Division of Rheumatology, Cincinnati Children' Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Division of Rheumatology, Children's of Alabama and Department of Pediatrics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
Genes Immun. 2020 May;21(3):169-181. doi: 10.1038/s41435-020-0098-4. Epub 2020 Apr 15.
Macrophage activation syndrome (MAS), or secondary hemophagocytic lymphohistiocytosis (HLH), is a cytokine storm syndrome associated with multi-organ system dysfunction and high mortality rates. Laboratory and clinical features resemble primary HLH, which arises in infancy (1 in 50,000 live births) from homozygous mutations in various genes critical to the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. MAS/secondary HLH is about ten times more common and typically presents beyond infancy extending into adulthood. The genetics of MAS are far less defined than for familial HLH. However, the distinction between familial HLH and MAS/secondary HLH is blurred by the finding of heterozygous perforin-pathway mutations in MAS patients, which may function as hypomorphic or partial dominant-negative alleles and contribute to disease pathogenesis. In addition, mutations in a variety of other pathogenic pathways have been noted in patients with MAS/secondary HLH. Many of these genetically disrupted pathways result in a similar cytokine storm syndrome, and can be broadly categorized as impaired viral control (e.g., SH2P1A), dysregulated inflammasome activity (e.g., NLRC4), other immune defects (e.g., IKBKG), and dysregulated metabolism (e.g., LIPA). Collectively these genetic lesions likely combine with states of chronic inflammation, as seen in various rheumatic diseases (e.g., still disease), with or without identified infections, to result in MAS pathology as explained by the threshold model of disease. This emerging paradigm may ultimately support genetic risk stratification for high-risk chronic and even acute inflammatory disorders. Moving forward, continued whole-exome and -genome sequencing will likely identify novel MAS gene associations, as well as noncoding mutations altering levels of gene expression.
巨噬细胞活化综合征（MAS），又称继发性噬血细胞性淋巴组织细胞增生症（HLH），是一种细胞因子风暴综合征，与多器官系统功能障碍和高死亡率有关。实验室和临床特征与原发性 HLH 相似，原发性 HLH 发生于婴儿期（每 50,000 例活产中 1 例），是由 NK 细胞和细胞毒性 CD8 T 淋巴细胞所采用的穿孔素介导的细胞溶解途径中的各种关键基因的纯合突变引起的。MAS/继发性 HLH 更为常见，通常发生在婴儿期之后，延伸至成年期。MAS 的遗传学远不如家族性 HLH 明确。然而，MAS 患者中存在杂合穿孔素途径突变，这使得家族性 HLH 和 MAS/继发性 HLH 之间的区别变得模糊，这些突变可能作为低功能或部分显性负等位基因，有助于疾病发病机制。此外，在 MAS/继发性 HLH 患者中还发现了各种其他致病途径的突变。这些遗传途径的破坏大多导致类似的细胞因子风暴综合征，可以广泛归类为病毒控制受损（例如，SH2P1A）、炎症小体活性失调（例如，NLRC4）、其他免疫缺陷（例如，IKBKG）和代谢失调（例如，LIPA）。这些遗传病变可能与各种风湿性疾病（例如，Still 病）中的慢性炎症状态共同作用，无论是伴有还是不伴有已确定的感染，从而导致 MAS 病理，正如疾病的阈值模型所解释的那样。这种新兴的范例可能最终支持对高风险慢性甚至急性炎症性疾病进行遗传风险分层。展望未来，持续的全外显子组和全基因组测序可能会发现新的 MAS 基因关联，以及改变基因表达水平的非编码突变。
