Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
EBioMedicine. 2019 Apr;42:76-85. doi: 10.1016/j.ebiom.2019.03.063. Epub 2019 Apr 3.
Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease.
Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb-) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated.
Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs.
Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. FUND: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.
自身免疫性疾病的预防需要工具来评估个体患特定疾病的风险。一种工具是与疾病相关的自身抗体，它们在无症状的临床前阶段积累。然而，患者有时会表现出与不同疾病分类相关的自身抗体。这些替代自身抗体最初何时以及如何出现仍然未知。本横断面研究描述了在患有相同疾病的患者的一级亲属（FDR）中，与疾病相关的自身免疫性以及相关的遗传和环境因素，这些患者具有增加的未来患病风险。
对来自疾病特异性自身抗体阳性（aAb+）系统性红斑狼疮（SLE）、类风湿关节炎（RA）和 1 型糖尿病（T1D）患者的样本（n=1321）；以及无症状 aAb+和自身抗体阴性（aAb-）SLE 和 RA FDR 进行 SLE、RA 和 T1D 自身抗体以及抗组织转谷氨酰胺酶、抗心磷脂和抗甲状腺过氧化物酶的检测。计算了 FDR SLE 和 RA 遗传风险评分（GRS）。
SLE 患者（56%）和 FDR（57.4%）、RA 患者（32.6%）和 FDR（34.8%）以及 T1D 患者出现了替代自身免疫。扩展自身免疫，定义为跨越至少两种其他疾病的自身抗体，发生在 18.5%的 SLE 患者、16.4%的 SLE FDR、7.8%的 RA 患者、5.3%的 RA FDR 和 10.8%的 T1D 患者中。SLE FDR 比 RA FDR 更有可能出现替代（优势比 [OR] 2.44）和扩展（OR 3.27）自身免疫。替代和扩展自身免疫与多种环境暴露有关。替代自身免疫与 RA FDR 中的 RA GRS 较高（OR 1.41）和 aAb+RA FDR 中的 SLE GRS 较高（OR 1.87）相关，但与 SLE FDR 无关。
自身免疫在系统性（RA、SLE）和器官特异性（T1D）自身免疫性疾病中通常跨越疾病特异性边界。SLE FDR 比 RA FDR 更常见替代自身免疫，并且受遗传和环境因素的影响。这些发现对临床前疾病发病机制和自身免疫性疾病预防研究具有重要意义。
NIH U01AI101981、R01AR051394、U19AI082714、P30AR053483、P30GM103510、U54GM104938、U01AI101934、R01AI024717、U01AI130830、I01BX001834、& U01HG008666。
