Syk inhibition limits autoimmunity and abnormal B cell phenotype and function in mice with B cell-specific TRAF3 deficiency

Emma L Hornick; Kyp Oxley; Ivy L Debreceni; Nathaniel Wieting; Tiffany K Ybarra; Bruce S Hostager; Scott M Lieberman; Gail A Bishop

doi:10.1093/jimmun/vkag049

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Syk inhibition limits autoimmunity and abnormal B cell phenotype and function in mice with B cell-specific TRAF3 deficiency

Journal article

Open access

Peer reviewed

Syk inhibition limits autoimmunity and abnormal B cell phenotype and function in mice with B cell-specific TRAF3 deficiency

Emma L Hornick, Kyp Oxley, Ivy L Debreceni, Nathaniel Wieting, Tiffany K Ybarra, Bruce S Hostager, Scott M Lieberman and Gail A Bishop

The Journal of immunology (1950), Vol.215(4), vkag049

04/15/2026

DOI: 10.1093/jimmun/vkag049

PMID: 42026764

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Abstract

Autoimmune disorders reduce quality of life and lifespan and can increase B cell lymphoma risk. The adaptor protein TRAF3 regulates B cell survival, activation, and differentiation by restraining signaling through Toll-like receptors, tumor necrosis factor (TNF) receptor superfamily members, and the B cell antigen receptor-pathways linked to autoimmunity and lymphoma. Mice lacking TRAF3 in B cells (B-Traf3-/-) develop both autoimmunity and B cell malignancies. TRAF3 negatively regulates activation of spleen tyrosine kinase (Syk), which is involved in multiple B cell signaling pathways. B-Traf3-/- mice treated with the Food and Drug Administration (FDA)-approved Syk inhibitor Fostamatinib, exhibited reduction in autoantibodies, gland inflammation, and expansion of autoimmune-associated B cell populations. Fostamatinib also corrected enhanced pro-survival proteins and aberrant B cell survival in Traf3-/- B cells, without inhibiting humoral responses to immunization. These findings identify elevated Syk activation as a key driver of B cell dysfunction and autoimmunity in B-Traf3-/- mice, suggesting therapeutic potential for Syk inhibitors in conditions linked to decreased B cell TRAF3 levels.

Phenotype

Signal Transduction

Aminopyridines

Animals

Autoimmunity - drug effects

Autoimmunity - immunology

B-Lymphocytes - drug effects

B-Lymphocytes - immunology

Mice

Mice, Inbred C57BL

Mice, Knockout

Morpholines

Pyridines - pharmacology

Pyrimidines

Syk Kinase - antagonists & inhibitors

Syk Kinase - metabolism

TNF Receptor-Associated Factor 3 - deficiency

TNF Receptor-Associated Factor 3 - genetics

TNF Receptor-Associated Factor 3 - immunology

UIOWA OA Agreement

Details

Title: Subtitle: Syk inhibition limits autoimmunity and abnormal B cell phenotype and function in mice with B cell-specific TRAF3 deficiency
Creators: Emma L Hornick - University of Iowa
Kyp Oxley - University of Iowa
Ivy L Debreceni - University of Iowa
Nathaniel Wieting - University of Iowa
Tiffany K Ybarra - University of Iowa
Bruce S Hostager - University of Iowa
Scott M Lieberman - University of Iowa
Gail A Bishop - University of Iowa
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.215(4), vkag049
DOI: 10.1093/jimmun/vkag049
PMID: 42026764
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: Oxford University Press
Grant note: University of Iowa P30 CA086862 / NCI NIH HHS R01AI162656 / NCI NIH HHS
Language: English
Date published: 04/15/2026
Academic Unit: Microbiology and Immunology; President; Stead Family Department of Pediatrics; Orthopedics and Rehabilitation; Fraternal Order of Eagles Diabetes Research Center; Rheumatology, Allergy, and Immunology
Record Identifier: 9985157631302771

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