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

Vanda Friman; Isabella Quinti; Alexey N Davydov; Mikhail Shugay; Chiara Farroni; Erik Engström; Shirin Pour Akaber; Sabina Barresi; Ahmed Mohamed; Federica Pulvirenti; Cinzia Milito; Guido Granata; Ezio Giorda; Sara Ahlström; Johanna Karlsson; Emiliano Marasco; Valentina Marcellini; Chiara Bocci; Simona Cascioli; Marco Scarsella; Ganesh Phad; Andreas Tilevik; Marco Tartaglia; Mats Bemark; Dmitriy M Chudakov; Rita Carsetti; Ola Grimsholm

doi:10.1016/j.celrep.2023.112446

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

Vanda Friman, Isabella Quinti, Alexey N Davydov, Mikhail Shugay, Chiara Farroni, Erik Engström, Shirin Pour Akaber, Sabina Barresi, Ahmed Mohamed, Federica Pulvirenti, Cinzia Milito, Guido Granata, Ezio Giorda, Sara Ahlström, Johanna Karlsson, Emiliano Marasco, Valentina Marcellini, Chiara Bocci, Simona Cascioli, Marco ScarsellaGanesh Phad, Andreas Tilevik, Marco Tartaglia, Mats Bemark, Dmitriy M Chudakov, Rita Carsetti, Ola Grimsholm

Research output: Contribution to journal › Article › peer-review

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, 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.

Original language	English
Article number	112446
Pages (from-to)	1-19
Journal	Cell Reports
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2023.112446
Publication status	Published - 2023 May 30
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Free keywords

Humans
Common Variable Immunodeficiency/genetics
B-Lymphocytes
Germinal Center
Precursor Cells, B-Lymphoid
Autoimmunity

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10.1016/j.celrep.2023.112446Licence: CC BY

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Friman, V., Quinti, I., Davydov, A. N., Shugay, M., Farroni, C., Engström, E., Pour Akaber, S., Barresi, S., Mohamed, A., Pulvirenti, F., Milito, C., Granata, G., Giorda, E., Ahlström, S., Karlsson, J., Marasco, E., Marcellini, V., Bocci, C., Cascioli, S., ... Grimsholm, O. (2023). Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations. Cell Reports, 42(5), 1-19. Article 112446. https://doi.org/10.1016/j.celrep.2023.112446

@article{79d4b3065c2b46acae29cfc3b559cc52,

title = "Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations",

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, 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. ",

keywords = "Humans, Common Variable Immunodeficiency/genetics, B-Lymphocytes, Germinal Center, Precursor Cells, B-Lymphoid, Autoimmunity",

author = "Vanda Friman and Isabella Quinti and Davydov, \{Alexey N\} and Mikhail Shugay and Chiara Farroni and Erik Engstr{\"o}m and \{Pour Akaber\}, Shirin and Sabina Barresi and Ahmed Mohamed and Federica Pulvirenti and Cinzia Milito and Guido Granata and Ezio Giorda and Sara Ahlstr{\"o}m and Johanna Karlsson and Emiliano Marasco and Valentina Marcellini and Chiara Bocci and Simona Cascioli and Marco Scarsella and Ganesh Phad and Andreas Tilevik and Marco Tartaglia and Mats Bemark and Chudakov, \{Dmitriy M\} and Rita Carsetti and Ola Grimsholm",

year = "2023",

month = may,

day = "30",

doi = "10.1016/j.celrep.2023.112446",

language = "English",

volume = "42",

pages = "1--19",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "5",

}

Friman, V, Quinti, I, Davydov, AN, Shugay, M, Farroni, C, Engström, E, Pour Akaber, S, Barresi, S, Mohamed, A, Pulvirenti, F, Milito, C, Granata, G, Giorda, E, Ahlström, S, Karlsson, J, Marasco, E, Marcellini, V, Bocci, C, Cascioli, S, Scarsella, M, Phad, G, Tilevik, A, Tartaglia, M, Bemark, M, Chudakov, DM, Carsetti, R & Grimsholm, O 2023, 'Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations', Cell Reports, vol. 42, no. 5, 112446, pp. 1-19. https://doi.org/10.1016/j.celrep.2023.112446

TY - JOUR

T1 - Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations

AU - Friman, Vanda

AU - Quinti, Isabella

AU - Davydov, Alexey N

AU - Shugay, Mikhail

AU - Farroni, Chiara

AU - Engström, Erik

AU - Pour Akaber, Shirin

AU - Barresi, Sabina

AU - Mohamed, Ahmed

AU - Pulvirenti, Federica

AU - Milito, Cinzia

AU - Granata, Guido

AU - Giorda, Ezio

AU - Ahlström, Sara

AU - Karlsson, Johanna

AU - Marasco, Emiliano

AU - Marcellini, Valentina

AU - Bocci, Chiara

AU - Cascioli, Simona

AU - Scarsella, Marco

AU - Phad, Ganesh

AU - Tilevik, Andreas

AU - Tartaglia, Marco

AU - Bemark, Mats

AU - Chudakov, Dmitriy M

AU - Carsetti, Rita

AU - Grimsholm, Ola

PY - 2023/5/30

Y1 - 2023/5/30

N2 - 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.

AB - 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.

KW - Humans

KW - Common Variable Immunodeficiency/genetics

KW - B-Lymphocytes

KW - Germinal Center

KW - Precursor Cells, B-Lymphoid

KW - Autoimmunity

UR - https://www.scopus.com/pages/publications/85153595326

U2 - 10.1016/j.celrep.2023.112446

DO - 10.1016/j.celrep.2023.112446

M3 - Article

C2 - 37119135

SN - 2211-1247

VL - 42

SP - 1

EP - 19

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 112446

ER -

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

Abstract

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