title: Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency.
abstract: Although common variable immunodeficiency (CVID) has long been considered as a group of primary Ab deficiencies, growing experimental data now suggest a global disruption of the entire adaptive immune response in a segment of patients. Oligoclonality of the TCR repertoire was previously demonstrated; however, the manner in which it relates to other B cell and T cell findings reported in CVID remains unclear. Using a combination approach of high-throughput TCRβ sequencing and multiparametric flow cytometry, we compared the TCR repertoire diversity between various subgroups of CVID patients according to their B cell immunophenotypes. Our data suggest that the reduction in repertoire diversity is predominantly restricted to those patients with severely reduced class-switched memory B cells and an elevated level of CD21(lo) B cells (Freiburg 1a), and may be driven by a reduced number of naive T cells unmasking underlying memory clonality. Moreover, our data indicate that this loss in repertoire diversity progresses with advancing age far exceeding the expected physiological rate. Radiological evidence supports the loss in thymic volume, correlating with the decrease in repertoire diversity. Evidence now suggests that primary thymic failure along with other well-described B cell abnormalities play an important role in the pathophysiology in Freiburg group 1a patients. Clinically, our findings emphasize the integration of combined B and T cell testing to identify those patients at the greatest risk for infection. Future work should focus on investigating the link between thymic failure and the severe reduction in class-switched memory B cells, while gathering longitudinal laboratory data to examine the progressive nature of the disease.
authors.affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston B15 2TT, United Kingdom; West Midlands Primary Immunodeficiency Centre, Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom;
authors.forename: Gabriel K
authors.identifier: 0000-0003-4987-4051
authors.initials: GK
authors.lastname: Wong
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston MA 02114; Department of Medicine, Harvard Medical School, Charlestown, MA 02129;
authors.forename: David
authors.identifier: 0000-0002-0104-9303
authors.initials: D
authors.lastname: Millar
authors.affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston B15 2TT, United Kingdom;
authors.forename: Sarah
authors.initials: S
authors.lastname: Penny
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom; and.
authors.forename: James M
authors.identifier: 0000-0002-1783-5181
authors.initials: JM
authors.lastname: Heather
authors.affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston B15 2TT, United Kingdom;
authors.forename: Punam
authors.initials: P
authors.lastname: Mistry
authors.affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston B15 2TT, United Kingdom;
authors.forename: Nico
authors.initials: N
authors.lastname: Buettner
authors.affiliation: Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham B15 2TG, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Bryon
authors.affiliation: West Midlands Primary Immunodeficiency Centre, Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom;
authors.forename: Aarnoud P
authors.initials: AP
authors.lastname: Huissoon
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston MA 02114; Department of Medicine, Harvard Medical School, Charlestown, MA 02129; mcobbold@mgh.harvard.edu.
authors.forename: Mark
authors.identifier: 0000-0001-8931-4142
authors.initials: M
authors.lastname: Cobbold
mesh_terms: D000367:Age Factors; D001402:B-Lymphocytes / Q000276:immunology; D017074:Common Variable Immunodeficiency / Q000276:immunology* / Q000503:physiopathology; D005434:Flow Cytometry / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017578:Immunoglobulin Class Switching; D007156:Immunologic Memory; D016130:Immunophenotyping; D008212:Lymphocyte Depletion; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D017464:Receptors, Complement 3d / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000473:pathology
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D017464:Receptors, Complement 3d