LAUSR

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by massive loss of adipose tissue through the body, causing severe metabolic complications. Autoimmune destruction of adipocytes is strongly suspected based on the frequent association of AGL with autoimmune disorders. In 2018 autoantibodies against Perilipin 1 (PLIN1) were identified in three patients with autoimmune-associated AGL. However, the pathogenic mechanism and clinical impact of anti-PLIN1 remain unsolved. The prevalence of anti-PLIN1 autoantibodies in an AGL cohort of 40 patients was 50% (20/40). Among positive patients, ten had the autoimmune variety and ten had panniculitis-associated AGL. The IgG isotype was predominant although some IgM antibodies were detected. Epitope mapping studies did not identify a single, major epitope. Instead, autoantibodies typically bound to several different peptides, among which the central (233-405) domain was detected in all antibody positive patients, both for IgG and IgM autoantibodies. In-depth epitope mapping indicated that anti-PLIN1 autoantibodies predominantly recognize the ABHD5 binding site (383-405). Autoantibodies dose-dependently blocked the binding of PLIN1 to ABHD5 and caused a dislocation of ABHD5 towards the cytosol, leading to an increase in lipolysis and lipase activities. Finally, anti-PLIN1 titers significantly correlated with the amount of fat loss, metabolic control impairment, and severity of liver injury. Our data strongly support that anti-PLIN1 autoantibodies are a diagnostic biomarker and a cause of lipodystrophy in patients with AGL.