Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA.
Diabetes Center, University of California, San Francisco, San Francisco, CA.
Diabetes. 2023 Jan 1;72(1):59-70. doi: 10.2337/db21-1172.
Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.
获得性脂肪萎缩症通常表现为特发性脂肪萎缩症亚型。尽管怀疑存在免疫介导的病理，但通常缺乏生物标志物，如自身抗体。在这里，我们使用一种无偏见的蛋白质组全谱筛选方法，在自身免疫性多内分泌综合征 1 型（APS1）的小鼠模型中鉴定出针对脂肪细胞特异性脂滴蛋白 perilipin 1（PLIN1）的自身抗体。然后，我们使用特定的放射性配体结合测定法和脂肪组织的间接免疫荧光法，在具有两种独立免疫耐受中断（包括 APS1）的获得性脂肪萎缩症人类受试者以及对照受试者中，检测 PLIN1 自身抗体。我们在这两个病例中鉴定出了针对 PLIN1 的自身抗体，包括首例报道的 APS1 合并获得性脂肪萎缩症病例和第二位在癌症免疫治疗后发生免疫相关不良事件而获得性脂肪萎缩症的患者。最后，我们还发现 PLIN1 自身抗体在获得性全身性脂肪萎缩症的一部分患者中特异性富集（46 例中的 17 例[37%]），尤其是那些伴有脂膜炎和其他自身免疫特征的患者。这些数据进一步支持新的文献，表明 PLIN1 自身抗体代表获得性自身免疫性脂肪萎缩症的标志物，并将其与免疫耐受中断联系起来。
