Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity

Hibbs, Margaret L.; Harder, Kenneth W.; Armes, Jane; Kountouri, Nicole; Quilici, Cathy; Casagranda, Franca; Dunn, Ashley R.; Tarlinton, David M.

doi:10.1084/jem.20020515

Cited by 168T-cell and B-cell ImmunologySystemic Lupus Erythematosus ResearchImmune Response and Inflammation

Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity

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Hibbs, Margaret L., Harder, Kenneth W., Armes, Jane, Kountouri, Nicole, Quilici, Cathy, Casagranda, Franca, Dunn, Ashley R., Tarlinton, David M.·2002·The Journal of Experimental Medicine

DOI 10.1084/jem.20020515PMC PMC2196073

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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.

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Lyn tyrosine kinase autoactivation (gain-of-function) mice, after BCR stimulation, showed constitutive phosphorylation of Syk/PLCγ2 with resultant increased calcium flux in their resting B cells.
“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]
In Results, “Altered Lyn Protein Levels and Signaling in Lynup/up B Cells,” Syk and PLCγ2 are phosphorylated in unstimulated mutant B cells, with phosphorylation increasing after BCR stimulation. In “Calcium Signaling in Lynup/up B Cells,” the higher calcium-flux peak occurs after BCR cross-linking, not consistently in resting cells; basal calcium was variably elevated. The paper also says the higher peak *possibly* reflects PLCγ2 hyperactivation, rather than establishing that causal link. (LLM, conf=0.86)
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PLCγ2 hyperactivation in Lyn tyrosine kinase autoactivation mice led to increased levels of autoantibodies and ultimately a lethal autoimmune glomerulonephritis.
“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]
The Abstract reports constitutive PLCγ2 phosphorylation in Lynup/up B cells and circulating autoreactive antibodies and lethal autoimmune glomerulonephritis in the mice. The Results section on circulating autoreactive antibodies finds antinuclear antibodies in most Lynup/up mice but weak or no staining in wild-type mice. The paper suggests that enhanced positive signaling contributes to the disease; it does not establish that PLCγ2 hyperactivation specifically caused it. (LLM, conf=0.85)
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Cholesterol-Rich Membrane Rafts and Lyn Are Involved in Phagocytosis during <i>Pseudomonas aeruginosa</i> Infection
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Regulation of B‐cell entry into the cell cycle
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Lyn- and PLC-β3–dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease
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Decreased Superoxide Production in Macrophages of Long-lived p66Shc Knock-out Mice
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Macrophages require Skap2 and Sirpα for integrin-stimulated cytoskeletal rearrangement
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Complement C4 maintains peripheral B-cell tolerance in a myeloid cell-dependent manner
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Tyrosine phosphorylation of SHIP promotes its proteasomal degradation
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Lyn, a Src family kinase, regulates activation of epidermal growth factor receptors in lung adenocarcinoma cells
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Fumarate suppresses B-cell activation and function through direct inactivation of LYN
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Lyn activity protects mice from DSS colitis and regulates the production of IL-22 from innate lymphoid cells
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p300 Protein Acetyltransferase Activity Suppresses Systemic Lupus Erythematosus-Like Autoimmune Disease in Mice
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Increased megakaryocytopoiesis in Lyn-deficient mice
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A Conserved Salt Bridge in the G Loop of Multiple Protein Kinases Is Important for Catalysis and for In Vivo Lyn Function
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Proteomic analysis of plasma exosomes from Cystic Echinococcosis patients provides in vivo support for distinct immune response profiles in active vs inactive infection and suggests potential biomarkers
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Phospholipase C-β3 Regulates FcɛRI-Mediated Mast Cell Activation by Recruiting the Protein Phosphatase SHP-1
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Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells
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Lyn but Not Fyn Kinase Controls IgG-Mediated Systemic Anaphylaxis
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Genetic Interdependence of Lyn and Negative Regulators of B Cell Receptor Signaling in Autoimmune Disease Development
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Role of inhibitory signaling in peripheral B cell tolerance*
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Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells
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CTLA4Ig Alters the Course of Autoimmune Disease Development in Lyn−/− Mice
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Upregulated Fcrl5 disrupts B cell anergy and causes autoimmune disease
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Perturbation of the CD4 T Cell Compartment and Expansion of Regulatory T Cells in Autoimmune-Prone Lyn-Deficient Mice
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Altered BCR signalling quality predisposes to autoimmune disease and a pre‐diabetic state
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Lupus pathobiology based on genomics
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Lyn Deficiency Leads to Increased Microbiota-Dependent Intestinal Inflammation and Susceptibility to Enteric Pathogens
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Channel catfish leukocyte immune-type receptor mediated inhibition of cellular cytotoxicity is facilitated by SHP-1-dependent and -independent mechanisms
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Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling
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Multiple paths to loss of anergy and gain of autoimmunity
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Role of antifibrotics in the management of idiopathic inflammatory myopathy associated interstitial lung disease
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Src Homology 2–Containing Inositol 5′-Phosphatase 1 Negatively Regulates IFN-γ Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12
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Atypical Response of B-1 Cells to BCR Ligation: A Speculative Model
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Phosphatidylinositol‐3 kinase activity in B cells is negatively regulated by Lyn tyrosine kinase
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A Kinase-Dead Allele of Lyn Attenuates Autoimmune Disease Normally Associated with Lyn Deficiency
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A Kinase-Dead Allele of Lyn Attenuates Autoimmune Disease Normally Associated with Lyn Deficiency
Verhagen, A. M., Wallace, M. E., Goradia, A., Jones, S. A., McQuilten, H. A., Metcalf, D., Collinge, J. E., Maxwell, M. J., Hibbs, M. L., Alexander, W. S., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803127 · Cited by 20 · see citing works
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Reduced Dosage of Bruton’s Tyrosine Kinase Uncouples B Cell Hyperresponsiveness from Autoimmunity in lyn −/− Mice
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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.
ORCID: Hibbs, Margaret L.
Harder, Kenneth W.
Casagranda, Franca
Tarlinton, David M.
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
DOI: 10.1084/jem.20020515
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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Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity

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