{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T10:02:20Z","timestamp":1791021740046,"version":"4.1.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Antibodies play a critical role in immunity in part by mediating clearance of pathogens and infected cells by antibody-dependent cellular phagocytosis (ADCP) through engagement of Fc gamma receptors (Fc\u03b3Rs) on innate immune cells. Among these, Fc\u03b3RIIa (CD32a) is a key activating receptor expressed on macrophages, dendritic cells, and other antigen-presenting cells. Its affinity for IgG and ability to mediate ADCP is influenced by allelic polymorphisms. In humans, a single amino acid polymorphism at position 131, where histidine (H) is substituted with arginine (R), leads to decreased IgG1 and IgG2 subclass binding affinity and, consequently, lower efficiency of phagocytic responses. Rhesus macaques (\n                      <jats:italic>Macaca mulatta<\/jats:italic>\n                      ), which are widely used as nonhuman primate models, exhibit a similar polymorphism at position 131 of Fc\u03b3RIIa, but with arginine replaced by proline (P). Here, we investigated structure-function relationships associated with the Fc\u03b3RIIa polymorphism at position 131 in both species, specifically with respect to IgG1 and IgG2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We determined the structures of complexes formed by each variant with IgG1 Fc and those formed by the higher affinity variant with IgG2 Fc for both species by x-ray crystallography and linked these structures to affinity and activity using SPR and an ADCP assay. We also determined the structure of human inhibitory Fc\u03b3RIIb (CD32b) in complex with IgG1 Fc by x-ray crystallography.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Through analysis of these structures, our studies reveal that Fc\u03b3RIIa engagement is minimally influenced by Fc glycan composition, distinguishing it from Fc\u03b3RIIIa whose affinity is strongly influenced by glycan-composition. Comparative structures of human and macaque Fc\u03b3RIIa variants demonstrate species- and allele-specific differences in Fc binding, but our functional assays showed only minimal allele-specific effects in humans. In contrast, allele-specific effects in macaques were highly significant; the macaque P\n                      <jats:sup>131<\/jats:sup>\n                      variant showing uniformly reduced IgG affinity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These insights highlight fundamental interspecies and allelic distinctions that are critical for interpreting Fc\u03b3RIIa-mediated effector functions in macaque models and for optimizing translational antibody and vaccine design.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1726068","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T15:02:37Z","timestamp":1765206157000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Cross-species analysis of Fc\u03b3RIIa\/b (CD32a\/b) polymorphisms at position 131: structural and functional insights into the mechanism of IgG- mediated phagocytosis in human and macaque"],"prefix":"10.3389","volume":"16","author":[{"given":"William D.","family":"Tolbert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula B.","family":"Nhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haleigh 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