Acquired CL (ACL) is an ultra-rare disease characterized by a late-onset, acute inflammation-mediated progressive destruction of dermal EF. ACL is likely highly underdiagnosed due to the lack of sensitive clinical or histological diagnostic handles. The pathophysiology is unknown but clinical observation and histology suggest that immune-driven mechanisms cause EF destruction. EF breakdown can spread to other internal organs, causing aortic aneurysms, pulmonary emphysema, or organ prolapse, indicating overlapping mechanisms of EF breakdown in skin, aorta and lungs.

We therefore hypothesize that ACL, abdominal aortic aneurysm (AAA), and genetically determined thoracic aortic nauerysms (TAA) as in Marfan syndrome (MFS) may share mechanisms of immune-mediated EF breakdown.

We will evaluate electron microscopy on presymptomatic skin (PS) and endstage skin (ES) as a diagnostic tool for ACL. We determine methylation of blood derived DNA to identify a diagnostic episignature and perform pathway analysis of differentially methylated genes. In PS and ES will will determine changes in matrix degrading enzyme acitvity and evaluate if elastin breakdown products activate T-cels. Next, we will verify these mechanisms of EF breakdown in human tissue and mouse models of abdominal aortic aneurysms and marfan syndrome.

We expect that the results will help to understand how an autoimmune response may cause EF frailty in the context of genetic predisposition and aging and will point to novel therapeutic targets to preserve and restore EF function.