Naturally occurring antibodies against serum amyloid A reduce IL-6 release from peripheral blood mononuclear cells

Serum amyloid A (SAA) is a sensitive inflammatory marker rapidly increased in response to infection, injury or trauma during the acute phase. Resolution of the acute phase and SAA reduction are well documented, however the exact mechanism remains elusive. Two inducible SAA proteins, SAA1 and SAA2, with their variants could contribute to systemic inflammation. While unconjugated human variant SAA1α is already commercially available, the variants of SAA2 are not. Antibodies against SAA have been identified in apparently healthy blood donors (HBDs) in smaller, preliminary studies. So, our objective was to detect anti-SAA and anti-SAA1α autoantibodies in the sera of 300 HBDs using ELISA, characterize their specificity and avidity. Additionally, we aimed to determine the presence of anti-SAA and anti-SAA1α autoantibodies in intravenous immunoglobulin (IVIg) preparations and examine their effects on released IL-6 from SAA/SAA1α-treated peripheral blood mononuclear cells (PBMCs). Autoantibodies against SAA and SAA1α had a median (IQR) absorbance OD (A450) of 0.655 (0.262–1.293) and 0.493 (0.284–0.713), respectively. Both anti-SAA and anti-SAA1α exhibited heterogeneous to high avidity and reached peak levels between 41–50 years, then diminished with age in the oldest group (51–67 years). Women consistently exhibited significantly higher levels than men. Good positive correlation was observed between anti-SAA and anti-SAA1α. Both anti-SAA and anti-SAA1α were detected in IVIg, their fractions subsequently isolated, and shown to decrease IL-6 protein levels released from SAA/SAA1α-treated PBMCs. In conclusion, naturally occurring antibodies against SAA and anti-SAA1α could play a physiological role in down-regulating their antigen and proinflammatory cytokines leading to the resolution of the acute phase and could be an important therapeutic option in patients with chronic inflammatory diseases.血清淀粉样蛋白A（Serum Amyloid A, SAA）是一种敏感的炎症标志物，可在急性期因感染、损伤或创伤而快速升高。急性期缓解与SAA水平降低已有充分文献记载，但其具体调控机制仍有待阐明。两种诱导型SAA蛋白——SAA1与SAA2及其变体可参与全身性炎症反应。目前未结合型人源变体SAA1α已实现商业化供应，但SAA2的变体尚未上市。既往小型初步研究已在看似健康的献血者（Healthy Blood Donors, HBDs）中检出针对SAA的自身抗体。因此本研究旨在通过酶联免疫吸附试验（Enzyme-Linked Immunosorbent Assay, ELISA）检测300名健康献血者血清中的抗SAA与抗SAA1α自身抗体，并对其特异性与亲和力进行表征。此外，本研究还旨在确定静脉注射免疫球蛋白（Intravenous Immunoglobulin, IVIg）制剂中是否存在抗SAA与抗SAA1α自身抗体，并考察其对经SAA/SAA1α处理的外周血单个核细胞（Peripheral Blood Mononuclear Cells, PBMCs）释放白细胞介素6（Interleukin-6, IL-6）的影响。抗SAA与抗SAA1α自身抗体的吸光度光密度（A450）中位数（四分位距）分别为0.655（0.262~1.293）与0.493（0.284~0.713）。抗SAA与抗SAA1α抗体均表现出异质性至高亲和力特征，其抗体水平在41~50岁年龄段达到峰值，随后在51~67岁的最年长组别中随年龄增长而逐渐下降。女性的抗体水平始终显著高于男性。抗SAA与抗SAA1α抗体之间呈现良好的正相关关系。研究人员在IVIg制剂中检出了抗SAA与抗SAA1α抗体，随后对其活性组分进行了分离，并证实其可降低经SAA/SAA1α处理的PBMCs所释放的IL-6蛋白水平。综上，天然存在的抗SAA与抗SAA1α抗体或可通过下调其靶抗原与促炎细胞因子的表达水平，在急性期炎症消退过程中发挥生理调控作用，同时也有望成为慢性炎症性疾病患者的重要治疗选择。