肾组织B淋巴细胞浸润及其异位淋巴样组织形成在狼疮肾炎诊治中的意义

Patterns of B Lymphocytes Infiltration in Kidney from Patients with Lupus Nephritis

目的了解肾组织中B淋巴细胞浸润及其相关异位淋巴样组织(ectopic lymphoid organ,ELT)形成在狼疮肾炎(lupus nephritis,LN)诊治中的临床意义。方法收集2009年1月至2013年12月在广东省人民医院住院的89例LN患者,入选病例连续肾组织切片免疫组织化学法检测CD20+、CD3+、CD21+细胞共表达。结果 89例LN患者中,光镜病理分析显示B、T淋巴细胞分布以肾间质为主77例(86.5%),肾小管周围为主9例,肾小球周围为主3例;CD20+细胞组69例(77.5%),CD20-细胞组20例(22.5%)。B细胞组[(21.8±9.9)个月]较非B细胞组[(9.8±6.2)个月]平均病程明显增加(P=0.045);治疗6个月LN完全缓解(complete remission,CR)率B细胞组(63.8%)与非B细胞组(90%)比较差异有统计学意义(P=0.047);但总缓解率两组间差异无统计学意义(P=0.241)。免疫组化显示B、T淋巴细胞浸润模式中,出现三种类型:0、1和2类,2类ELT形成为主要模式,占51例(73.9%),无3类;2类ELT形成LN患者病程[(24.4±10.2)个月]较0类病程[(9.8±6.2)个月]和1类病程[(16.4±7.8)个月]明显延长,差异具有统计学意义(P=0.017和P=0.039);相较Ⅴ型LN患者,Ⅲ型和Ⅳ型LN患者中,ELT分布三类型比例之间差异有统计学意义,其中2类ELT分布比例较0或1类明显增多,差异具有统计学意义(Ⅲ型:P=0.013;Ⅳ型:P=0.001)。结论 B细胞异常浸润及其ELT形成可能是长病程和难治性LN患者发病机制中重要环节。阻断B细胞在肾组织异常聚集可能是难治性LN治疗研究中的重要靶点。

Objective To understand the value of B lymphocytes infiltration and associated ectopic lymphoid tissue （ELT） formation in the diagnosis and treatment of lupus nephritis （LN）. Methods Eight-nine cases of established LN patients were enrolled. The renal specimen were analyzed by light microscopy examination for routine pathology and immunohistochemistry was used to the detection of expression of CD3^＋T lymphocytes, CD20^ ＋ B lymphocytes and CD21^＋ Follicular dendritic cells （FDCs）. All patients had received traditional high-dose glucocorticoid （GC） and immunosuppressants （IS）. Results Pathology analysis showed B and T lymphocyts infiltration mainly located at the interstitial region with 77 cases （86. 5% ） , at peritubular area in 9 cases and periglomerular area in 3 cases. WHO III 21 （23.6%） , WHO IV 53 （59.6%） and WHO V 15 （16.8%） LN were diagnosed. Based on whether or not there was CD20^＋ cells expression in renal tissues , 69 cases were CD20^＋ cells （77.5%） and 20 were CD20-cells （22.5 % ）. Compared to the CD20-group, significant difference could be found in the CD20^＋ group at a mean disease duration （CD20^＋ group： 21.8 ± 9.9 months vs. CD20-group： 9.8 ± 6.2 months, P = 0. 045 ） and complete disease remission rate （ CD20^＋ group： 63.8% vs. CD20-group： 90% , P = 0. 047） after 6 months of treatment. For B lymphocytes infiltration associated ELT formation, focal distribution of CD3^＋ T cells and CD20^＋ B cells （ type 2 ） could be observed in 51 cases （57.3 % ） , scattering distribution of CD3^＋ T ceils and CD20^＋ B cells （type 1 ） were found in 18 cases （20. 2% ） and no CD20^＋B ceils infiltration in 20 cases （22. 5% ） but no expression of CD21^＋ FDCs expression in all. The disease duration was longer in type 2 ELT patients than those in type 1 or type 0 ELT patients. Compared to WHO V-LN patients, there were different ELT distribution patterns in WHO m and WHO IV-LN patients, but there were no difference in ELT distribution patterns between WHO m and WHO IV-LN patients. Conclusion Abnormal B-cell infiltration-associated ELT formation may be one of the key process in the pathogenesis of LN patients with a longer disease duration and poor response to conventional combination therapy with high-dose GC and IS. Prohibition of B lymphocytes aggregation in the kidney may be one of the key therapeutic targets for the treatment of refractory LN.