aDepartment of Paediatric Rheumatology and Immunology, University Children's Hospital bInstitute of Immunology, University Hospital Muenster, Muenster, Germany.
Curr Opin Rheumatol. 2016 Sep;28(5):550-9. doi: 10.1097/BOR.0000000000000314.
To give an overview about the expanding spectrum of autoinflammatory diseases due to mutations in proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) and new insights into their pathogenesis.
In addition to classical pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome has been described as a distinct clinical phenotype of PSTPIP1-associated inflammatory diseases (PAID) and other entities are emerging. In addition to dysregulation of IL-1ß release from activated PAPA monocytes that requires NLR family, pyrin domain containing 3 (NLRP3), PSTPIP1 mutations have an general impact on cellular dynamics of cells of the innate immune system. In addition, overwhelming expression and release of the alarmins myeloid-related protein (MRP) 8 and 14 by activated phagocytes and keratinocytes, which promote innate immune mechanisms in a Toll like receptor (TLR) 4-dependent manner, are a characteristic feature of these diseases and form a positive feed-back mechanism with IL-1ß.
Autoinflammatory diseases due to PSTPIP1 mutations are not restricted to the classical PAPA phenotype but might present with other distinct clinical features. MRP8/14 serum levels are a hallmark of PAPA and PAMI and can be used as screening tool to initiate targeted genetic testing in suspected cases. The feedback mechanism of IL-1ß and MRP-alarmin release may offer novel targets for future therapeutic approaches.
介绍 PSTPIP1 基因突变导致的炎症性疾病谱不断扩大，以及对其发病机制的新认识。
除了经典的化脓性无菌性关节炎、坏疽性脓皮病和痤疮（PAPA）综合征外，PSTPIP1 相关髓样相关蛋白血症炎症（PAMI）综合征已被描述为 PSTPIP1 相关炎症性疾病（PAID）的独特临床表型，其他疾病也在不断出现。除了需要 NLR 家族、含吡喃结构域的 NOD 样受体 3（NLRP3）激活的 PAPA 单核细胞中 IL-1β释放的失调外，PSTPIP1 突变对固有免疫系统细胞的细胞动力学具有普遍影响。此外，激活的吞噬细胞和角质形成细胞过度表达和释放警报素髓样相关蛋白（MRP）8 和 14，以 Toll 样受体（TLR）4 依赖的方式促进固有免疫机制，这是这些疾病的一个特征，并与 IL-1β形成正反馈机制。
PSTPIP1 突变引起的自身炎症性疾病不仅限于经典的 PAPA 表型，还可能表现出其他独特的临床特征。MRP8/14 血清水平是 PAPA 和 PAMI 的标志，可以作为疑似病例中启动靶向基因检测的筛选工具。IL-1β和 MRP-警报素释放的反馈机制可能为未来的治疗方法提供新的靶点。
