Complete human CD1a deficiency on Langerhans cells due to a rare point mutation in the coding sequence Daniela Cerny, PhD, Duyen Huynh Thi Le, MSc, Trung.

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Presentation transcript:

Complete human CD1a deficiency on Langerhans cells due to a rare point mutation in the coding sequence Daniela Cerny, PhD, Duyen Huynh Thi Le, MSc, Trung Dinh The, MD, PhD, Roland Zuest, PhD, Srinivasan KG, PhD, Sumathy Velumani, MSc, Chiea Chuen Khor, MD, PhD, Lucia Mori, PhD, Cameron P. Simmons, PhD, Michael Poidinger, PhD, Francesca Zolezzi, PhD, Florent Ginhoux, PhD, Muzlifah Haniffa, MD, PhD, Bridget Wills, MD, DM, Katja Fink, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 6, Pages 1709-1712.e11 (December 2016) DOI: 10.1016/j.jaci.2016.05.028 Copyright © 2016 The Authors Terms and Conditions

Fig 1 CD1a deficiency on skin DCs of a healthy adult. A, Single cells were isolated from skin biopsies from a healthy individual and donor 007 and skin APCs were analyzed by flow cytometry. B, Epidermal sheets from a control donor and from donor 007 were stained for HLA-DR (red) and CD1a expression (green). Hoechst (blue) was used to stain cell nuclei, and samples were analyzed by confocal microscopy. Control data are representative of more than 20 healthy donors. AF, Autofluorescence; DAPI, 4′-6-diamidino-2-phenylindole, dihydrochloride; FSC-W, forward scatter-width; SSC, side scatter. Journal of Allergy and Clinical Immunology 2016 138, 1709-1712.e11DOI: (10.1016/j.jaci.2016.05.028) Copyright © 2016 The Authors Terms and Conditions

Fig 2 Recombinant expression of the mutant CD1a-L285P reproduces the in vivo expression defect. A, Structure of the CD1a molecule in complex with a sulfatide (Protein Data Bank 1ONQ). The α domains (pink), β2 microglobulin (blue), and the position of L285P in the α3 subunit (green) are shown. B, CD1a surface expression of WT and L285P CD1a-transfected HEK and K562 cells analyzed by flow cytometry 24 hours after transfection. Cells were transfected with the indicated ratios of WT and L285P CD1a plasmid. Bar graphs show means ± SEM of % CD1a-expressing cells measured in 2 independent experiments with total n = 4. C, CD1a expression on transfected HEK cells analyzed by immunofluorescence microscopy. HEK, Human embryonic kidney; SSC-A, side scatter-area; WT, wild-type. Journal of Allergy and Clinical Immunology 2016 138, 1709-1712.e11DOI: (10.1016/j.jaci.2016.05.028) Copyright © 2016 The Authors Terms and Conditions

Fig E1 CD1a deficiency is generic and not confined to primary skin APCs. A, moDCs from a healthy control donor and from donor 007 were stained either on the surface or intracellularly (i.c.) with anti-CD1a and analyzed by flow cytometry. B, Immunohistochemistry of moDCs stained with anti-CD1a (green), anti-EEA, an early endosome marker (red), and Hoechst (blue). Healthy control data are representative of 2 individuals. EEA, Early endosome antigen; FSC-A, Forward scatter-area; SSC-A, side scatter-area. Journal of Allergy and Clinical Immunology 2016 138, 1709-1712.e11DOI: (10.1016/j.jaci.2016.05.028) Copyright © 2016 The Authors Terms and Conditions

Fig E2 Absence of surface CD1a detection in donor 007 is independent of the antibody clone used. Monocyte-derived DCs from donors 003 and 007 were stained with anti-human CD1a clone OKT6. A positive signal was observed only for donor 003. FSC-A, Forward scatter-area; SSC-A, side scatter-area. Journal of Allergy and Clinical Immunology 2016 138, 1709-1712.e11DOI: (10.1016/j.jaci.2016.05.028) Copyright © 2016 The Authors Terms and Conditions

Fig E3 CD1a L285P is transcribed but not expressed as a protein on the cell surface. A, mRNA expression of HEK and K562 cells-transfected WT and mutant forms of CD1a. B, Detection of WT and mutant CD1a by anti-CD1a clone NA1/34-HLK. HEK and K562 cells were transfected for 72 hours before analyzing the surface expression of CD1a by flow cytometry. The expression pattern is similar to the one detected by anti-CD1a clone HI149 (Fig 2). HEK, Human embryonic kidney; SSC-A, side scatter-area; WT, wild-type. Journal of Allergy and Clinical Immunology 2016 138, 1709-1712.e11DOI: (10.1016/j.jaci.2016.05.028) Copyright © 2016 The Authors Terms and Conditions

Fig E4 CD1a deficiency is selective and spares CD1c and CD1d expression. CD1a expression on moDCs from affected individuals and family members analyzed by flow cytometry (A) and immunofluorescence microscopy (B). C, Frequency of peripheral blood myeloid DC subsets, pDCs, and CD34+ stem cells in the affected family (black symbols) and healthy controls (open symbols). D, Frequency of total B cells and naive B cells (CD19+IgD+) in 007 family members and control donors. CD1c (E) and CD1d expression (F) on blood DCs from 007 family members and control donors. Representative histograms for 007 and 1 control donor are shown. Donor 007 (with the CD1a defect) is indicated in red. Cells from donor 005 were not available for this analysis. MFI, Median fluorescence intensity; ns, nonsignificant. Journal of Allergy and Clinical Immunology 2016 138, 1709-1712.e11DOI: (10.1016/j.jaci.2016.05.028) Copyright © 2016 The Authors Terms and Conditions

Fig E5 Sequence analysis of CD1a mRNA and gDNA identifies a novel mutation causing CD1a deficiency. A, mRNA length of the CD1a ORF amplified from mRNA extracted from moDCs generated from 4 family members. B, A thymidine (T) to cytidine (C) mutation identified by mRNA sequencing of donor 007 and family members is indicated with a red box. C, Sequences of the genomic DNA (gDNA) of family members; the CD1a gene position coding for the mutated mRNA is indicated with a red box. D, CD1a genotype tree of the family members. The family members with CD1a deficiency are indicated in red. gDNA, Genomic DNA; ORF, Open Reading Frame. Journal of Allergy and Clinical Immunology 2016 138, 1709-1712.e11DOI: (10.1016/j.jaci.2016.05.028) Copyright © 2016 The Authors Terms and Conditions