{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T17:44:38Z","timestamp":1769708678939,"version":"3.49.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"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>Objective<\/jats:title>\n                    <jats:p>To elucidate causal roles of circulating immune cells and plasma proteins in diabetic peripheral neuropathy (DPN) pathogenesis using integrative Mendelian randomization (MR) and single-cell validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed two-sample MR to assess causal effects of 731 immune traits and 4,719\/2,923 plasma proteins on DPN risk (FinnGen: 2,843 cases\/389,580 controls). Significant exposures underwent mediation MR to identify protein-immune interactions. Validation included scRNA-seq of sural nerves (4 DPN vs. 3 controls) and flow cytometry\/immunofluorescence for dendritic cell infiltration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Five HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      immune phenotypes (predominantly dendritic subsets) increased DPN risk (OR\u00a0=\u00a01.27\u20131.63, FDR&amp;lt;0.05). Six plasma proteins conferred protection (MICB, HLA-DRA, CAPS, CD79B, AGER, PRKCG; OR\u00a0=\u00a00.10\u20130.58). Mediation MR revealed pathogenic immune cells suppress CAPS\/HLA-DRA expression (mediating 26.3% of neurotoxicity, P&amp;lt;0.001), while MICB attenuated DPN by inhibiting immune phenotypes. scRNA-seq confirmed conventional dendritic cell infiltration in DPN nerves and disrupted reparative crosstalk with Schwann cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We establish a causal neuroimmune network wherein HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      dendritic cells drive DPN through suppression of protective plasma proteins (CAPS\/HLA-DRA), while MICB exerts dual protection. These findings reveal novel therapeutic targets for DPN intervention.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1681223","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T06:41:39Z","timestamp":1769668899000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunoproteomic mediators of diabetic peripheral neuropathy: causal insights from Mendelian randomization and single-cell validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Chenhao","family":"Hu","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengqiao","family":"Sun","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dezhi","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical University","place":["Beijing, China"]},{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lebao","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Guo","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Central Nervous System Injury, Beijing Neurosurgical Institute, Capital Medical 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