Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.
Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
Diabetes. 2023 Jan 1;72(1):71-84. doi: 10.2337/db21-1086.
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 of 40). Among positive patients, 10 had the autoimmune variety and 10 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, for both IgG and IgM autoantibodies. In-depth epitope mapping indicated that anti-PLIN1 autoantibodies predominantly recognize the αβ-hydrolase domain containing 5 (ABHD5) binding site (383-405). Autoantibodies dose-dependently blocked the binding of PLIN1 to ABHD5 and caused a dislocation of ABHD5 toward 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.
获得性全身性脂肪营养不良（AGL）是一种罕见的疾病，其特征是全身大量脂肪组织丧失，导致严重的代谢并发症。根据 AGL 常与自身免疫性疾病相关，强烈怀疑脂肪细胞的自身免疫破坏。2018 年，在 3 名自身免疫相关 AGL 患者中发现了针对 perilipin 1（PLIN1）的自身抗体。然而，抗-PLIN1 的致病机制和临床影响仍未解决。在 40 名 AGL 患者的队列中，抗-PLIN1 自身抗体的患病率为 50%（20/40）。在阳性患者中，10 例为自身免疫性，10 例为脂膜炎相关 AGL。IgG 同种型占优势，尽管也检测到一些 IgM 抗体。表位作图研究未确定单一的主要表位。相反，自身抗体通常与几个不同的肽结合，其中核心（233-405）域在所有抗体阳性患者中均有检测到，无论是 IgG 还是 IgM 自身抗体。深入的表位作图表明，抗-PLIN1 自身抗体主要识别含 5 个αβ-水解酶域（ABHD5）结合位点（383-405）。自身抗体剂量依赖性地阻断了 PLIN1 与 ABHD5 的结合，并导致 ABHD5 向细胞质移位，从而增加脂肪分解和脂肪酶活性。最后，抗-PLIN1 滴度与脂肪丢失量、代谢控制受损程度和肝损伤严重程度显著相关。我们的数据强烈支持抗-PLIN1 自身抗体是 AGL 患者的诊断生物标志物和脂肪营养不良的原因。
