mmpc-logo mmpc-logo
twitter-logo    bluesky-logo
| Create Account | login
Publication
Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells
in Nonobese Diabetic Mice.
Authors Case JB, Bonami RH, Nyhoff LE, Steinberg HE, Sullivan AM, Kendall PL
Submitted By Submitted Externally on 10/1/2015
Status Published
Journal Journal of immunology (Baltimore, Md. : 1950)
Year 2015
Date Published 7/1/2015
Volume : Pages 195 : 61 - 70
PubMed Reference 26034172
Abstract Expansion of autoimmune-prone marginal zone (MZ) B cells has been implicated in
type 1 diabetes. To test disease contributions of MZ B cells in NOD mice, Notch2
haploinsufficiency (Notch2(+/-)) was introduced but failed to eliminate the MZ,
as it does in C57BL/6 mice. Notch2(+/-)/NOD have MZ B cell numbers similar to
those of wild-type C57BL/6, yet still develop diabetes. To test whether BCR
signaling supports Notch2(+/-)/NOD MZ B cells, Bruton's tyrosine kinase (Btk)
deficiency was introduced. Surprisingly, MZ B cells failed to develop in
Btk-deficient Notch2(+/-)/NOD mice. Expression of Notch2 and its transcriptional
target, Hes5, was increased in NOD MZ B cells compared with C57BL/6 MZ B cells.
Btk deficiency reduced Notch2(+/-) signaling exclusively in NOD B cells,
suggesting that BCR signaling enhances Notch2 signaling in this autoimmune
model. The role of BCR signaling was further investigated using an anti-insulin
transgenic (Tg) BCR (125Tg). Anti-insulin B cells in 125Tg/Notch2(+/-)/NOD mice
populate an enlarged MZ, suggesting that low-level BCR signaling overcomes
reliance on Notch2. Tracking clonotypes of anti-insulin B cells in H chain-only
VH125Tg/NOD mice showed that BTK-dependent selection into the MZ depends on
strength of antigenic binding, whereas Notch2-mediated selection does not.
Importantly, anti-insulin B cell numbers were reduced by Btk deficiency, but not
Notch2 haploinsufficiency. These studies show that 1) Notch2 haploinsufficiency
limits NOD MZ B cell expansion without preventing type 1 diabetes, 2) BTK
supports the Notch2 pathway in NOD MZ B cells, and 3) autoreactive NOD B cell
survival relies on BTK more than Notch2, regardless of MZ location, which may
have important implications for disease-intervention strategies.




Menu

Home
Contact
About MMPC
Animal Husbandry
Tests Data
Search Data
Analysis
Clients
MMPC Centers

Newsletter

Interested in receiving MMPC News?
twitter-logo Mouse Phenotyping
@NationalMMPC



2017 National MMPC. All Rights Reserved.