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Evidence for enhanced Bruton's tyrosine kinase activity in transitional and naive B cells of patients with granulomatosis with polyangiitis
- Source :
- Rheumatology, 58(12), 2230-2239. Oxford University Press, Rheumatology (Oxford)
- Publication Year :
- 2019
- Publisher :
- Oxford University Press, 2019.
-
Abstract
- Objectives To determine Bruton’s tyrosine kinase (BTK) protein and phosphorylation levels in B cell subsets of granulomatosis with polyangiitis (GPA) patients and to investigate the effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production. Methods BTK protein and phosphorylation levels were determined by flow cytometry in peripheral blood B cells of 29 untreated GPA patients [9 active and 20 remission GPA patients (10 ANCA– and 10 ANCA+)], 9 age- and sex-matched healthy controls (HCs) and 9 untreated active RA patients. The effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production was determined in the same donors in peripheral blood mononuclear cell cultures. Results BTK protein levels were significantly increased in transitional and naïve B cells of active GPA and RA patients compared with remission GPA patients and HCs. Both B cell subsets of active patients were more sensitive to B cell receptor stimulation, as BTK and phospholipase Cγ2 phosphorylation were increased in these patients. In vitro BTK blockade had profound effects on B cell cytokine production, plasma cell formation and (auto)antibody production in both GPA patients and HCs. Interestingly, the effect of BTK blockade was less pronounced in active GPA patients, possibly due to increased activation of B cells. Conclusion We show that BTK protein and phosphorylation levels are most profoundly increased in newly emerging B cells of active GPA patients compared with remission patients. BTK blockade greatly inhibits in vitro B cell effector functions in GPA patients and HCs. These promising data identify BTK as an interesting novel therapeutic target in the treatment of GPA.
- Subjects :
- Male
0301 basic medicine
Plasma cell
ACTIVATION
0302 clinical medicine
immune system diseases
hemic and lymphatic diseases
CYCLOPHOSPHAMIDE
VASCULITIS
CRITERIA
Pharmacology (medical)
Phosphorylation
Cells, Cultured
B-Lymphocytes
Immunity, Cellular
medicine.diagnostic_test
biology
Middle Aged
Clinical Science
Flow Cytometry
Bruton's tyrosine kinase
medicine.anatomical_structure
Disease Progression
Cytokines
Female
Tyrosine kinase
Adult
B-cell receptor
Naive B cell
Enzyme-Linked Immunosorbent Assay
macromolecular substances
AMERICAN-COLLEGE
Peripheral blood mononuclear cell
CLASSIFICATION
Flow cytometry
Young Adult
03 medical and health sciences
Rheumatology
stomatognathic system
medicine
Humans
BTK blocker
RITUXIMAB
B cell
Aged
Autoantibodies
030203 arthritis & rheumatology
B cells
business.industry
Granulomatosis with Polyangiitis
030104 developmental biology
Cancer research
biology.protein
business
Biomarkers
Subjects
Details
- Language :
- English
- ISSN :
- 14620332 and 14620324
- Volume :
- 58
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Rheumatology
- Accession number :
- edsair.doi.dedup.....976aab191a521e4e0664f39ee45466dd