自身免疫性血细胞减少症免疫发病机制、临床特征及利妥昔单抗疗效研究
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摘要
自身免疫性血细胞减少症是血液系统疾病中的一大类疾病,包括自身免疫性溶血性贫血(成熟红细胞抗体介导)、免疫性血小板减少性紫癜(血小板抗体介导)、Evans综合征(成熟红细胞抗体和血小板抗体均有)、免疫相关性全血细胞减少症(未成熟血细胞抗体)等。长期以来对该类疾病发病机制的认识并不清楚,仅局限于是由自身抗体介导的血细胞破坏所致,至于抗体产生的原因和病理机制,则缺乏系统的认识。由于病理机制的研究没有大的进步,治疗效果也并不满意。多年来该病治疗以肾上腺皮质激素为主,复发率高(多在80%以上)。也有部分患者如冷抗体型自身免疫性溶血性贫血激素疗效差,缺乏更好的治疗方法,患者常迁延不愈。本文探讨自身免疫性溶血性贫血(AIHA)患者的免疫发病机制、难治及复发患者的新型免疫抑制剂利妥昔单抗的疗效及安全性。另外免疫相关性全血细胞减少症是由本课题组提出,多年来致力于该病的发病及病理机制研究,本文对该病的临床及实验室特征做出总结。通过对以上内容的研究,能对该类疾病的发生发展有更系统清楚的认识,提高治疗效果,造福患者。
内容
第一部分目的研究自身免疫性溶血性贫血(AIHA)的免疫发病机制。方法应用流式细胞仪检测54例AIHA患者的免疫指标,其中B淋巴细胞方面,检测项目包括CD19+,CD5+CD19+淋巴细胞；T淋巴细胞检测CD4+,CD8+,CD4+/CD8+;NK细胞；T辅助细胞中(CD4+细胞)检测Thl,Th2；检测调节T细胞和激活的效应T细胞,即CD25+和HLA-DR+的T细胞,检测树突状细胞(mDC和pDC)数量,将患者分为溶血发作组、缓解组,与正常对照组进行比较,进行三组之间的两两比较和统计学分析。应用SPSS13.0统计软件进行分析,计量数据以均数±标准差的形式表示,正态分布数据两组间比较以t检验,三组间比较以单因素方差分析；非正态分布数据以非参数检验Kruskal-Wallis检验。以P<0.05为差异有统计学意义。
结果1.AIHA患者中,B淋巴细胞即CD19+细胞：溶血发作组较正常组明显增高,两组差异有统计学意义(P=0.000,<0.01)；CD5+CD19+细胞：溶血发作组高于正常对照组(P=0.033,P<0.05)；在患病组中,缓解组与溶血发作组比较,CD19+、CD5+CD19+淋巴细胞明显减少(P=0.000,P=0.000,P<0.01)；CD5+CD19+/CD19+：缓解组低于溶血发作组(P=0.004,P<0.01)。缓解组的CD19+、CD5+CD19+及CD5+CD19+/CD19+甚至低于正常对照组(P=0.008,P=0.000,P=0.028；P<0.01,P<0.01,P<0.05)。在美罗华(CD20单克隆抗体、即利妥昔单抗)治疗组：CD19+：美罗华治疗组低于非美罗华治疗组(P=0.017,P<0.05),CD5+CD19+细胞利妥昔单抗治疗组与非美罗华治疗组差异无统计学意义,CD5+CD19+/CD19+：美罗华治疗组高于非美罗华治疗组(P=0.032,P<0.05)。
2.在T淋巴细胞研究中,发现CD4,CD8,CD4/CD8、NK细胞、调节T细胞和激活的效应T细胞,即CD25+和HLA-DR+的T细胞,患病组与正常对照相比,差异无统计学意义；但在T辅助细胞中检测Thl,Th2亚群时,发现患者的Thl细胞在溶血发作组(P=0.002,P<0.05)与缓解组均高于正常对照组(P=0.021,P<0.05),而Thl细胞在溶血发作组和缓解组差异无统计学意义(P>0.05)；而在Th2细胞,溶血发作组的Th2细胞比率显著高于高于正常对照组(P=0.000,P<0.01),同时缓解组患者Th2细胞比率显著低于溶血发作组(P=0.002,P<0.01)。提示随着免疫抑制剂的使用,Th2细胞降至正常,疾病也处于缓解状态。3.树突状细胞(DC)检测mDC(DC1)和pDC(DC2),将患病组与正常对照组进行比较,CD123+细胞患病组低于正常组(P=0.000,P值均<0.01)；CDllc+细胞比例在溶血发作组低于缓解组(P=0.011,P<0.05),缓解组与正常对照组对比差异无统计学意义,CD123+细胞比例在溶血发作组与缓解组均低于正常对照组(P=0.000,P=0.001,P值均<0.01),溶血发作组与缓解组对比差异无统计学意义。CDllc+/CD123+：溶血发作组(P=0.022,P<0.05)与缓解组均高于正常对照组(P=0.002,P<0.01),发作组与缓解组无差异。结论AIHA的发病与CD5+CD19+的即激活的B淋巴细胞密切相关,在溶血发作状态,CD19+、CD5CD19+两群淋巴细胞比值明显增高,提示存在B淋巴细胞增殖；在利妥昔单抗治疗组(美罗华组)CD19+淋巴细胞低于非美罗华治疗组,CD5+CD19+细胞美罗华治疗组与非美罗华治疗组差异无统计学意义,提示美罗华免疫抑制作用明显较强；T淋巴细胞的调控尤其是Th2细胞增殖与AIHA的发病亦密切相关,溶血发作时Th1、Th2比值均明显增高；缓解时Th2比值明显降低,Th1无明显变化；DC亚群与AIHA发病也有关系,mDC、pDC在发病时比值均明显减低,经免疫抑制剂治疗后,mDC结果趋于正常,pDC比值仍明显降低,提示溶血发作时可能存在DC的外周淋巴组织迁移。
第二部分：目的进行病例分析,探讨新型免疫抑制剂利妥昔单抗联合环磷酰胺治疗难治性自身免疫性溶血性贫血疗效,并进行长期随访,对其及长期疗效及安全性做一评价。病例自身免疫性溶血性贫血7例(其中Evans综合征1例),均为难治患者。方法利妥昔单抗(美罗华)：375mg/m2,每1周1次,连用2-6次；环磷酰胺：1g/次,每10天1次,连用2-7次；同时加用静注免疫球蛋白5g/次,1次/周,利妥昔单抗之后1天使用。结果所有患者3个月时均有效(7/7),完全缓解(CR)率占6/7,部分缓解占1/7,平均随访27月,12个月复查时所有完全缓解患者均未见复发,部分缓解患者血红蛋白正常,仅间接胆红素升高,网织红细胞升高；24个月复查时2例患者出现间接胆红素升高,网织红细胞升高,1例患者单独加用利妥昔单抗强化治疗后再达CR,1例未加用其他强化治疗,仍用环孢菌素A维持治疗。36个月时该未强化患者复发,经加用上述利妥昔单抗+环磷酰胺方案治疗3疗程再达部分缓解。所有患者对该治疗耐受性好,不良反应轻微。结论利妥昔单抗联合CTX用于治疗难治性自身免疫性溶血性贫血,疗效较前显著,未见严重不良反应,但停药12-24个月后部分患者有复发趋势,再用利妥昔单抗进行强化治疗仍有效。
第三部分：目的总结157例免疫相关性血细胞减少症(IRP)患者的临床特征。方法回顾性分析天津医科大学总医院血液科课题组2006年1月至2010年7月诊治的157例骨髓单个核细胞膜抗体试验阳性的IRP患者的基本情况、发病诱因、临床表现、血象及骨髓象、自身抗体类型及免疫治疗效果。结果44.6%(70/157)IRP患者发病前有感染、过敏、妊娠及装修等诱因。全血细胞减少者占73.2%(115/157),其次为贫血合并血小板减少[18.5%(29/157)]；贫血轻中重度均可见,贫血类型以大细胞贫血为主,占61.3%(95/155),其次为正细胞贫血[32.9%(51/155)]；白细胞减少者占78.9%(124/157)；绝大多数患者血小板减少[91.7%(144/157)],可见血小板轻、中、重度减少,出血表现以皮肤黏膜出血为主。髂骨骨髓增生多为活跃和明显活跃68.8%(108/157),少数增生减低和重度减低31.2%(49/157)。粒系比例减低占64.3%(101/157),比例正常和升高占35.7%(56/157),红系比例多为增高[49.7%(78/157)]和正常[24.1%(38/157)],少数减低[26.1%(41/157)]。骨髓淋巴细胞比例与疗效呈负相关；大部分患者[85.7%(102/119)]胸骨骨髓为增生活跃或明显活跃。巨核细胞数减少者占61.1%(96/157),正常者占32.5%(51/157),增多者占6.4%(10/157),多合并血小板形成不良。流式细胞仪检测的骨髓单个核细胞膜抗体试验皆阳性,检出不同细胞群的自身抗体,各种类型和组合方式均可见,提示自身抗体的多克隆性。共有56.7%(89/157)的患者合并轻微溶血,但不符合任何种类的溶血性疾病的诊断标准;57.9%(91/157)患者同时出现其它自身免疫指标异常,其中最常见的为补体C3减低42.6%(67/157),其次为补体C418.5%(29/157)降低,给予免疫抑制和促造血治疗后,3年有效率为86.8%(33/38)。结论IRP是一类获得性自身抗体介导的骨髓细胞破坏或抑制性疾病,自身抗体为多克隆性,约半数患者有感染或过敏等诱因,主要表现为网织红细胞或(和)中性粒细胞比例不低的两系或三系血细胞减少,多数患者至少一个部位骨髓为增生活跃,常有轻微溶血迹象但溶血试验均为阴性,常合并其他自身免疫指标异常,如补体降低,抗核抗体阳性等,对免疫抑制和促造血治疗反应好。
全文结论AIHA的发病与B淋巴细胞及CD5+B淋巴细胞密切相关,受到Th细胞调控,TH2细胞可能起主要作用；溶血发作时mDC、pDC均减少,可能与溶血发作时的外周淋巴组织转移有关。利妥昔单抗治疗难治复发AIHA效果较好,但1年后可有复发；IRP是一类获得性自身抗体介导的骨髓细胞破坏或抑制性疾病,自身抗体为多克隆性,约半数患者有感染或过敏等诱因,主要表现为网织红细胞或(和)中性粒细胞比例不低的两系或三系血细胞减少,多数患者至少一个部位骨髓为增生活跃,常有轻微溶血迹象但溶血试验均为阴性,常合并其他自身免疫指标异常,如补体降低,抗核抗体阳性等,对免疫抑制和促造血治疗反应好。
Section1Objective This study was designed to investigate the pathogenesis of Autoimmune Hemolytic Anemia (AIHA).
Methods:The following indexes were detected by flow cytometry using blood samples from54patients with AIHA. They were the amount of CD19+and CD5+CD19+B lymphocytic cells, the amount of CD4+and CD8+T lymphocytic cells,the amount of NK cell, the amount of Thl and Th2T helper cells(CD4+cells), the amount of T regular cells and T effective cells (CD25+and HLA-DR+T cells), the amount of mDC and pDC dendritic cells. Patients were divided into hemolytic attack group and remission group. The indexes from each group were statistically analyzed and compared. Measurement data were described as mean±standard deviation. Applying SPSS13.0statistics software, we compared two normal distribution data based on t-test, abnormal distribution data based on non-parametric test (Kruskal-Wallis test), we analyzed three groups by analysis of variance (one-way ANOVA). Statistical significance was defined as P<0.05.
Results1. B cells:The amount of B lymphocytic cells (CD19+cells) from hemolytic attack group was significantly higher than that from normal control (P=0.000,<0.01). CD5+CD19+B cells from hemolytic attack group were in excess of those from normal control (P=0.033, P<0.05). CD19+and CD5+CD19+B cells from remission group were significantly lower than from hemolytic attack group (P=0.000, P=0.000, P<0.01). The ratio of CD5+CD19+/CD19+from remission group was lower than from hemolytic attack group(P=0.004, P<0.01). The amount of CD19+cells,CD5+CD19+cells and the ratio of CD5+CD19+/CD19+were lower than from health control group (P=0.008, P=0.000, P=0.028; P<0.01, P<0.01, P<0.05).We also divided the patients based on treatment whether using rituximab. The amount of CD19+cells from rituximab treatment group was lower than the counterpart group (P=0.017, P<0.05). There was no statistically difference of CD5+CD19+cell quantity between rituximab group and the counterpart group. The ratio of CD5+CD19+/CD19+from rituximab group was higher than the counterpart group (P=0.032, P<0.05)
2. T cells:There were no significant differences of the amount of CD4+cells, CD8+cells,NK cells, CD25+cells and HLA-DR+T cells between patients and healthy controls. The ratio of CD4/CD8was not significantly different between the two groups either. The amount of Thl cells from hemolytic attack group (P=0.002, P<0.05)and remission group(P=0.021, P<0.05)was both higher than normal control. There was no significantly differences of the amount of Thl cells between hemolytic attack group and remission group (P>0.05). The percentage of Th2cells from hemolytic attack group was higher than control (P=0.000, P<0.01). Meanwhile, the percentage of Th2cells from remission group was lower than hemolytic attack group (P=0.002, P<0.01). This indicated that after immunosuppressive therapy, Th2cells tended to become normal while the disease tended into remission.
3. Dendritric cells:The amount of CD123+cells from patients was lower than control (P=0.000, P<0.01), the percentage of CD11c+cells from hemolytic attack group was lower than remission group (P=0.011, P<0.05). There was no statistically difference of CDllc+cells between remission group and control group. The percentages of CD123+cells from both hemolytic attack group and remission group were lower than control (P=0.000, P=0.001). There was no statistically significance of the amount of CD123+cells between hemolytic attack group and remission group. The ratio of CD11c+/CD123+from both hemolytic attack group (P=0.022, P<0.05) and remission group (P=0.002, P<0.01) were higher than control. There was no significantly differences of the ratio between hemolytic attack group and remission group.
Conclusions The pathogenesis of AIHA is associated with activation of B lymphocytic cells(CD5+CD19+). During the hemolytic attack, the percentages of CD19+B cells and CD5+CD19+B cells substantially elevate, indicating the proliferation of B lymphocytic cells. The amount of CD19+lymphocytic cells from rituximab group was lower than the counterpart group, while there was no statistically significance of CD5+CD19+cells between rituximab group and the counterpart group. this suggests that rituximab exhibits a strong inhibition effect towards immune system. The regulation of T lymphocytic cells (especially Th2proliferation) is also related to the mechanism of AIHA. The percentages of Thl and Th2cells both increased during hemolytic attack, and Th2decreased when remission was achieved while Thl showed no alteration. The pathogenesis of AIHA is related to DC cells. The percentages of DC1and DC2cells both decreased during the attack, yet DC1tended to become normal while DC2decreased after immunosuppressive therapy. This indicates that DCs maybe migrate into peripheral lymphoid tissue when hemolysis attacks.
Section2. Objective To better assess the efficacy and safety of monoclonal anti-CD20antibody rituximab combined cyclophosphamide with in treatment of refractory and recurrent autoimmune hemolytic anemia. Cases The study included7cases of autoimmune hemolytic anemia (including1case of Evans syndrome), which all of them were refractory or recurrent. Methods rituximab:375mg/m2, once per week,2-6times; Cyclophosphamide:1g/10days,2-7times; combined with intravenous immunoglobulin (IVIG)5g/week, given1day after rituximab treatment. Results All7patients showed good responses.6patients achieved complete remission (CR) and1patient achieved partial remission (PR). Responses occurred1to10months after the first dose of rituximab and the mean effective time is approximately2.5months. Average follow-up for the patients is around27months. All patients remained in remission at the12-month follow-up visits. At the time of24-month visits,2patients showed elevated indirect bilirubin and increased reticulocyte counts. One patient achieved CR after additional rituximab therapy, and the other patient just wait and watch without additional therapy. At the time of36-month visits,1patient relapsed and was retreated with3cycles of rituximab and eventually reached PR. All patients tolerated the treatment well with only mild side effects. Conclusions rituximab combined with and recurrent autoim cyclophosphamide is highly effective and relatively safe in patients with refractory mune hemolytic anemia. Additional treatment can be given in patients with relapse after1-2years.
Section3. Objective To study the clinical and laboratory features of the patients with immuno-related pancytopenia(IRP). Methods The risk factors,manifestations, blood cell counts,bone marrow phenotypes,autoantibodies and immunosuppressive therapy response of157patients with IRP were analyzed.Then they were followed up for (3～48) monthS,to see their long-term outcome and the prognostic factors. Results The infection,anaphylaxis and pregnancy were highly suspected to be the risk factors of IRP.Most of these patients were with pancytopenia73.2%(115/157), some patients were with anemia and thrombocytopenial8.5%(29/157)];61.3%(95/155) of them were anemic with large MCV,32.9%(51/155) of them were anemic with normal MCV;78.9%(124/157) of them were with leukopenia,23.6%(37/157) of them had fever. Thrombocytopenia was common[91.7%(144/157)],but serious bleeding was rare.68.8%(108/157)of these cases were with nomal or increased bone marrow cellularities and increased normoblasts.They were all found to have positive results of bone marrow mononuclear cell antibody Facs test,negative results of rutine hemolysis tests and no evidence of malignant clonal hematopoiesis.42.6%(67/157) of these patients had C3decreased, and18.5%(29/157) C4decreased. Immunosuppressive therapy was administered to157IRP patients,The response rate at36months was87.5%(28/32). Conclusions Immuno-related pancytopenia(IRP) is an acquired multiclonal autoimmunoantibody conducted bone marrow failure syndrome, featuring pancytopenia without reducing of reticulocytes and neutrophilic granulocytes. More than half of the patients used to have infections or allergies. A few patients'bone marrow have higher proliferation at least one site, with mild hemolysis yet negative hemolytic test. The following abnormalities often complicates with IRP, such as low amount of complements, positive ANA. Those patients may receive good responses to immunosuppressants and hemopoiesis improving treatment.
Conclusions The pathogenesis of AIHA is closely associated with B lymphocytic cells and CD5+B lymphocytic cells. Th2cells, the regulating cells of B lymphocytic cells, may play an important part in hemolysis. The amount of mDC and pDC decrease during hemolytic attack, which caused by DC peripheral migration. Refractory AIHA has good response to Rituximab,but sometimes relapse1year later. Immuno-related pancytopenia is an acquired multiclonal autoimmunoantibody conducted bone marrow failure syndrome, featuring pancytopenia without reducing of reticulocytes and neutrophilic granulocytes. More than half of the patients used to have infections or allergies. A few patients'bone marrow have higher proliferation at least one site, with mild hemolysis yet negative hemolytic test. The following abnormalities often complicates with IRP, such as low amount of complements, positive ANA. Those patients may receive good responses to immunosuppressants and hemopoiesis improving treatment.
内容
第一部分目的研究自身免疫性溶血性贫血(AIHA)的免疫发病机制。方法应用流式细胞仪检测54例AIHA患者的免疫指标,其中B淋巴细胞方面,检测项目包括CD19+,CD5+CD19+淋巴细胞；T淋巴细胞检测CD4+,CD8+,CD4+/CD8+;NK细胞；T辅助细胞中(CD4+细胞)检测Thl,Th2；检测调节T细胞和激活的效应T细胞,即CD25+和HLA-DR+的T细胞,检测树突状细胞(mDC和pDC)数量,将患者分为溶血发作组、缓解组,与正常对照组进行比较,进行三组之间的两两比较和统计学分析。应用SPSS13.0统计软件进行分析,计量数据以均数±标准差的形式表示,正态分布数据两组间比较以t检验,三组间比较以单因素方差分析；非正态分布数据以非参数检验Kruskal-Wallis检验。以P<0.05为差异有统计学意义。
结果1.AIHA患者中,B淋巴细胞即CD19+细胞：溶血发作组较正常组明显增高,两组差异有统计学意义(P=0.000,<0.01)；CD5+CD19+细胞：溶血发作组高于正常对照组(P=0.033,P<0.05)；在患病组中,缓解组与溶血发作组比较,CD19+、CD5+CD19+淋巴细胞明显减少(P=0.000,P=0.000,P<0.01)；CD5+CD19+/CD19+：缓解组低于溶血发作组(P=0.004,P<0.01)。缓解组的CD19+、CD5+CD19+及CD5+CD19+/CD19+甚至低于正常对照组(P=0.008,P=0.000,P=0.028；P<0.01,P<0.01,P<0.05)。在美罗华(CD20单克隆抗体、即利妥昔单抗)治疗组：CD19+：美罗华治疗组低于非美罗华治疗组(P=0.017,P<0.05),CD5+CD19+细胞利妥昔单抗治疗组与非美罗华治疗组差异无统计学意义,CD5+CD19+/CD19+：美罗华治疗组高于非美罗华治疗组(P=0.032,P<0.05)。
2.在T淋巴细胞研究中,发现CD4,CD8,CD4/CD8、NK细胞、调节T细胞和激活的效应T细胞,即CD25+和HLA-DR+的T细胞,患病组与正常对照相比,差异无统计学意义；但在T辅助细胞中检测Thl,Th2亚群时,发现患者的Thl细胞在溶血发作组(P=0.002,P<0.05)与缓解组均高于正常对照组(P=0.021,P<0.05),而Thl细胞在溶血发作组和缓解组差异无统计学意义(P>0.05)；而在Th2细胞,溶血发作组的Th2细胞比率显著高于高于正常对照组(P=0.000,P<0.01),同时缓解组患者Th2细胞比率显著低于溶血发作组(P=0.002,P<0.01)。提示随着免疫抑制剂的使用,Th2细胞降至正常,疾病也处于缓解状态。3.树突状细胞(DC)检测mDC(DC1)和pDC(DC2),将患病组与正常对照组进行比较,CD123+细胞患病组低于正常组(P=0.000,P值均<0.01)；CDllc+细胞比例在溶血发作组低于缓解组(P=0.011,P<0.05),缓解组与正常对照组对比差异无统计学意义,CD123+细胞比例在溶血发作组与缓解组均低于正常对照组(P=0.000,P=0.001,P值均<0.01),溶血发作组与缓解组对比差异无统计学意义。CDllc+/CD123+：溶血发作组(P=0.022,P<0.05)与缓解组均高于正常对照组(P=0.002,P<0.01),发作组与缓解组无差异。结论AIHA的发病与CD5+CD19+的即激活的B淋巴细胞密切相关,在溶血发作状态,CD19+、CD5CD19+两群淋巴细胞比值明显增高,提示存在B淋巴细胞增殖；在利妥昔单抗治疗组(美罗华组)CD19+淋巴细胞低于非美罗华治疗组,CD5+CD19+细胞美罗华治疗组与非美罗华治疗组差异无统计学意义,提示美罗华免疫抑制作用明显较强；T淋巴细胞的调控尤其是Th2细胞增殖与AIHA的发病亦密切相关,溶血发作时Th1、Th2比值均明显增高；缓解时Th2比值明显降低,Th1无明显变化；DC亚群与AIHA发病也有关系,mDC、pDC在发病时比值均明显减低,经免疫抑制剂治疗后,mDC结果趋于正常,pDC比值仍明显降低,提示溶血发作时可能存在DC的外周淋巴组织迁移。
第二部分：目的进行病例分析,探讨新型免疫抑制剂利妥昔单抗联合环磷酰胺治疗难治性自身免疫性溶血性贫血疗效,并进行长期随访,对其及长期疗效及安全性做一评价。病例自身免疫性溶血性贫血7例(其中Evans综合征1例),均为难治患者。方法利妥昔单抗(美罗华)：375mg/m2,每1周1次,连用2-6次；环磷酰胺：1g/次,每10天1次,连用2-7次；同时加用静注免疫球蛋白5g/次,1次/周,利妥昔单抗之后1天使用。结果所有患者3个月时均有效(7/7),完全缓解(CR)率占6/7,部分缓解占1/7,平均随访27月,12个月复查时所有完全缓解患者均未见复发,部分缓解患者血红蛋白正常,仅间接胆红素升高,网织红细胞升高；24个月复查时2例患者出现间接胆红素升高,网织红细胞升高,1例患者单独加用利妥昔单抗强化治疗后再达CR,1例未加用其他强化治疗,仍用环孢菌素A维持治疗。36个月时该未强化患者复发,经加用上述利妥昔单抗+环磷酰胺方案治疗3疗程再达部分缓解。所有患者对该治疗耐受性好,不良反应轻微。结论利妥昔单抗联合CTX用于治疗难治性自身免疫性溶血性贫血,疗效较前显著,未见严重不良反应,但停药12-24个月后部分患者有复发趋势,再用利妥昔单抗进行强化治疗仍有效。
第三部分：目的总结157例免疫相关性血细胞减少症(IRP)患者的临床特征。方法回顾性分析天津医科大学总医院血液科课题组2006年1月至2010年7月诊治的157例骨髓单个核细胞膜抗体试验阳性的IRP患者的基本情况、发病诱因、临床表现、血象及骨髓象、自身抗体类型及免疫治疗效果。结果44.6%(70/157)IRP患者发病前有感染、过敏、妊娠及装修等诱因。全血细胞减少者占73.2%(115/157),其次为贫血合并血小板减少[18.5%(29/157)]；贫血轻中重度均可见,贫血类型以大细胞贫血为主,占61.3%(95/155),其次为正细胞贫血[32.9%(51/155)]；白细胞减少者占78.9%(124/157)；绝大多数患者血小板减少[91.7%(144/157)],可见血小板轻、中、重度减少,出血表现以皮肤黏膜出血为主。髂骨骨髓增生多为活跃和明显活跃68.8%(108/157),少数增生减低和重度减低31.2%(49/157)。粒系比例减低占64.3%(101/157),比例正常和升高占35.7%(56/157),红系比例多为增高[49.7%(78/157)]和正常[24.1%(38/157)],少数减低[26.1%(41/157)]。骨髓淋巴细胞比例与疗效呈负相关；大部分患者[85.7%(102/119)]胸骨骨髓为增生活跃或明显活跃。巨核细胞数减少者占61.1%(96/157),正常者占32.5%(51/157),增多者占6.4%(10/157),多合并血小板形成不良。流式细胞仪检测的骨髓单个核细胞膜抗体试验皆阳性,检出不同细胞群的自身抗体,各种类型和组合方式均可见,提示自身抗体的多克隆性。共有56.7%(89/157)的患者合并轻微溶血,但不符合任何种类的溶血性疾病的诊断标准;57.9%(91/157)患者同时出现其它自身免疫指标异常,其中最常见的为补体C3减低42.6%(67/157),其次为补体C418.5%(29/157)降低,给予免疫抑制和促造血治疗后,3年有效率为86.8%(33/38)。结论IRP是一类获得性自身抗体介导的骨髓细胞破坏或抑制性疾病,自身抗体为多克隆性,约半数患者有感染或过敏等诱因,主要表现为网织红细胞或(和)中性粒细胞比例不低的两系或三系血细胞减少,多数患者至少一个部位骨髓为增生活跃,常有轻微溶血迹象但溶血试验均为阴性,常合并其他自身免疫指标异常,如补体降低,抗核抗体阳性等,对免疫抑制和促造血治疗反应好。
全文结论AIHA的发病与B淋巴细胞及CD5+B淋巴细胞密切相关,受到Th细胞调控,TH2细胞可能起主要作用；溶血发作时mDC、pDC均减少,可能与溶血发作时的外周淋巴组织转移有关。利妥昔单抗治疗难治复发AIHA效果较好,但1年后可有复发；IRP是一类获得性自身抗体介导的骨髓细胞破坏或抑制性疾病,自身抗体为多克隆性,约半数患者有感染或过敏等诱因,主要表现为网织红细胞或(和)中性粒细胞比例不低的两系或三系血细胞减少,多数患者至少一个部位骨髓为增生活跃,常有轻微溶血迹象但溶血试验均为阴性,常合并其他自身免疫指标异常,如补体降低,抗核抗体阳性等,对免疫抑制和促造血治疗反应好。
Section1Objective This study was designed to investigate the pathogenesis of Autoimmune Hemolytic Anemia (AIHA).
Methods:The following indexes were detected by flow cytometry using blood samples from54patients with AIHA. They were the amount of CD19+and CD5+CD19+B lymphocytic cells, the amount of CD4+and CD8+T lymphocytic cells,the amount of NK cell, the amount of Thl and Th2T helper cells(CD4+cells), the amount of T regular cells and T effective cells (CD25+and HLA-DR+T cells), the amount of mDC and pDC dendritic cells. Patients were divided into hemolytic attack group and remission group. The indexes from each group were statistically analyzed and compared. Measurement data were described as mean±standard deviation. Applying SPSS13.0statistics software, we compared two normal distribution data based on t-test, abnormal distribution data based on non-parametric test (Kruskal-Wallis test), we analyzed three groups by analysis of variance (one-way ANOVA). Statistical significance was defined as P<0.05.
Results1. B cells:The amount of B lymphocytic cells (CD19+cells) from hemolytic attack group was significantly higher than that from normal control (P=0.000,<0.01). CD5+CD19+B cells from hemolytic attack group were in excess of those from normal control (P=0.033, P<0.05). CD19+and CD5+CD19+B cells from remission group were significantly lower than from hemolytic attack group (P=0.000, P=0.000, P<0.01). The ratio of CD5+CD19+/CD19+from remission group was lower than from hemolytic attack group(P=0.004, P<0.01). The amount of CD19+cells,CD5+CD19+cells and the ratio of CD5+CD19+/CD19+were lower than from health control group (P=0.008, P=0.000, P=0.028; P<0.01, P<0.01, P<0.05).We also divided the patients based on treatment whether using rituximab. The amount of CD19+cells from rituximab treatment group was lower than the counterpart group (P=0.017, P<0.05). There was no statistically difference of CD5+CD19+cell quantity between rituximab group and the counterpart group. The ratio of CD5+CD19+/CD19+from rituximab group was higher than the counterpart group (P=0.032, P<0.05)
2. T cells:There were no significant differences of the amount of CD4+cells, CD8+cells,NK cells, CD25+cells and HLA-DR+T cells between patients and healthy controls. The ratio of CD4/CD8was not significantly different between the two groups either. The amount of Thl cells from hemolytic attack group (P=0.002, P<0.05)and remission group(P=0.021, P<0.05)was both higher than normal control. There was no significantly differences of the amount of Thl cells between hemolytic attack group and remission group (P>0.05). The percentage of Th2cells from hemolytic attack group was higher than control (P=0.000, P<0.01). Meanwhile, the percentage of Th2cells from remission group was lower than hemolytic attack group (P=0.002, P<0.01). This indicated that after immunosuppressive therapy, Th2cells tended to become normal while the disease tended into remission.
3. Dendritric cells:The amount of CD123+cells from patients was lower than control (P=0.000, P<0.01), the percentage of CD11c+cells from hemolytic attack group was lower than remission group (P=0.011, P<0.05). There was no statistically difference of CDllc+cells between remission group and control group. The percentages of CD123+cells from both hemolytic attack group and remission group were lower than control (P=0.000, P=0.001). There was no statistically significance of the amount of CD123+cells between hemolytic attack group and remission group. The ratio of CD11c+/CD123+from both hemolytic attack group (P=0.022, P<0.05) and remission group (P=0.002, P<0.01) were higher than control. There was no significantly differences of the ratio between hemolytic attack group and remission group.
Conclusions The pathogenesis of AIHA is associated with activation of B lymphocytic cells(CD5+CD19+). During the hemolytic attack, the percentages of CD19+B cells and CD5+CD19+B cells substantially elevate, indicating the proliferation of B lymphocytic cells. The amount of CD19+lymphocytic cells from rituximab group was lower than the counterpart group, while there was no statistically significance of CD5+CD19+cells between rituximab group and the counterpart group. this suggests that rituximab exhibits a strong inhibition effect towards immune system. The regulation of T lymphocytic cells (especially Th2proliferation) is also related to the mechanism of AIHA. The percentages of Thl and Th2cells both increased during hemolytic attack, and Th2decreased when remission was achieved while Thl showed no alteration. The pathogenesis of AIHA is related to DC cells. The percentages of DC1and DC2cells both decreased during the attack, yet DC1tended to become normal while DC2decreased after immunosuppressive therapy. This indicates that DCs maybe migrate into peripheral lymphoid tissue when hemolysis attacks.
Section2. Objective To better assess the efficacy and safety of monoclonal anti-CD20antibody rituximab combined cyclophosphamide with in treatment of refractory and recurrent autoimmune hemolytic anemia. Cases The study included7cases of autoimmune hemolytic anemia (including1case of Evans syndrome), which all of them were refractory or recurrent. Methods rituximab:375mg/m2, once per week,2-6times; Cyclophosphamide:1g/10days,2-7times; combined with intravenous immunoglobulin (IVIG)5g/week, given1day after rituximab treatment. Results All7patients showed good responses.6patients achieved complete remission (CR) and1patient achieved partial remission (PR). Responses occurred1to10months after the first dose of rituximab and the mean effective time is approximately2.5months. Average follow-up for the patients is around27months. All patients remained in remission at the12-month follow-up visits. At the time of24-month visits,2patients showed elevated indirect bilirubin and increased reticulocyte counts. One patient achieved CR after additional rituximab therapy, and the other patient just wait and watch without additional therapy. At the time of36-month visits,1patient relapsed and was retreated with3cycles of rituximab and eventually reached PR. All patients tolerated the treatment well with only mild side effects. Conclusions rituximab combined with and recurrent autoim cyclophosphamide is highly effective and relatively safe in patients with refractory mune hemolytic anemia. Additional treatment can be given in patients with relapse after1-2years.
Section3. Objective To study the clinical and laboratory features of the patients with immuno-related pancytopenia(IRP). Methods The risk factors,manifestations, blood cell counts,bone marrow phenotypes,autoantibodies and immunosuppressive therapy response of157patients with IRP were analyzed.Then they were followed up for (3～48) monthS,to see their long-term outcome and the prognostic factors. Results The infection,anaphylaxis and pregnancy were highly suspected to be the risk factors of IRP.Most of these patients were with pancytopenia73.2%(115/157), some patients were with anemia and thrombocytopenial8.5%(29/157)];61.3%(95/155) of them were anemic with large MCV,32.9%(51/155) of them were anemic with normal MCV;78.9%(124/157) of them were with leukopenia,23.6%(37/157) of them had fever. Thrombocytopenia was common[91.7%(144/157)],but serious bleeding was rare.68.8%(108/157)of these cases were with nomal or increased bone marrow cellularities and increased normoblasts.They were all found to have positive results of bone marrow mononuclear cell antibody Facs test,negative results of rutine hemolysis tests and no evidence of malignant clonal hematopoiesis.42.6%(67/157) of these patients had C3decreased, and18.5%(29/157) C4decreased. Immunosuppressive therapy was administered to157IRP patients,The response rate at36months was87.5%(28/32). Conclusions Immuno-related pancytopenia(IRP) is an acquired multiclonal autoimmunoantibody conducted bone marrow failure syndrome, featuring pancytopenia without reducing of reticulocytes and neutrophilic granulocytes. More than half of the patients used to have infections or allergies. A few patients'bone marrow have higher proliferation at least one site, with mild hemolysis yet negative hemolytic test. The following abnormalities often complicates with IRP, such as low amount of complements, positive ANA. Those patients may receive good responses to immunosuppressants and hemopoiesis improving treatment.
Conclusions The pathogenesis of AIHA is closely associated with B lymphocytic cells and CD5+B lymphocytic cells. Th2cells, the regulating cells of B lymphocytic cells, may play an important part in hemolysis. The amount of mDC and pDC decrease during hemolytic attack, which caused by DC peripheral migration. Refractory AIHA has good response to Rituximab,but sometimes relapse1year later. Immuno-related pancytopenia is an acquired multiclonal autoimmunoantibody conducted bone marrow failure syndrome, featuring pancytopenia without reducing of reticulocytes and neutrophilic granulocytes. More than half of the patients used to have infections or allergies. A few patients'bone marrow have higher proliferation at least one site, with mild hemolysis yet negative hemolytic test. The following abnormalities often complicates with IRP, such as low amount of complements, positive ANA. Those patients may receive good responses to immunosuppressants and hemopoiesis improving treatment.
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