抗线粒体抗体阳性的生化指标正常个体中不断演变的肝脏炎症

Evolving liver inflammation in biochemically normal individuals with anti-mitochondria antibodies.

作者信息

Baldo Danielle Cristiane, Dellavance Alessandra, Ferraz Maria Lucia Gomes, Andrade Luis Eduardo C

机构信息

1Rheumatology Division, Universidade Federal de São Paulo, UNIFESP, Rua Botucatu 740, São Paulo, SP 04023-900 Brazil.

Research and Development Division, Fleury Medicine and Health Laboratories, São Paulo, Brazil.

出版信息

Auto Immun Highlights. 2019 Oct 31;10(1):10. doi: 10.1186/s13317-019-0120-x. eCollection 2019 Dec.

BACKGROUND

Anti-mitochondria autoantibodies (AMA) occur in > 95% primary biliary cholangitis (PBC) patients. Biochemically normal AMA-positive (BN/AMA+) individuals, occasionally noticed by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed in AMA-specific assays, may represent early stages of PBC. The Enhanced Liver Fibrosis (ELF) score is a surrogate marker for liver fibrosis. This prospective study investigated the ELF score in BN/AMA+ individuals and PBC patients, considering autoantibody avidity and serum levels along the years.

METHODS

327 samples from 35 PBC and 59 BN/AMA+ were prospectively obtained in average 3.83 (range 0.50-7.40) years apart. Samples were tested by IIF on rat-kidney (IIF-AMA), western-blot for AMA (WB-AMA), and ELISA for antibodies against pyruvate-dehydrogenase (PDC-E2), gp210, sp100 and CENP-A/B. Anti-PDC-E2 avidity was determined by 6 M urea-elution ELISA. Alkaline phosphatase (ALP), gamma glutamyl transferase (ɣGT) and ELF score were measured by automated methods.

RESULTS

Along the follow-up period BN/AMA+ subjects and PBC patients presented significant increase in serum anti-PDC-E2 (mean 10.45% and 8.86% per year; respectively), anti-PDC-E2 avidity (3.02% and 4.94%/year) and ELF score (3.24% and 2.71%/year). IIF-AMA and ɣGT increased in BN/AMA+ (6.59% and 2.36%) and decreased in PBC (- 4.89%/year and - 3.88%/year). In BN/AMA+ individuals there was positive correlation of ELF with IIF-AMA titer (r = 0.465; p < 0.001) and with anti-PDC-E2 levels (r = 0.239; p < 0.001). Expansion of autoantibody targets along time occurred in 39% BN/AMA+ and 49% PBC patients. The frequency of BN/AMA+ with high probability of having established PBC increased from 7 to 14%.

CONCLUSIONS

BN/AMA+ individuals present an orchestrated increase in ELF score and humoral autoimmune response over time, indicating an opportunity for early therapeutic intervention and prevention in autoimmunity.

背景

抗线粒体自身抗体（AMA）在超过95%的原发性胆汁性胆管炎（PBC）患者中出现。通过间接免疫荧光法（IIF）在人喉表皮样癌细胞（HEp-2细胞）上偶尔检测到且在AMA特异性检测中得到证实的生化指标正常的AMA阳性（BN/AMA+）个体，可能代表PBC的早期阶段。增强肝纤维化（ELF）评分是肝纤维化的替代标志物。这项前瞻性研究调查了BN/AMA+个体和PBC患者的ELF评分，并考虑了多年来自身抗体亲和力和血清水平。

方法

前瞻性地获取了来自35例PBC患者和59例BN/AMA+个体的327份样本，样本采集间隔平均为3.83年（范围0.50 - 7.40年）。通过大鼠肾间接免疫荧光法（IIF-AMA）、AMA免疫印迹法（WB-AMA）以及针对丙酮酸脱氢酶（PDC-E2）、gp210、sp100和CENP-A/B抗体的酶联免疫吸附测定（ELISA）对样本进行检测。通过6M尿素洗脱ELISA法测定抗PDC-E₂抗体亲和力。采用自动化方法检测碱性磷酸酶（ALP）、γ-谷氨酰转移酶（ɣGT）和ELF评分。

结果

在随访期间，BN/AMA+个体和PBC患者血清中抗PDC-E2水平（分别为每年平均升高10.45%和8.86%）、抗PDC-E2抗体亲和力（分别为每年升高3.02%和4.94%）以及ELF评分（分别为每年升高3.24%和2.71%）均显著升高。IIF-AMA和ɣGT在BN/AMA+个体中升高（分别为6.59%和2.36%），而在PBC患者中降低（分别为每年降低4.89%和3.88%）。在BN/AMA+个体中，ELF评分与IIF-AMA滴度呈正相关（r = 0.465；p < 0.001），与抗PDC-E2水平呈正相关（r = 0.239；p < 0.001）。39%的BN/AMA+个体和49%的PBC患者随着时间推移出现自身抗体靶点扩展。具有确诊PBC高概率的BN/AMA+个体的比例从7%增加到14%。