Department of Rheumatology, Kanazawa University Hospital, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
Department of Nephrology, Takaoka City Hospital, 4-1, Takara-machi, Takaoka, Toyama, 933-0000, Japan.
BMC Nephrol. 2021 Mar 25;22(1):108. doi: 10.1186/s12882-021-02306-0.
Primary Sjögren's syndrome (pSS) is an auto-immune disease characterized by sialadenitis and dacryoadenitis with lymphoplasmacytic cell infiltration. In pSS, not only sicca symptoms, but also extra-glandular involvement induced by immune abnormalities based on pSS occurs. Renal involvement is one such important life-threatening extra-glandular involvement. Although the aberrant glycosylated IgA in pSS as a product of over-activated B cells is a risk factor of renal involvement, its association has not been clarified. Here we report a case of glomerulonephritis (GN) induced by immune complexes (IC) composed of galactose-deficient IgA1 (Gd-IgA1) in a patient with pSS.
A 48-year-old Japanese woman with pSS was admitted to our hospital because of a two-month history of nephrotic syndrome. Seven years before she had been diagnosed with pSS from keratoconjunctivitis sicca, elevation of serum anti-Ro/SSA antibody titer and lymphoplasmacytic cell infiltration around salivary ducts of the small salivary glands. Renal biopsy revealed diffuse bubbling appearance in glomerular basement membrane (GBM) with scarce mesangial proliferation. Immunofluorescence showed granular IgA, C3 and Gd-IgA1 staining of GBM. Light chain staining showed no monoclonality. Electron microscopy showed electron dense deposits mainly in the intra-membranous and paramesangial areas and slightly in the subepithelial area. Additional serum analysis confirmed elevation of Gd-IgA1 (13.5 μg/mL), which was comparable with that seen in IgA nephropathy, and qualitative enzyme-linked immunosorbent assay of IgA-containing circulating immune complex (IgA-CIC) was positive. Thus, we diagnosed GN induced by IC composed of Gd-IgA1. Furthermore, retrospectively performed immunofluorescence of the small salivary gland evaluated at the diagnosis of pSS showed positive Gd-IgA1 staining of infiltrating lymphoplasmacytic cells. Therefore, we concluded that Gd-IgA1 produced by over-activated B cells in pSS formed circulating IC and thereby induced GN. After induction therapy with high dose prednisolone and mycophenolate mofetil, the nephrotic syndrome remitted within 3 weeks, the serum Gd-IgA1 level decreased to the normal range (3.8 μg/mL), and serum IgA-CIC disappeared in the 6th month after induction therapy.
Our findings clearly demonstrate an association between aberrant glycosylated IgA and the renal involvement seen in pSS, thereby helping to clarify the renal significance of aberrant glycosylated IgA in pSS.
原发性干燥综合征（pSS）是一种自身免疫性疾病，其特征为唾液腺和泪腺的淋巴细胞浸润性炎症。在 pSS 中，不仅存在干燥症状，还会发生免疫异常引起的腺外浸润。肾脏受累是一种重要的危及生命的腺外浸润。虽然 pSS 中过度激活 B 细胞产生的异常糖基化 IgA 是肾脏受累的危险因素，但两者之间的关联尚未阐明。本文报道了一例由 pSS 患者免疫复合物（IC）引起的肾小球肾炎（GN），该 IC 由半乳糖缺乏 IgA1（Gd-IgA1）组成。
一名 48 岁的日本女性，因两个月的肾病综合征病史而被收入我院。七年前，她因干燥性角膜炎被诊断为 pSS，血清抗 Ro/SSA 抗体滴度升高，小唾液腺导管周围出现淋巴细胞浸润。肾脏活检显示肾小球基底膜（GBM）弥漫性泡状外观，系膜细胞增生不明显。免疫荧光显示 GBM 呈颗粒状 IgA、C3 和 Gd-IgA1 染色。轻链染色未见单克隆性。电子显微镜显示电子致密物主要位于内皮下和系膜区，少量位于上皮下区。进一步的血清学分析证实 Gd-IgA1 升高（13.5μg/ml），与 IgA 肾病相当，IgA 包含的循环免疫复合物（IgA-CIC）的定性酶联免疫吸附试验呈阳性。因此，我们诊断为由 Gd-IgA1 组成的 IC 引起的 GN。此外，回顾性分析 pSS 诊断时的小唾液腺免疫荧光检查，显示浸润的淋巴细胞中有 Gd-IgA1 阳性染色。因此，我们得出结论，pSS 中过度激活的 B 细胞产生的 Gd-IgA1 形成循环 IC，从而诱导 GN。在高剂量泼尼松龙和吗替麦考酚酯诱导治疗后，3 周内肾病综合征缓解，血清 Gd-IgA1 水平降至正常范围（3.8μg/ml），诱导治疗后第 6 个月血清 IgA-CIC 消失。
我们的研究结果清楚地表明，异常糖基化 IgA 与 pSS 中的肾脏受累之间存在关联，从而有助于阐明 pSS 中异常糖基化 IgA 的肾脏意义。
