Uncovering the Role of Tertiary Lymphoid Organs in the Inflammatory Landscape: A Novel Immunophenotype of Diabetic Foot Ulcers

Abstract

Diabetes foot ulcers (DFU) are the most common foot injuries leading to lower extremity amputation. Our study aimed to provide the first representative analysis highlighting the vital role of Tertiary Lymphoid Organs (TLO) inflammatory landscape in diabetic foot ulcers. The study explores mechanisms of TLO formation and the disease-specific roles of TLOs in regulating peripheral inflammatory and immune responses. Additionally, comprehensive analysis of clinical data from DFU cases, focused on TLO pathophysiology and systemic immune-inflammation landscape, is documented, aiming to identify the risk factors contributing to the development of DFUs. Our experimental results showed very significant differences were observed among the IL-17 and IFN-γ cytokine levels between the DFU vs. Control and DFU vs. NIDFU (Non-Infectious Diabetic Foot Ulcers) groups, while minimal differences were observed in IL-6 and TNF-α cytokine levels. Immunohistochemistry staining or Immunophenotyping of DFU patient-derived wound samples for TLO inflammatory stratification showed remarkable differences between DFU, NIDFU, and control groups both in CD3⁺ T Cells and CD20⁺ B cells. Overall, our study findings highlight the perspective role of TLO in DFU mechanisms and its prudent role in regulating peripheral inflammatory-immune responses. TLO study-related significant findings might be one of the important mechanisms, and its effective unveil might be a valuable treatment modality for DFU-complications.