title: IgH sequences in common variable immune deficiency reveal altered B cell development and selection.
abstract: Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ~1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients and 105 control subjects and sorted naïve and memory B cells from 13 of the CVID patients and 10 of the control subjects. The CVID patients showed abnormal VDJ rearrangement and abnormal formation of complementarity-determining region 3 (CDR3). We observed a decreased selection against antibodies with long CDR3s in memory repertoires and decreased variable gene replacement, offering possible mechanisms for increased patient autoreactivity. Our data indicate that patient immunodeficiency might derive from both decreased diversity of the naïve B cell pool and decreased somatic hypermutation in memory repertoires. The CVID patients also exhibited an abnormal clonal expansion of unmutated B cells relative to the controls. Although impaired B cell germinal center activation is commonly viewed as causative in CVID, these data indicate that CVID B cells diverge from controls as early as the pro-B stage, cell and suggest possible explanations for the increased incidence of autoimmunity, immunodeficiency, and lymphoma CVID patients.
authors: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors: Krishna M
authors: KM
authors: Roskin
authors: Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Noa
authors: N
authors: Simchoni
authors: Department of Pathology, Stanford University, Stanford, CA 94305, USA. Biomedical Informatics Training Program, Stanford University, Stanford, CA 94305, USA.
authors: Yi
authors: Y
authors: Liu
authors: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors: Ji-Yeun
authors: JY
authors: Lee
authors: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors: Katie
authors: K
authors: Seo
authors: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors: Ramona A
authors: RA
authors: Hoh
authors: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors: Tho
authors: T
authors: Pham
authors: Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Joon H
authors: JH
authors: Park
authors: Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305, USA.
authors: David
authors: D
authors: Furman
authors: Departments of Medicine, Pediatrics, and Otolaryngology, Stanford University, Stanford, CA 94305, USA.
authors: Cornelia L
authors: CL
authors: Dekker
authors: Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
authors: Mark M
authors: MM
authors: Davis
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation and Oklahoma Clinical and Translational Science Institute and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors: Judith A
authors: JA
authors: James
authors: Departments of Medicine, Pediatrics, and Otolaryngology, Stanford University, Stanford, CA 94305, USA.
authors: Kari C
authors: KC
authors: Nadeau
authors: Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. sboyd1@stanford.edu charlotte.cunningham-rundles@mssm.edu.
authors: Charlotte
authors: C
authors: Cunningham-Rundles
authors: Department of Pathology, Stanford University, Stanford, CA 94305, USA. sboyd1@stanford.edu charlotte.cunningham-rundles@mssm.edu.
authors: Scott D
authors: SD
authors: Boyd
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology; D004247:DNA / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology; D009154:Mutation
chemical_list: D007143:Immunoglobulin Heavy Chains; D004247:DNA