|
| Status |
Public on Dec 19, 2022 |
| Title |
Combination CTLA4Ig and anti-CD40L treatment modifies T and B cell metabolic profiles and promotes BCR and membrane protein remodeling in a mouse model of SLE |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant morbidity - demanding further examination of tolerance inducing treatments. Short-term treatment of lupus-prone NZB/WF1 mice with combination CTLA4Ig and anti-CD40L but not single treatment alone, suppresses disease for > 6 months via modulation of B and T cell function while maintaining immune responses to exogenous antigens. Three months after a 2-week course of combination costimulatory blockade, we found a modest decrease in the number of activated T and B cells in both combination and single treatment cohorts compared to untreated controls. However, only combination treatment group showed a 50% decrease in spare respiratory capacity of splenic B and T cells. RNA-sequencing and gene set enrichment analysis of germinal center (GC) B cells confirmed a reduction in the oxidative phosphorylation signature in the combination treatment cohort. This cohort also manifested an increase in expression of B Cell Receptor (BCR) associated signaling molecules and an increase in phosphorylation of PLCĪ³ in GC B cells after stimulation with anti-IgG and anti-CD40. GC B cells from combination treatment mice also displayed a signature involving remodeling of GPI-linked surface proteins. Accordingly, we found a decrease in cell surface expression of the inhibitory molecule CD24 on class-switched memory B cells from aged NZB/W mice that corrected in the combination treatment cohort. Since both a profound decrease in BCR signaling and increased immune cell metabolism enhance loss of tolerance in lupus-prone mice, our findings help to explain the restoration of tolerance observed after short-term combination costimulatory blockade.
|
| |
|
| Overall design |
Examination of phenotypic changes in B and T cell subsets in NZBWF1/J mice treated with short term CTLA4IG and Anti-CD40L
|
| |
|
| Contributor(s) |
Raparia C, Yi Z, Zhang W, Davidson A |
| Citation(s) |
36645445 |
| |
| Submission date |
Aug 09, 2021 |
| Last update date |
Mar 20, 2023 |
| Contact name |
Weijia Zhang |
| E-mail(s) |
[email protected]
|
| Organization name |
Icahn School of Medicine at Mount Sinai
|
| Department |
Renal
|
| Lab |
Bioinfomatics
|
| Street address |
1 Gustave L. Levy Pl
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA753144 |
| SRA |
SRP331744 |
Less...
More...