Year: 2025
Type: article
Abstract: Description Systemic autoimmunity is caused by breaches in tolerance mechanisms that normally prevent adaptive immune responses to ubiquitous self-antigens such as double-stranded DNA (dsDNA). B cells express the dsDNA sensor Toll-like Receptor 9 (TLR9), which can guard against activation of dsDNA-specific autoreactive B cells, preventing breaks in tolerance. The ubiquitin ligase, Itch, is a key enforcer of tolerance that prevents emergence of autoimmune disease and autoantibodies in humans and mice via a presently unclear mechanism. Our previous studies revealed Itch directly limits B cell responses to immunization in vivo and suppresses B cell proliferation and metabolism after stimulation with TLR9 in vitro. We hypothesized that Itch deficiency perturbs TLR9 signaling to disrupt the TLR9-dependent tolerance checkpoint to dsDNA. To test this, we triggered a TLR9-dependent peripheral tolerance checkpoint using STIC9 (Stimulatory TLR9 Immune Complex) or AM14 transgenic B cells. Both systems are known to induce transient proliferation followed by cell death, modeling a peripheral tolerance checkpoint. Death can be prevented by B lymphocyte stimulator (BLyS/BAFF), modeling a breach in tolerance. We compared survival and proliferation in wild-type and Itch deficient B cells in both the STIC9 and AM14 systems and found Itch deficient B cells proliferate and survive more compared to wild type. These studies suggest that Itch deficient B cells lose tolerance to dsDNA-containing self-antigens. Funding Sources 1K22AI148597-01A1; 1R01AI185774-01 Topic Categories Basic Autoimmunity (BA)
Source: The Journal of Immunology
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416446328
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