Active PI3K abrogates central tolerance in high-avidity autoreactive B cells.
Animals
Autoantibodies
/ immunology
Autoantigens
/ immunology
Autoimmunity
/ immunology
B-Lymphocytes
/ immunology
Bone Marrow Cells
/ metabolism
Cell Differentiation
/ immunology
Central Tolerance
/ immunology
Class Ia Phosphatidylinositol 3-Kinase
/ metabolism
Female
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Models, Animal
Receptors, Antigen, B-Cell
/ metabolism
Receptors, Complement 3d
/ metabolism
Spleen
/ cytology
T-Lymphocytes
/ immunology
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
06 05 2019
06 05 2019
Historique:
received:
27
08
2018
revised:
23
01
2019
accepted:
22
03
2019
pubmed:
6
4
2019
medline:
6
5
2020
entrez:
6
4
2019
Statut:
ppublish
Résumé
Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell-mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell-intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.
Identifiants
pubmed: 30948496
pii: jem.20181652
doi: 10.1084/jem.20181652
pmc: PMC6504226
doi:
Substances chimiques
Autoantibodies
0
Autoantigens
0
Receptors, Antigen, B-Cell
0
Receptors, Complement 3d
0
Class Ia Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1135-1153Subventions
Organisme : NIAID NIH HHS
ID : R21 AI131639
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI136534
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI052310
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI052310
Pays : United States
Informations de copyright
© 2019 Greaves et al.
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