Department of Medicine Solna, Division of Rheumatology, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
ORGENTEC Diagnostika GmbH, Mainz, Germany.
Front Immunol. 2021 May 20;12:627986. doi: 10.3389/fimmu.2021.627986. eCollection 2021.
Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), -acetylated (KAc), and malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. In this comprehensive study, we analyze 30 different IgG and IgA AMPA reactivities to Cit, Carb, KAc, and MAA antigens detected by ELISA and autoantigen arrays in N=1985 newly diagnosed RA patients. Association with patient characteristics such as smoking and disease activity were explored. Carb and KAc reactivities by different assays were primarily seen in patients also positive for anti-citrulline reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG reactivity to acetylation was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking status. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles. Our serology results were complemented by screening of monoclonal antibodies derived from single B cells from RA patients for the same antigens as the RA cohort. Certain CCP2+ clones had Carb or Carb+KAc+ multireactivity, while such reactivities were not found in CCP2- clones. We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Carb and KAc could be considered reactivities within the "Cit-umbrella" similar to ACPA fine-specificities, while MAA reactivity is distinctly different.
血清阳性类风湿关节炎 (RA) 的特征是存在类风湿因子 (RF) 和抗瓜氨酸化蛋白自身抗体 (ACPA)，且具有不同的精细特异性。然而，其他血清抗修饰蛋白自身抗体 (AMPA)，例如抗碳化 (Carb)、乙酰化 (KAc) 和丙二醛乙醛 (MAA) 修饰蛋白抗体，已被描述。在这项综合研究中，我们分析了 1985 例新诊断的 RA 患者中通过 ELISA 和自身抗原阵列检测到的 30 种不同 IgG 和 IgA AMPA 反应性与 Cit、Carb、KAc 和 MAA 抗原的关系，并探讨了与患者特征（如吸烟和疾病活动度）的关联。不同检测方法检测到的 Carb 和 KAc 反应性主要见于同时抗瓜氨酸反应性阳性的患者中。修饰的波形蛋白 (mod-Vim) 肽用于直接比较不同的 AMPA 反应性，结果表明，识别 mod-Vim 的 IgA AMPA 主要存在于高 IgG 抗 Cit-Vim 水平和吸烟史的患者亚组中。IgG 对乙酰化的反应性主要存在于 Cit 和 Carb 反应性的患者亚组中。抗乙酰化组蛋白的反应性是 RA 特异性的，与高抗 CCP2 IgG 水平、多种 ACPA 精细特异性和吸烟状态有关。在没有关节炎的 CCP2+RA 风险个体中也发现了这种反应性。我们的数据进一步表明，与对照组相比，RA 患者 IgG 对 MAA 的自身反应性增加，在 CCP2+RA 中水平最高，但不是 RA 特异性的，与其他 AMPA 的相关性较低。抗 MAA 与疾病活动度相关，在 CCP2+RA 风险个体中并未显著增加。值得注意的是，根据其 AMPA IgG 和 IgA 反应性谱，RA 患者可细分为四个不同亚组。我们的血清学结果通过筛选 RA 患者的单克隆抗体进行补充，这些抗体来自相同的抗原作为 RA 队列。某些 CCP2+克隆具有 Carb 或 Carb+KAc+多反应性，而 CCP2-克隆中则没有发现这种反应性。我们得出的结论是，具有不同 ACPA 精细特异性以及 Carb 和 KAc 反应性的自身抗体存在于 RA 中，可能来自多反应性 B 细胞克隆。Carb 和 KAc 可被视为类似于 ACPA 精细特异性的“Cit-umbrella”内的反应性，而 MAA 反应性则明显不同。
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