Department of Internal Medicine, Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE, USA; Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
Department of Internal Medicine, Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE, USA; Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
Int Immunopharmacol. 2020 Jun;83:106433. doi: 10.1016/j.intimp.2020.106433. Epub 2020 Mar 27.
BACKGROUND/OBJECTIVE: Malondialdehyde-acetaldehyde adducts (MAA) act as potent immune adjuvants and co-localize with citrullinated antigens in tissues effected by rheumatoid arthritis (RA). We sought to examine the role of MAA-adducts in promoting RA-related autoimmunity and inflammation.
DBA/J1 mice were immunized with human serum albumin (HSA), HSA-MAA, citrullinated HSA (HSA-Cit), or HSA-MAA-Cit with subsequent measurement of serum anti-citrullinated protein antibody (ACPA) and anti-Cit T cell responses. Cellular binding of the same antigens was examined using THP-1 monocytes and Chinese Hamster Ovary (CHO) cells transfected with specific scavenger receptors (SRs: TLR4, SR-B2, SREC-1). The effects of these antigens on THP-1 activation were then examined by quantifying plate adherence, pro-inflammatory (TNFα, IL-1β, IL-10) cytokine release, and SR (CD14, SR-B2)/co-stimulatory molecule (CD80, HLA-DR) expression. Comparisons were completed using one-way ANOVA with Tukey's post-hoc test.
Mice immunized with co-modified HSA produced significantly higher ACPA concentrations than all other groups whereas T cell responses to citrullinated proteins were highest following immunization with HSA-MAA. Both transfected CHO and THP-1 cells demonstrated significantly higher binding of HSA-MAA-Cit vs. HSA or HSA-Cit. THP-1 cells exposed to HSA-MAA-Cit expressed significantly higher concentrations of TNFα, IL-1β, and IL-10 vs. all other groups. Furthermore, THP-1 cells demonstrated significantly increased plate adherence and higher expression of CD14, SR-B2, and HLA-DR following incubation with HSA-MAA-Cit vs. HSA or HSA-Cit.
These studies demonstrate that MAA-adduction of citrullinated antigen greatly enhances immune and cellular responses, potentially acting as a key co-factor in RA pathogenesis.
背景/目的：丙二醛-乙醛加合物（MAA）作为有效的免疫佐剂，与类风湿关节炎（RA）受累组织中的瓜氨酸化抗原共存。我们试图研究 MAA 加合物在促进 RA 相关自身免疫和炎症中的作用。
用人血清白蛋白（HSA）、HSA-MAA、瓜氨酸化 HSA（HSA-Cit）或 HSA-MAA-Cit 免疫 DBA/J1 小鼠，随后测量血清抗瓜氨酸蛋白抗体（ACPA）和抗 Cit T 细胞反应。使用 THP-1 单核细胞和转染了特定清道夫受体（TLR4、SR-B2、SREC-1）的中国仓鼠卵巢（CHO）细胞检测相同抗原的细胞结合。然后通过定量平板黏附、促炎（TNFα、IL-1β、IL-10）细胞因子释放和清道夫受体（CD14、SR-B2）/共刺激分子（CD80、HLA-DR）表达来检测这些抗原对 THP-1 激活的影响。使用单因素方差分析和 Tukey 事后检验进行比较。
与其他组相比，用共修饰 HSA 免疫的小鼠产生的 ACPA 浓度显著更高，而用 HSA-MAA 免疫的小鼠对瓜氨酸化蛋白的 T 细胞反应最高。转染的 CHO 和 THP-1 细胞均显示出与 HSA 或 HSA-Cit 相比，HSA-MAA-Cit 的结合显著增加。与其他组相比，暴露于 HSA-MAA-Cit 的 THP-1 细胞表达了更高浓度的 TNFα、IL-1β 和 IL-10。此外，与 HSA 或 HSA-Cit 相比，用 HSA-MAA-Cit 孵育的 THP-1 细胞表现出更高的平板黏附率和更高的 CD14、SR-B2 和 HLA-DR 表达。
这些研究表明，瓜氨酸化抗原的 MAA 加合物大大增强了免疫和细胞反应，可能是 RA 发病机制中的关键协同因子。
