B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease.
B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease.
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DOI：
10.1136/annrheumdis-2014-205799
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发表时间：
2015-12
影响因子：
27.4
通讯作者：
Stone JH
中科院分区：
文献类型：
--
作者：
Della-Torre E;Feeney E;Deshpande V;Mattoo H;Mahajan V;Kulikova M;Wallace ZS;Carruthers M;Chung RT;Pillai S;Stone JH
纤维化是IgG 4相关疾病（IgG 4-RD）的主要特征。B细胞耗竭在IgG 4-RD患者中诱导迅速的临床和免疫应答，但这种干预对IgG 4-RD中纤维化的影响尚不清楚。我们使用增强的肝纤维化（ELF）评分来说明利妥昔单抗对成纤维细胞活化的影响。ELF评分是基于前胶原-III氨基末端前肽、基质金属蛋白酶组织抑制剂-1和透明质酸的血清浓度的算法。入组了10例活动性、未经治疗的IgG 4-RD患者。测量ELF评分，并将其与IgG 4-RD应答指数、血清IgG 4、循环浆母细胞和成像研究相关联。通过免疫组织化学染色CD 3、CD 20、IgG 4和α-平滑肌肌动蛋白，我们评估了1例患者利妥昔单抗治疗前后组织活检中淋巴浆细胞浸润的程度和成纤维细胞活化的程度。与健康对照组相比，IgG 4-RD患者的ELF评分增加（8.3±1.4 vs 6.2±0.9; p=0.002），并与受累器官数量相关（R2=0.41; p=0.04）。利妥昔单抗诱导ELF评分、循环浆母细胞数量和IgG 4-RD反应指数显着降低（所有三个参数p<0.05）。利妥昔单抗减少淋巴浆细胞浸润和肌成纤维细胞活化。IgG 4-RD复发与ELF评分的复发性增加一致，表明胶原沉积的再活化。ELF评分可能是IgG 4-RD中活动性纤维化和疾病程度的临床有用指标。B细胞耗竭有可能通过减弱IgG 4-RD病变中肌成纤维细胞的分泌表型来停止持续的胶原沉积。
Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid. Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab. The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R2=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition. The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.