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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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Roskin KM,Simchoni N,Liu Y,Lee JY,Seo K,Hoh RA,Pham T,Park JH,Furman D,Dekker CL,Davis MM,James JA,Nadeau KC,Cunningham-Rundles C,Boyd SD

doi

10.1126/scitranslmed.aab1216

subject

Has Abstract

pub_date

2015-08-26 00:00:00

pages

302ra135

issue

302

eissn

1946-6234

issn

1946-6242

pii

7/302/302ra135

journal_volume

7

pub_type

杂志文章

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