution of DCs in thymic biopsy specimens from healthy subjects and ZAP70−/− patients. All thymic DCs belonging to the 3 major subsets (mDCs, CD11c+/CD163−; Langerhans cell DCs, S100+ and Langerin+; and pDCs, CD123+/BDCA2+) were significantly reduced in ZAP70−/− thymuses compared with those in healthy control subjects. For each marker, the mean ± SD of positive DCs per square millimeter measured in 10 different high-power fields in each thymic biopsy specimen are shown. Journal of Allergy and Clinical Immunology 2013 131, 597-600.e2DOI: (10.1016/j.jaci.2012.11.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Scheme of thymic lymphostromal cross-talk (indicated by red arrows) and abnormalities observed in the thymuses of ZAP70−/− patients. The numbers circled in red identify abnormalities observed in the thymuses of patients with ZAP70 deficiency, which include (1) defective differentiation of CD8+ single-positive thymocytes and impaired function of CD4+ single-positive cells; (2) reduced number of FOXP3+ Treg cells; (3) reduced size of thymic medulla; (4) reduced number of Aire+ mTECs; (5) lack of terminal maturation of post-AIRE mTECs in the Hassall corpuscles, with lack of IVL expression; and (6) reduced number of medullary DCs. CK, Cytokeratin; cTEC, cortical thymic epithelial cell; DN, double-negative thymocyte; MHC-II, MHC class II antigen; SP, single-positive thymocytes; TRA, tissue-restricted antigen; TSLP, thymic stromal lymphopoietin. Journal of Allergy and Clinical Immunology 2013 131, 597-600.e2DOI: (10.1016/j.jaci.2012.11.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Distribution and relative abundance of DCs in thymic biopsy specimens from healthy subjects and ZAP70−/− patients. A, Representative images from both control and ZAP70−/− thymic medullary areas stained for markers of the 3 different major DCs subtypes. Combined CD11c (blue) and CD163 (brown) staining allows one to distinguish CD11c+CD163− DCs from CD11c+CD163+ macrophages, which are primarily distributed in the cortex, with only rare CD11c+CD163+ macrophages within the medulla (asterisk). B, Staining for XCL1 and XCR1 expressed by mature mTECs and DCs, respectively, showed no significant differences between ZAP70−/− and control thymuses. Interaction between XCL1+ mTECs and DCs is highlighted by double staining for CD11c (blue) and XCL1 (brown, inset). All staining is from ×20 and ×40 (insets) original magnifications, and the scale bar corresponds to 100 and 50 μm, respectively. Journal of Allergy and Clinical Immunology 2013 131, 597-600.e2DOI: (10.1016/j.jaci.2012.11.002) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions