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Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity
Open accessAbstract
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.
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“Lyn tyrosine kinase autoactivation (gain-of-function) mice, after BCR stimulation, showed constitutive phosphorylation of Syk/PLCγ2, with a resultant increased calcium flux, observed in their resting B cells (118).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [118]
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“These circumstances of PLCγ2 hyperactivation led to an increased level of autoantibodies in these mice and ultimately a lethal autoimmune glomerulonephritis (118).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [118]
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Metadata
- Authors
- Hibbs, M. L., Harder, K. W., Armes, J., Kountouri, N., Quilici, C., Casagranda, F., Dunn, A. R., & Tarlinton, D. M.
- Affiliations
- Ludwig Cancer Research (AU)
- Royal Women's Hospital (AU)
- The Royal Melbourne Hospital (AU)
- Corresponding author
- Hibbs, Margaret L.
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2002-12-16
- Volume
- 196
- Issue
- 12
- Pages
- 1593-1604
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2196073
- OpenAlex
- W2168601978
- Cited by
- 168
- References
- 63
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 4 · 2023: 10 · 2022: 5 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 12 · 2013: 13 · 2012: 13
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-sa)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Lyn kinase, B cell signaling, autoimmunity, B cell tolerance, B cell receptor signaling, CD22, SHP-1, SHIP1, Syk, PLCγ2, calcium flux, autoantibodies, glomerulonephritis
- MeSH terms
- Animals, Antigen-Antibody Complex, Autoantibodies, Autoimmune Diseases, B-Lymphocytes, Calcium, Cell Separation, Cells, Cultured, Enzyme Activation, Female, Flow Cytometry, Glomerulonephritis, Humans, Immunoglobulins, Kidney, Lymph Nodes, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Spleen, Signal Transduction, Autoimmunity, Antigens, CD, Up-Regulation, Point Mutation, src-Family Kinases, Mice
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