Integrated Profiling of TNF Superfamily Ligands and Lung Inflammatory Markers in Tuberculosis-Type 2 Diabetes Mellitus Comorbidity

Background: Type 2 diabetes mellitus (T2DM) increases susceptibility to tuberculosis (TB) and contributes to immune dysregulation, exaggerated inflammation and poor clinical outcomes. Acute-phase proteins (APPs), lung-associated markers (LMs) and TNF superfamily ligands play a crucial role in inflammatory and immune signaling; however, an integrated approach in understanding the inflammatory profile and their immunological association in TB-T2DM remains underexplored. Methods: Plasma levels of APPs and LMs including CRP, SAA1, Haptoglobin, α2M, IDO, CHI3L1, S100A8, S100A9 and granulysin were evaluated for the study cohort of 176 individuals (TB = 44, TB–T2DM = 44, T2DM-only = 44 and healthy-controls = 44). TNF superfamily ligands, including 4-1BBL, APRIL, BAFF, CD30L, CD40L, EDA-1, Fas-L, GITRL, LIGHT, RANKL, NGF- β, TNF-β, TRAIL and TWEAK, were measured using a multiplex immunoassay for 88 individuals (TB = 22, TB–T2DM = 22, T2DM-only = 22 and healthy-controls = 22). Spearman correlation analysis, protein–protein interaction (PPI) network analysis and pathway enrichment analysis were also performed. Results: TB-T2DM individuals exhibited significantly increased inflammatory burden compared with TB, T2DM and HC groups. Increased levels of CRP, SAA1, S100A8, S100A9, haptoglobin, CH3IL1 and α2M were observed (p < 0.05), indicating amplified systemic and pulmonary inflammation. TNF superfamily ligands including BAFF, APRIL, CD40L, GITRL, LIGHT and TRAIL were significantly altered in TB-T2DM individuals, suggesting dysregulated TNF-mediated immune signaling. Correlation analysis revealed strong associations between HbA1c levels and inflammatory markers including BAFF, TRAIL, GITRL, LIGHT, CD40L, APRIL, S100A8 and SAA1 (p < 0.05). Network and enrichment analyses identified significant involvement of cytokine–cytokine receptor interaction, IL-17 signaling, NF-κB signaling, apoptosis and necroptosis pathways. Conclusions: Overall, TB-T2DM comorbidity is characterized by exaggerated inflammatory responses and altered TNF superfamily ligand signaling associated with poor glycemic control. This interconnected immune dysregulation may provide future insights into biomarkers and pathway-related investigation to establish more clinical and biological relevance.