Immunoproteomic mediators of diabetic peripheral neuropathy: causal insights from Mendelian randomization and single-cell validation

Objective 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. Methods 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. Results Five HLA-DR+ immune phenotypes (predominantly dendritic subsets) increased DPN risk (OR = 1.27–1.63, FDR<0.05). Six plasma proteins conferred protection (MICB, HLA-DRA, CAPS, CD79B, AGER, PRKCG; OR = 0.10–0.58). Mediation MR revealed pathogenic immune cells suppress CAPS/HLA-DRA expression (mediating 26.3% of neurotoxicity, P<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. Conclusion We establish a causal neuroimmune network wherein HLA-DR+ 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.

• Publication year

  2026

• Venue

  Frontiers in Immunology

• Publication date

  2026-01-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3389/fimmu.2026.1681223PMID 41694368PMCID 12894356
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Therapeutic targets for diabetic kidney disease: proteome-wide Mendelian randomization and colocalization analyses.

  2024cited by this paper
• Integrative Analysis of Acupuncture Targets and Immune Genes in Diabetes, Diabetic Peripheral Neuropathy, and Adjunct Therapy of Cancer

  2024cited by this paper
• The causal relationship between immune cells and diabetic retinopathy: a Mendelian randomization study

  2024cited by this paper
• Elucidating the causal nexus and immune mediation between frailty and chronic kidney disease: integrative multi-omics analysis

  2024cited by this paper
• Autoreactive T cells target peripheral nerves in Guillain–Barré syndrome

  2024cited by this paper
• Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy

  2023cited by this paper
• Plasma proteins and onset of type 2 diabetes and diabetic complications: Proteome-wide Mendelian randomization and colocalization analyses

  2023cited by this paper
• Inhibition of hexokinase 2 with 3-BrPA promotes MDSCs differentiation and immunosuppressive function.

  2023cited by this paper
• Dendritic Cells and Their Immunotherapeutic Potential for Treating Type 1 Diabetes

  2022cited by this paper
• Structural principles of B cell antigen receptor assembly

  2022cited by this paper
• The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas.

  2022cited by this paper
• BLOOD MOLECULAR BIOMARKERS FOR CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY: FROM PRECLINICAL MODELS TO CLINICAL PRACTICE.

  2021cited by this paper
• Clinical and biochemical markers in CIPN: A reappraisal.

  2021cited by this paper
• Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients With Painful Diabetic Neuropathy

  2021cited by this paper
• Aging and the immune response in diabetic peripheral neuropathy.

  2021cited by this paper
• Calcyphosine promotes the proliferation of glioma cells and serves as a potential therapeutic target

  2021cited by this paper
• Plasma protein N-glycosylation is associated with cardiovascular disease, nephropathy, and retinopathy in type 2 diabetes

  2021cited by this paper
• Quantification of Early-Stage Myeloid-Derived Suppressor Cells in Cancer Requires Excluding Basophils

  2020cited by this paper
• Synaptic Dynamics of the Feed-forward Inhibitory Circuitry Gating Mechanical Allodynia in Mice

  2020cited by this paper
• CD33+ HLA-DR– Myeloid-Derived Suppressor Cells Are Increased in Frequency in the Peripheral Blood of Type1 Diabetes Patients with Predominance of CD14+ Subset

  2018influential reference
• Differentially expressed and survival‐related proteins of lung adenocarcinoma with bone metastasis

  2018cited by this paper
• Soluble NKG2D ligand promotes MDSC expansion and skews macrophage to the alternatively activated phenotype

  2015cited by this paper
• Population dynamics of islet-infiltrating cells in autoimmune diabetes

  2015cited by this paper
• Identification of a novel MICB allele, MICB*030, by cloning and sequencing

  2015cited by this paper
• B cells and type 1 diabetes ...in mice and men.

  2014cited by this paper
• Inflammation: Therapeutic Targets for Diabetic Neuropathy

  2014cited by this paper
• In Vivo Detection of Peripherin-Specific Autoreactive B Cells during Type 1 Diabetes Pathogenesis

  2014cited by this paper
• Diabetic neuropathy: clinical manifestations and current treatments.

  2012cited by this paper
• Type 2 diabetes as an inflammatory disease

  2011cited by this paper
• Receptor for advanced glycation endproducts and atherosclerosis: From basic mechanisms to clinical implications.

  2008cited by this paper
• Human HLA-DR Transgenes Protect Mice from Fatal Virus-Induced Encephalomyelitis and Chronic Demyelination

  2008cited by this paper
• Epidemiology and Impact on Quality of Life of Postherpetic Neuralgia and Painful Diabetic Neuropathy

  2002influential reference
• Expression and crystallization of the complex of HLA-DR2 (DRA, DRB1*1501) and an immunodominant peptide of human myelin basic protein.

  1998cited by this paper

• No citing papers are available for this paper.