免疫相关性血细胞减少症41例临床分析

目的:观察41例免疫相关性血细胞减少(immunorelated hemocytopenia,IRH)或全血细胞减少症(immunorelated pancytopenia,IRP)患者的临床特点,以提高对本病的认识。方法:分析41例IRH/IRP患者临床表现、血常规、骨髓象、骨髓单个核细胞抗人球蛋白(BMMNC-Coombs)试验、抗核抗体ANA和ENA抗体谱、T淋巴细胞亚群、染色体核型等以及对肾上腺糖皮质激素、环孢素A等免疫抑制剂的治疗反应。结果:本组病例临床主要表现为贫血、出血、感染;血常规呈三系、二系或一系减少,网织红细胞百分比不低;骨髓增生以活跃或明显活跃为主(82.9%),红系比例多增高;BMMNC-Coombs试验阳性率78.0%;除外了再生障碍性贫血(AA)、骨髓增生异常综合征(MDS)、阵发性睡眠性血红蛋白尿(PNH)等疾病;小部分病例(19.5%)并发系统性红斑狼疮(SLE)等自身免疫性疾病;对肾上腺糖皮质激素、环孢素A等治疗有良好反应。结论:IRH/IRP是由于T淋巴细胞调控异常致B淋巴细胞产生针对骨髓未成熟造血细胞的自身抗体而使血细胞减少,BMMNC-Coombs试验对IRH/IRP的...     

骨髓单个核细胞Coombs试验阳性血细胞减少患者骨髓巨噬细胞活化抗原表达及其临床意义

目的 探讨骨髓单个核细胞Coombs(BMMNC-Coombs)试验阳性血细胞减少(又称免疫相关性血细胞减少,IRP)患者骨髓巨噬细胞(MΦ)活化抗原表达及其临床意义.方法 采用流式细胞仪(FACS)检测61例IRP患者及10例重型再生障碍性贫血(SAA)(病例对照组)和13例正常人(正常对照组)骨髓造血细胞膜自身抗体类型、骨髓MΦ数量(CD_(68)~+/CD_(45)~+)%及MΦ活化抗原(CD_(69))表达水平(CD_(68)~+CD_(68)~+CD_(68)~+)%,并探讨其临床意义.结果 61例IRP患者其MΦ数量及活化抗原表达水平[(0.57±0.30)%和(40.30±18.49)%]均高于病例对照组[(0.46±0.08)%和(32.44±19.37)%]及正常对照组[(0.44±0.69)%和(29.71±11.67)%](P值均<0.05);且其MΦ数量与活化抗原表达水平呈明显正相关(r=0.89,P<0.01).根据MΦ数量分为A组(MΦ百分率≥0.5%)和B组(MΦ百分率<0.5%),A组34例患者中32例(94.1%)有自身抗体IgG,B组27例患者中仅2例(7.4%);A组患者骨髓MΦ活化抗原表达水平(49.19±16.63)%显著高于B组患者(29.11±14.30)%(P<0.05),而B组患者和病例对照组及正常组无统计学意义(P值均>0.05);A组患者的3、6个月的总有效率(分别为47.06%、79.41%)均明显优于B组患者同期的疗效(22.22%、51.85%)(P<0.05);并且A、B组患者6个月的总有效率(79.41%、51.85%)均明显高于3个月的疗效(47.06%、22.22%)(P值均<0.05).34例自身抗体IgG(+)IRP患者按MΦ数量分为高(≥0.75%)、低(<0.75%)水平2组,25例MΦ低水平组24例仅能检测到1系骨髓细胞(CD_(34)~+或CD_(15)~+或GlycoA~+)有自身抗体IgG(96%),1例检测到2系骨髓细胞有自身抗体1gG;9例MΦ高水平组有8例能检测到2系骨髓细胞有自身抗体Igc,1例为3系骨髓细胞均有自身抗体IgG;高水平组IRP患者MΦ活化抗原表达水平(56.12±15.11)%显著高于低水平组(44.58±18.16)%(P<0.05);外周血红细胞、血红蛋白、血小板计数均显著低于低水平组(P<0.05);而外周血网织红细胞比例、总胆红素、间接胆红素及胸骨红系比例均显著高于低水平组(P<0.05).结论 IRP患者(尤其有骨髓造血细胞膜自身抗体IgG的IRP患者)骨髓MΦ数量明显增多,活化抗原高表达,即多呈激活状态,激活的巨噬细胞可能参与IRP患者骨髓早期造血细胞的破坏.     

免疫相关性全血细胞减少症的诊断及治疗

近年来,我们在鉴别骨髓造血功能衰竭“综合征”时发现了一类抗骨髓造血细胞(未成熟血细胞)自身抗体导致的一系、二系或三系血细胞减少,我们暂称之为免疫相关性血细胞减少症(IRP)[1]。通过对此类疾病发病机制所做的初步研究,我们发现IRP是由T淋巴细胞调控失衡导致B淋巴细胞数量、亚群、功能异常,进而产生抗骨髓未成熟造血细胞自身抗体并破坏或抑制之,最后导致外周血细胞减少的一类疾病[2,3]。现将IRP的诊断和治疗方法综述如下。1诊断1·1临床特点IRP患者的主要临床表现是贫血、出血、感染;部分患者有造血系统以外组织受损(主要是自身免…     

自身免疫性血细胞减少症患者骨髓CD+5B细胞数量变化及其临床意义

目的探讨自身免疫性血细胞减少症患者骨髓CD5 B细胞数量及其临床意义。方法2001-032002-04对中国医学科学院血液病医院的住院患者14例检测自身免疫性溶血性贫血(AIHA)和Evans综合征和22例免疫相关性全血细胞减少症(IRP)及10名正常对照骨髓CD5 B细胞数量并与临床及实验室指标做相关分析。结果AIHA、Evans综合征和IRP患者CD5 B细胞数量[(34·64±9·81)%,(35·81±16·83)%]高于正常人[(12·0±1·97)%],(P<0·05),CD5 B细胞的数量与补体C3呈负相关(P<0·05),与间接胆红素呈正相关(P<0·05);与Evans综合征患者血小板抗体PAIgG(P<0·05)、PAIgM(P<0·05)呈正相关;与临床疗效呈负相关(P<0·05)。结论CD5 B细胞在自身免疫性血细胞减少症的发病机制中可能具有重要意义。     

免疫相关性血/全血细胞减少症诊断和治疗

免疫相关性血/全血细胞减少症（IRH/IRP）是一种自身抗体介导的骨髓造血功能衰竭性疾病,常常被误诊为“不典型或难治性再生障碍性贫血”或“骨髓增生异常综合症-难治性贫血”,造血细胞自身抗原耐受丧失到自身抗体产生并攻击自体骨髓造血的发病过程,是免疫细胞“瀑布链”异常激活所致。识别其异常体液免疫功能亢进的发病本质是IRH/IRP精准诊治的关键。     

免疫相关性血细胞减少症

近10余年,在鉴别骨髓衰竭性疾病时,发现了一类由针对骨髓未成熟造血细胞自身抗体介导的2系或3系血细胞减少,暂称之为狭义的"免疫相关性血细胞减少症(IRH)"[1-6]。该症以往多被误诊为不典型再生障碍性贫血(AA)或归于骨髓增生异常综合征(MDS),但按AA或MDS治疗疗效欠佳,迁延不愈。正确认识并诊治此类血细胞减少,不仅有益于患者,而且有益于丰富造血调控学说、纯化     

免疫相关性血细胞减少症的诊断及鉴别诊断

免疫相关性血细胞减少症（immuno-related hemocytopenia,IRH）是近十余年从骨髓衰竭性疾病中分离出的一类新的疾病体系。其发病机制是由于某种未知病原刺激后,主要抗原呈递细胞树突状细胞亚群出现异常,引起下游T淋巴细胞调控失衡,导致B淋巴细胞数量、亚群、功能异常,进而产生仅针对骨髓造血细胞的自身抗体,通过介导巨噬细胞吞噬、激活补体原位溶血或封闭造血细胞膜上的功能蛋白,抑制造血细胞增殖分化而导致骨髓衰竭或无效造血〔1-10〕。临床上,IRH常被误诊为不典型再生障碍性贫血（AA）或骨髓增生异常综合征（MDS）,且疗效欠佳,迁延不愈。因此,正确诊断IRH,将其与其他骨髓衰竭性疾病鉴别开是临床上提高疗效的前提。以往IRH的诊断主要依靠骨髓库姆试验（BMMNC-Coombs试验）或流式细胞术（FCM）检测骨髓造血细胞膜自身抗体,近几年随着检测技术的发展,IRH的诊断亦不断进展,现阐述如下。     

免疫相关性血细胞减少症

目的：免疫相关性血细胞减少症有原发性与继发性两种，为提高其诊断率及鉴别诊断．以便及时治疗。方法：采用西班牙格瑞索(GRIFOLS)自动分析仪进行Coomb试验，将其分为AHG、IgG、IgG G3、C3、骨髓单个核Coomb试验及Coomb试验阴性几种类型。结果：561例贫血患者157例Coomb阳性。其中原发性107例，包括自身免疫性溶血性贫血(AIHA)；原发性血小板减少性紫癜(ITP)；Evans综合征。3例骨髓单个核细胞Coomb阳性，Coomb试验阴性者8例。继发免疫相关血细胞减少症50例，包括多种微生物感染、癌症、器官移植术后、结缔组织病等。结论：无论原发或是继发免疫相关血细胞减少症均是机体免疫功能紊乱，产生针对自身红细胞的抗体和(或)补体，其吸附于红细胞表面，导致红细胞破坏而溶血。同时对Coomb试验阴性者及骨髓单个核细胞Coomb阳性者进行探讨，并针对不同情况给予个体化治疗。     

全血细胞减少症 106 例骨髓检查及病因分析

目的探讨骨髓检查对全血细胞减少症病因诊断的作用。方法对106例全血细胞减少症患者骨髓检查及诊断资料进行回顾分析。结果首次骨髓涂片检查确诊80例(75.5%),"血稀"18例、"干抽"6例,需重抽或行骨髓活检得以确诊。106例全血细胞减少症中由造血系统疾病引起的84例(79.2%),以再生障碍性贫血最常见,非造血系统疾病22例(20.8%)。结论骨髓检查是全血细胞减少症病因诊断的主要手段,部分非造血系统疾病的诊断需结合临床。     

骨髓检查在全血细胞减少中的诊断价值及320例病因分析

目的:对比分析骨髓涂片与组织活检在全血细胞减少中的诊断价值以及引起全血细胞减少的常见病因。方法:选常规骨髓穿刺部位,用骨髓穿刺针先抽吸骨髓液行涂片,在隔2mm远处用骨髓活检针进针取骨髓组织活检;对比分析320例全血细胞减少患者的骨髓涂片与组织切片的结果。结果:骨髓活检切片与骨髓涂片增生程度一致者118例(36.9%),增生程度切片>涂片者41例(12.8%)。增生程度减低及重度减低者切片组152例(47.5%),骨髓涂片组193例(60.3%)。比较两者的骨髓增生程度,其差异存在统计学意义(P<0.01),骨髓活检对骨髓增生程度的判断优于涂片。两者结合起来更能反映骨髓细胞造血,提高诊断率。造血系统疾病是全血细胞减少的常见病因,也不能忽视非造血系统疾病所致的全血细胞减少。     

Aplastic anaemia with 13q-: a benign subset of bone marrow failure responsive to immunosuppressive therapy

In an attempt to determine the pathological significance of a long arm deletion of chromosome 13 (13q-) in bone marrow failure syndrome, we reviewed the clinical records of nine patients who were initially diagnosed with aplastic anaemia due to bone marrow hypoplasia without dysplasia. Six patients responded to immunosuppressive therapy and the other three improved with steroids. None of the patients developed acute leukaemia (follow up: 54-129 months) and the estimated 5-year survival was 78%. These findings indicate that pancytopenia with 13q- represents bone marrow failure of a benign nature, similar to aplastic anaemia without karyotypic abnormalities, rather than preleukaemia.     

Epstein-Barr virus-associated lymphoproliferative disorder developed after anti-thymocyte globulin therapy in a patient with bone marrow failure associated with T-cell large granular lymphocytic leukemia

A 75-year-old man was referred to our hospital for marked neutropenia and anemia. Bone marrow examination showed marked hypoplasia with 45.2% infiltration of CD3+, CD8+, CD16+ and CD57+ granular lymphocytes. Monoclonal rearrangement of T-cell receptor gene was observed by Southern blot analysis. Taking these findings together, T-cell large granular lymphocyte leukemia (T-LGL) with bone marrow failure was diagnosed. The patient was treated with immunosuppressive therapy (IST) consisting of anti-thymocyte globulin and cyclosporine. Although pancytopenia subsided after IST, fever and lymphoadenopathy developed on the 29th day after IST. The presence of Epstein-Barr virus (EBV) in peripheral blood was confirmed using real time PCR (3.5×10(6) copies/10(6)WBC). Although gancyclovir and foscarnet were started, rapidly progressive hepatomegaly and liver dysfunction developed. The patient died on the 42nd day after IST. Autopsy specimen showed infiltration of abnormal CD20-positive large lymphocytes in the portal area of the liver, white pulp of the spleen, kidneys and adrenal glands. The nuclear EBV-encoded RNA (EBER) stain was positive in the abnormal large lymphocytes and a diagnosis of EBV-associated B-cell lymphoproliferative disorder (EBV-LPD) was made. We should regard the potential risk of EBV-LPD after immunosuppressive therapy for patients with bone marrow failure caused by T-LGL.     

Clinical management of aplastic anemia

Acquired aplastic anemia is a potentially fatal bone marrow failure disorder that is characterized by pancytopenia and a hypocellular bone marrow. Hematopoietic stem-cell transplantation or bone marrow transplantation (BMT) is the treatment of choice for young patients who have a matched sibling donor. Immunosuppression with either anti-thymocyte globulin and cyclosporine or high-dose cyclophosphamide is an effective therapy for patients who are not suitable BMT candidates owing to age or lack of a suitable donor. Results of BMT from unrelated and mismatched donors are improving, but presently this treatment option is best reserved for those patients who do not respond, relapse or develop secondary clonal disorders following immunosuppressive therapy. Efforts are currently underway to both improve immunosuppressive regimens and to expand the application of BMT.     

Persistent Remission after Immunosuppressive Therapy of Hairy Cell Leukemia Mimicking Aplastic Anemia: Two Case Reports

Some patients with hairy cell leukemia (HCL) manifest pancytopenia and bone marrow hypoplasia without an apparent increase in atypical cells, so their disease resembles severe aplastic anemia at onset. We treated 2 HCL patients, who were initially diagnosed with aplastic anemia, with antithymocyte globulin (ATG) in combination with cyclosporine or antilymphocyte globulin (ALG). Both patients obtained partial remission in response to the immunosuppressive therapy and did not need transfusion treatment for more than 3 years. Sustained improvement of hematopoiesis in such B-cell malignancies after ATG/ ALG therapy suggests that the mechanisms underlying successful immunosuppressive therapy for aplastic anemia may involve B-cell suppression, inhibiting hematopoietic stem cells.     

Successful immunosuppressive therapy for a patient with hypoplastic myelodysplastic syndrome

We encountered a patient with hypoplastic myelodysplastic syndrome (MDS) who responded to immunosuppressive therapy including antithymocyte globulin and cyclosporin A (CsA). A 13-year-old girl was referred to our hospital because of pancytopenia. Bone marrow smears disclosed extreme hypocellularity without cellular atypism. A diagnosis of aplastic anemia was made, and immunosuppressive therapy consisting of ATG, CsA, granulocytecolony-stimulating factor (G-CSF), methylprednisolone, and danazol was started. A month later dysplastic cells appeared in the bone marrow. The karyotype of pretreatment bone marrow cells was 46, XX, del (13) (q12; q14). Therefore, the final diagnosis was hypoplastic MDS. CsA and danazol were continued. The patient became transfusion-independent 1 month later and dysplastic cells disappeared from bone marrow 3 months later. The chromosomal abnormality also became undetectable 6 months after the initiation of treatment. These findings indicated that immunosuppressive therapy is beneficial for patients with hypoplastic MDS.     

Current considerations of the etiology of aplastic anemia

Aplastic anemia is a disorder characterized by marrow aplasia and pancytopenia. The pathogenetic mechanisms that lead to bone marrow aplasia have been intensively studied. Data obtained from these studies suggest that aplastic anemia is a heterogeneous disorder with regards to pathogenesis. Bone marrow aplasia may result from a number of abnormalities including qualitative or quantitative abnormalities of hematopoietic stem cells, abnormal interaction between bone marrow accessory cells (lymphocytes and macrophages) and hematopoietic stem cells, cytotoxic humoral inhibitors of hematopoiesis, and abnormalities of the bone marrow microenvironment. A number of new therapeutic options have improved the survival of patients with aplastic anemia. Allogeneic bone marrow transplantation has actually resulted in the cure of patients. Unfortunately, only a minority of patients have a suitable bone marrow donor and alternate modes of therapy have been sought. Encouraging results have been reported from several centers concerning the use of antilymphocyte serum in patients with aplastic anemia. Certainty of the ultimate long-term benefit of this type of immunosuppressive therapy is not possible until careful, randomized, prospective studies of its use are completed.     

Pancytopenia in untreated patients with Graves' disease.

Severe pancytopenia is a rare but severe complication of thyrotoxicosis. In this report, we describe four patients with Graves' disease who presented with pancytopenia at diagnosis. Methimazole (30-40 mg/d) or propylthiouracil (400 mg/d) restored normal hematopoiesis in three of the patients. The remaining patient evolved to aplastic anemia under therapy with methimazole (60 mg/d), but had an increased peripheral blood count that almost reached normal values after radioiodinetherapy and standard immunosuppressive treatment with antithymocyte globulin (700 mg/d, intravenous infusion for 5 days), oral cyclosporin (400 mg/d), prednisone (30-60 mg/d), and granulocyte colony-stimulating factor (150 microg subcutaneous injection, 3 times per week). We conclude that: (1) a hematologic evaluation of all patients with Graves' disease should be performed before administering antithyroid drugs, (2) antithyroid drugs may be administered to patients with pancytopenia and bone marrow hypercellularity but a reevaluation of the bone marrow must be done if there is no recovery of the peripheral blood cell count when euthyroidism state is achieved, (3) standard immunosuppressive treatment of aplastic anemia caused by antithyroid drugs restores normal hematopoiesis, and (4) a thyroid evaluation of patients with pancytopenia should be done, even though no related symptoms are found.     

Panzytopenie und generalisierte Lymphknotenschwellung

A 47-year-old woman was admitted to our emergency room because of anemia and acute tonsillitis. She reported recurrent fever and a sore throat. Clinical examination and CT scans showed general lymph node swelling and liver enlargement. In the course of the disease she developed pancytopenia with neutropenic fever, pleuropneumonia, and deep vein thrombosis. The histological examination of a lymph node showed a reactive, EBV-associated lymphadenitis. The examination of the bone marrow showed an activated marrow. The diagnosis of an active EBV infection was established with 2x10⁶/ml EBV gene copies in the blood. In addition, systemic lupus erythematosus was diagnosed because of the typical autoantibody constellation and clinical findings. The immunohematological examination showed autoantibodies against the three blood cell compartments. Because of the severe pancytopenia as a result of the EBV- and SLE-associated autoantibodies and despite recurrent infections, we initiated immunosuppressive therapy with low-dose corticosteroids. This therapy resulted in normalization of the blood counts. Anitibody levels and the EBV genome levels became negative.     

A case report: a pediatric patient with acute lupus hemophagocytic syndrome; differences from reactive hemophagocytosis caused by hypercytokinemia

We report the youngest known girl with acute lupus hemophagocytic syndrome (ALHS) at the onset of her illness. We investigated the pathogenesis of ALHS by assessment of factors thought to influence the onset, such as cytokines, Th1/Th2 balance, immune complexes, and autoantibodies. A girl 8 years and 10 months old with systemic lupus erythematosus (SLE) had high fever, pancytopenia, and hemophagocytosis in the bone marrow. We diagnosed SLE complicated by ALHS. Treatment with predonisolone (2 mg/kg/day) was started, and her clinical features improved. Th2 dominance of the Th1/Th2 balance, hypocomplementemia, and high levels of anti-ds-DNA antibody, PAIgG, and immune complexes were seen, but no hypercytokinenemia, hyperferritinemia, or hypertriglyceridemia. ALHS at the onset of SLE, excluding that caused by infections, could be a form of reactive hemophagocytosis caused by excessive production of autoantibodies and immune complexes. High-dose steroid therapy is effective without need for immunosuppressive drugs. Our patient showed hypocomplementemia along with high levels of anti-dsDNA antibody, anticardiolipin antibody, platelet-associated IgG (PAIgG), and immune complexes. The autoimmune-associated hemophagocytic syndrome (AAHS) is thought to involve an autoantibody-mediated mechanism or an immune complex-mediated mechanism. On the basis of our data, ALHS could simultaneously involve both these mechanisms. We demonstrated that there was no hypercytokinemia and no hyperferritinemia in ALHS associated with Th2 dominance. Autoantibodies and immune complexes may cause histiocytic hemophagocytosis in ALHS. High-dose steroids and high-dose immunoglobulin are effective but immunosuppressive drugs are not needed. Received: September 21, 2000 / Accepted: July 5, 2001