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Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2002
- Publisher :
- Rockefeller University Press, 2002.
-
Abstract
- Genetic ablation of the Lyn tyrosine kinase has revealed unique inhibitory roles in B lymphocyte signaling. We now report the consequences of sustained activation of Lyn in vivo using a targeted gain-of-function mutation (Lynup/up mice). Lynup/up mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. Lynup/up B cells are characterized by the constitutive phosphorylation of negative regulators of B cell antigen receptor (BCR) signaling including CD22, SHP-1, and SHIP-1, and display attributes of lymphocytes rendered tolerant by constitutive engagement of the antigen receptor. However, exaggerated positive signaling is also apparent as evidenced by the constitutive phosphorylation of Syk and phospholipase Cγ2 in resting Lynup/up B cells. Similarly, Lynup/up B cells show a heightened calcium flux in response to BCR stimulation. Surprisingly, Lynup/up mice develop circulating autoreactive antibodies and lethal autoimmune glomerulonephritis, suggesting that enhanced positive signaling eventually overrides constitutive negative signaling. These studies highlight the difficulty in maintaining tolerance in the face of chronic stimulation and emphasize the pivotal role of Lyn in B cell signaling.
- Subjects :
- Male
Immunology
B-cell receptor
Immunoglobulins
Syk
Autoimmunity
Mice, Transgenic
autoimmune disease
Antigen-Antibody Complex
Cell Separation
Biology
Kidney
Article
Autoimmune Diseases
Mice
Glomerulonephritis
Antigens, CD
LYN
medicine
Animals
Humans
Point Mutation
Immunology and Allergy
Cells, Cultured
B cell
Autoantibodies
B cell signal transduction
B-Lymphocytes
CD22
Lyn gain-of-function mutant mice
Flow Cytometry
Src family kinase
Up-Regulation
Enzyme Activation
Mice, Inbred C57BL
Phenotype
src-Family Kinases
medicine.anatomical_structure
B cell tolerance
Cancer research
Phosphorylation
Calcium
Female
Lymph Nodes
Signal transduction
Tyrosine kinase
Spleen
Signal Transduction
Subjects
Details
- ISSN :
- 15409538 and 00221007
- Volume :
- 196
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....214ef7b35433405666be4dd0995642f1
- Full Text :
- https://doi.org/10.1084/jem.20020515