SAA1 Protein Isoforms Induce Rheumatoid Arthritis

Background: Secondary amyloid A amyloidosis, a lethal complication, is induced when acute or chronic infection coexisted with over-secretion of the SAA1 protein and deposition of SAA1 in key internal organs. Previously, using the whole-exome sequencing method, we identified the novel deleterious mutation SAA1.2 in rheumatoid arthritis (RA) patients. However, the role of SAA1 in RA pathogenesis and its complications remains unknown, making early diagnosis and risk prevention difficult. Methods: We modified an experimental adenovirus infection protocol in order to successfully introduce SAA1.2, SAA1.3, SAA1.5 gene alleles into the rear knee joints of C57BL/6 mice. micro-CT analysis was applied to determine changes in bone morphology and density. IHC, flow cytometry, ELISA and real-time PCR were used to investigate disease progression and cytokine alterations in the course of adenoviral SAA-induced knee joint inflammation and bone destruction. Findings: The pathogenetic functions of SAA1.2, SAA1.3 and SAA1.5 protein isoforms in promoting the initiation and progression of RA were determined. We established that SAA1.2 was the most aggressive factor in RA induction and progression. Mechanistically, we found that the arthritis-inducing effect of SAA1.2 transcription in the knee joints and mutant SAA1 protein secretion in blood results in stimulation of immune responses, leading to CD8 + T cell and pro-inflammatory cytokine elevation, with subsequent synovial inflammation and bone destruction. Interpretation: 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 for RA. Funding Statement: This work was funded by The Science and Technology Development Fund, Macau SAR (file no. FDCT-FDCT-17-002-SKL). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study protocol was approved by the institutional committee for animal welfare.