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Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations

Friman, Vanda ; Quinti, Isabella ; Davydov, Alexey N ; Shugay, Mikhail ; Farroni, Chiara ; Engström, Erik ; Pour Akaber, Shirin ; Barresi, Sabina ; Mohamed, Ahmed and Pulvirenti, Federica , et al. (2023) In Cell Reports 42(5). p.1-19
Abstract

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27
bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally,... (More)

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27
bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.

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publishing date
type
Contribution to journal
publication status
published
keywords
Humans, Common Variable Immunodeficiency/genetics, B-Lymphocytes, Germinal Center, Precursor Cells, B-Lymphoid, Autoimmunity
in
Cell Reports
volume
42
issue
5
article number
112446
pages
1 - 19
publisher
Cell Press
external identifiers
  • scopus:85153595326
  • pmid:37119135
ISSN
2211-1247
DOI
10.1016/j.celrep.2023.112446
language
English
LU publication?
no
additional info
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
id
79d4b306-5c2b-46ac-ae29-cfc3b559cc52
date added to LUP
2023-11-16 12:31:34
date last changed
2024-04-14 16:58:37
@article{79d4b306-5c2b-46ac-ae29-cfc3b559cc52,
  abstract     = {{<p>Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27 <br>
 bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.<br>
 </p>}},
  author       = {{Friman, Vanda and Quinti, Isabella and Davydov, Alexey N and Shugay, Mikhail and Farroni, Chiara and Engström, Erik and Pour Akaber, Shirin and Barresi, Sabina and Mohamed, Ahmed and Pulvirenti, Federica and Milito, Cinzia and Granata, Guido and Giorda, Ezio and Ahlström, Sara and Karlsson, Johanna and Marasco, Emiliano and Marcellini, Valentina and Bocci, Chiara and Cascioli, Simona and Scarsella, Marco and Phad, Ganesh and Tilevik, Andreas and Tartaglia, Marco and Bemark, Mats and Chudakov, Dmitriy M and Carsetti, Rita and Grimsholm, Ola}},
  issn         = {{2211-1247}},
  keywords     = {{Humans; Common Variable Immunodeficiency/genetics; B-Lymphocytes; Germinal Center; Precursor Cells, B-Lymphoid; Autoimmunity}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{5}},
  pages        = {{1--19}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2023.112446}},
  doi          = {{10.1016/j.celrep.2023.112446}},
  volume       = {{42}},
  year         = {{2023}},
}