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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Inflammation

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1641351

A genetically determined molecular switch modulates the anti-inflammatory potential of human IgA

Provisionally accepted
  • 1Department of Medicine, University of Alabama at Birmingham, Birmingham, United States
  • 2Department of Veterinary and Biomedical Sciences, University of Minnesota Twin Cities, Minneapolis, United States
  • 3Department of Microbiology, University of Alabama at Birmingham, Birmingham, United States
  • 4Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, United States

The final, formatted version of the article will be published soon.

Fc receptor-driven immune system activity typically reflects a balance of activating and inhibitory mechanisms, mediated by the immunoreceptor tyrosine-based activation motif (ITAM) or inhibition motif (ITIM) in the ligand-binding alpha chain (FcγRIIa,b and c) or the canonical ITAM in the associated Fc receptor γ-chain (FcRγ). A second role for the ITAM, an inhibitory role known as ITAMi, was initially recognized for the FcαRI-FcRγ signaling pair. We report an FcRγ-independent mechanism for inhibitory signaling by FcαRI in which the natural Ser 248 Gly variant in the cytoplasmic domain of the FcαRI α-chain alters the signaling capacity of FcαRI and constitutes a serine-based, genetically determined switch for regulation of the anti-and proinflammatory potentials of human IgA. To elucidate the basis for this α-chain mechanism, we sought allele-specific FcαRI-associated molecules. Sab (SH3BP5), a trans-inhibitor for Bruton's tyrosine kinase (Btk), is recruited by the more common Ser 248 allele, whereas the src-family tyrosine kinase Lyn, a Btk activator, is reciprocally recruited by the Gly 248 variant. Ser 248 phosphorylation amplifies Sab association and disrupts Lyn binding through an overlapping region containing an unconventional SH3-domain binding motif. In contrast to FcαRI Gly 248 , recruitment of Sab by FcαRI Ser 248 results in inhibition of Btk activation and suppression of IgA effector functions independent of FcRγ-pairing. Expression of a dominant negative Sab construct releases FcαRI-mediated inhibition in a Ser 248 -allele specific manner. These findings reveal a reversible serine-based phosphorylation-dependent molecular switch for regulation of receptormediated activation/inhibition that couples FcαRI α-chain to divergent inflammatory properties of human IgA.

Keywords: FCAR, Alleles, Signal Transduction, CD89, inhibition

Received: 04 Jun 2025; Accepted: 04 Aug 2025.

Copyright: © 2025 Gibson, Wu, Hendrickson, Ptacek, Mobley, Edberg and Kimberly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Andrew Winston Gibson, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States

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