Systemic Genetic Susceptibility and Lung Tissue Remodeling in Autoimmune-Associated Interstitial Lung Disease

Background: Systemic autoimmune disease-associated interstitial lung disease (SAID-ILD) involves systemic immune susceptibility superimposed on complex pulmonary inflammation and fibrosis. Methods: A multi-layer framework integrating two-sample Mendelian randomization (MR) of 91 circulating inflammatory proteins and 1400 serum metabolites with lung-focused bulk transcriptomics, explanted-lung single-nucleus RNA sequencing, and bronchoalveolar-lavage single-cell RNA sequencing was used to connect systemic susceptibility signals with cell-resolved lung biology. Results: MR prioritized multiple inflammatory signals, including risk-increasing estimates for CD244 and CX3CL1; neither met the 91-protein BH threshold, and power at OR = 1.5 was below 25% for both. Bulk transcriptomic meta-analysis identified a reproducible disease context dominated by epithelial injury, myeloid activation, and extracellular-matrix remodeling. Cell-resolved integration localized CD244 predominantly to T cells/natural killer cells and CX3CL1 to endothelial, epithelial, and stromal compartments, supporting evaluation of CD48–CD244 and CX3CL1–CX3CR1 as candidate communication axes. The CX3CL1–CX3CR1 recruitment program was increased in disease myeloid cells (Hedges g = 1.27, q = 3.86 × 10−4), whereas CD48–CD244 showed receiver-program compatibility, with CD48 ranking first among the two tested ligands in 20 of 21 NicheNet scenarios. Communication effects varied across pulmonary compartments, and neither focal axis represented the strongest disease-associated route; SPP1–CD44 showed the largest fixed-effect global shift, although its nine-pair evidence was not significant in the random-effects sensitivity analysis. Conclusions: These results distinguish systemic genetic susceptibility from local communication magnitude and identify CD48–CD244 and CX3CL1–CX3CR1 as biologically distinct, compartment-dependent hypotheses linking immune-cell state and recruitment to the fibrotic lung environment in SAID-ILD.