Secondary amyloid A amyloidosis, a lethal complication, is induced when acute or chronic infection coexists with over-secretion of the serum amyloid A 1 (SAA1) protein and deposition in key internal organs. Previously, using the whole-exome sequencing method, we identified a novel deleterious mutation SAA1.2 in rheumatoid arthritis (RA) patients. However, the role of SAA1 in RA pathogenesis and its complications remains unknown. The purpose of this study was to determine the pathogenetic roles of SAA1 protein isoforms in RA progression. We modified an experimental adenovirus infection protocol to introduce SAA1.2 gene alleles into the knee joints of mice and used SAA1.3 and SAA1.5 as controls. Micro-computed tomography analysis was applied to determine changes in bone morphology and density. Immunohistochemical (IHC) analysis, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and real-time polymerase chain reaction (RT-PCR) were used to investigate disease progression and cytokine alterations in the course of adenoviral SAA-induced knee joint inflammation and bone destruction. We found that the arthritis-inducing effect of SAA1.2 transcription in the knee joints and mutant SAA1 protein secretion in blood resulted in the stimulation of immune responses, leading to CD8⁺ T cell and pro-inflammatory cytokine elevation, such as interleukin (IL)-6, IL-22, matrix metalloproteinase (MMP)-3, MMP-9, with subsequent synovial inflammation and bone destruction. These findings indicate that SAA1 protein isoforms, particularly SAA1.2, play a significant role in the induction and progression of RA and may have potential value in the early diagnosis and severity prediction of RA.

当急性或慢性感染与血清淀粉样蛋白 A 1 (SAA1) 蛋白的过度分泌和关键内脏器官的沉积共存时，会诱发继发性淀粉样蛋白 A 淀粉样变性病，这是一种致命的并发症。以前，我们使用全外显子组测序方法，在类风湿关节炎 (RA) 患者中发现了一种新的有害突变SAA1.2。然而，SAA1 在 RA 发病机制及其并发症中的作用仍然未知。本研究的目的是确定 SAA1 蛋白亚型在 RA 进展中的致病作用。我们修改了实验性腺病毒感染方案，将SAA1.2基因等位基因引入小鼠膝关节，并使用SAA1.3和SAA1.5作为控件。应用微型计算机断层扫描分析来确定骨形态和密度的变化。免疫组织化学 (IHC) 分析、流式细胞术、酶联免疫吸附试验 (ELISA) 和实时聚合酶链反应 (RT-PCR) 用于研究腺病毒 SAA 诱导的膝关节炎症过程中的疾病进展和细胞因子改变和骨质破坏。我们发现膝关节中SAA1.2转录的关节炎诱导作用和血液中 SAA1 蛋白突变的分泌导致免疫反应的刺激，导致 CD8 ⁺T 细胞和促炎细胞因子升高，如白细胞介素 (IL)-6、IL-22、基质金属蛋白酶 (MMP)-3、MMP-9，随后出现滑膜炎症和骨破坏。这些发现表明，SAA1 蛋白亚型，特别是 SAA1.2，在 RA 的诱导和进展中起重要作用，可能在 RA 的早期诊断和严重程度预测中具有潜在价值。