Abstract Th0046: Downregulation of fibroblast-mediated immune activation in Prolidase deficient patients

Background: Prolidase deficiency (PD) is a rare autosomal recessive disorder in which mutations in the PEPD gene lead to a mutated prolidase protein with no or reduced enzymatic activity. Prolidase plays an essential role in digesting and recycling dipeptides to generate free proline and hydroxyproline, which are essential amino acids in the turnover for key structural proteins like collagen. Clinically, 80% of these patients have dermatological manifestations such as improper wound healing, ulcer formation, and a weakened immune system is also common for PD patients. Fibroblasts have a major role in wound healing including immune cell activation and tissue remodeling, but it is unknown if their activity is dysregulated in the context of PD patients. Methods: PD patients were recruited to NIH/NHLBI. Fibroblasts from 5 PD and 5 healthy volunteers were grown in DMEM with 10% Fetal Bovine Serum (FBS). RNA was extracted for bulk RNA sequencing. Results: Sequencing analysis revealed 162 differentially expressed genes (DEGs) between PD patients and healthy groups. Pathway enrichment analysis showed DEGs were predominantly involved in adaptive and innate immune system functions, suggesting that PD fibroblasts have a decreased ability to regulate immune cell functions. The well-known chemokine IL-8 was strongly downregulated in PD. Other genes involved in activation of innate and adaptive immune cells such as NMRAL1, DDX60L, BRD4, and TIAM2 were downregulated in PD. Conclusion: Fibroblast regulation of immune cells appears to be dysregulated in PD patients. In the future, we will investigate the role of fibroblast-mediated immune cell activation in improper wound healing.