The Putative Role of Fibroblasts in the Pathogenesis of Graves' Disease: Evidence for the Involvement of the Insulin-like Growth Factor-1 Receptor in Fibroblast Activation

Graves' disease when fully expressed affects the thyroid gland and connective tissues of the orbit and pretibium. While the glandular disease is relatively well-characterized, the pathogenesis of the orbital and dermal components remains enigmatic. In the following article, we review some of the evidence suggesting that fibroblast activation in Graves' disease might play an integral role in the tissue remodeling associated with ophthalmopathy. The thyrotropin receptor (TSHR) is expressed at low levels in several connective tissue depots and by their derivative fibroblasts, including those from the orbit. Little direct evidence currently links extra-thyroidal TSHR expression with Graves' disease. Very recent observations now implicate the insulin-like growth factor-1 receptor (IGF-1R) as a fibroblast activating antigen. When immunoglobulins from patients with the disease, with or without clinical ophthalmopathy, bind IGF-1R on the surface of fibroblasts, the receptor becomes activated and upregulates the expression of two T lymphocyte chemoattractants, IL-16 and RANTES. Thus, IGF-1R may represent a second self-antigen with a pathogenic role in extra-thyroidal Graves' disease.     

Ⅰ型自身免疫性胰腺炎的CT及MRI表现

目的探讨Ⅰ型自身免疫性胰腺炎(Ⅰ-AIP)的CT及MRI表现。资料与方法回顾性分析16例经病理证实的I-AIP的临床资料、CT及MRI表现。结果 16例I-AIP中,14例IgG4水平升高;胰腺弥漫型受累9例,呈"腊肠状"改变,其中6例可见"胶囊征";局灶型受累7例。CT平扫呈均匀等或低密度,MRI平扫T1WI呈低信号,T2WI呈稍高信号,扩散加权成像呈轻度扩散受限,病灶内未见坏死、囊变、钙化征象,动态增强扫描呈延迟强化。磁共振胰胆管造影显示主胰管弥漫性扩张6例,局限性扩张3例,伴肝内外胆管扩张8例。7例出现腹腔内淋巴结肿大,1例合并腹膜后纤维化。结论Ⅰ-AIP的影像表现多样,呈"腊肠状"改变、"胶囊征"、胰胆管受累及胰外器官受累等特征。结合血清学IgG4升高有助于早期鉴别诊断。     

Carbohydrate-associated Immunodominant Epitope(s) of CA215

RP215 monoclonal antibody (Mab) was initially generated against OC-3-VGH ovarian cancer cells and was shown to react with a cancer-associated carbohydrate epitope in glycoproteins designated as CA215. Additional five high affinity Mabs, designated as RCA-10, -100, -104, -110 and -111, respectively, were generated by using affinity-purified CA215 as the immunogen in this study. All RCA Mabs were found to recognize periodate-sensitive carbohydrate-associated epitope(s) and to pair with RP215 in typical sandwich enzyme immunoassays for the quantification of CA215. When compared with those of RP215, the amino acid sequence homology of the Fab regions ranged from 100% for RCA-100 to 65% for RCA-110, based on which 3 distinct Mab groups were categorized. In vitro TUNEL apoptosis and complement-dependent cytotoxicity assays were performed with these Mabs and found to have comparable inhibitory efficacy to cancer cells. Results of biochemical and immunological assays revealed that RP215, RCA-100 and RCA-10 react with the linear carbohydrate-associated epitope, whereas the others recognize the conformational form of the epitope in CA215. This study has suggested that the unique carbohydrate-associated epitope(s) is immunodominant in mice when immunized with CA215. It remains to be demonstrated if the differential anti-cancer efficacy exists among the distinct groups of these anti-CA215 Mabs.     

儿童过敏性紫癜急性期免疫功能探讨

目的:总结儿童过敏性紫癜(Henoch-Schonlein purpura,HSP)的细胞及体液免疫特征,分析其与紫癜性肾炎(Henoch-Sch(o)nlein purpura nephritis,HSPN)的关系,探讨细胞免疫及体液免疫功能在HSP发病机制中的作用及临床检测价值.方法:HSP急性期患儿190例,按有无肾脏损害分为紫癜性肾炎组(HSPN)和非肾炎组(NHSPN),流式细胞仪免疫荧光法检测T淋巴细胞亚群、自然杀伤细胞(Natural killer cells,NK cells)、B淋巴细胞变化,ELISA法检测血清IL4、IL-10、TNF-α的含量,速率散射比浊法检测外周血免疫球蛋白IgG、IgM、IgA、IgE、C3、C4水平.结果:190例HSP患儿中,合并肾脏损害33例,不合并肾脏损害157例.与对照组相比,急性期HSP组CD19细胞绝对值、IL-4、IL-10、TNF-α、IgG、IgA、IgE、补体C3显著升高(P均＜0.05),CD3、CD4、CD8、NK细胞绝对值显著降低(P均＜0.05);HSP患儿中,HSPN组的IL-10、IgA水平高于NHSPN组(P＜0.05),两组之间其余指标的差异无统计学意义(P均＞0.05).IgA水平升高组HSPN发生率(21.64％)高于IgA水平正常组(7.14％,x2=5.785,P＜0.05).IL-10水平与IgA呈正相关(r=0.425 9,P＜0.05),IL-4水平与IgE呈正相关(r=0.541 7,P＜0.05).结论:HSP急性期存在细胞及体液免疫功能的紊乱,均参与了HSP的发病机制,表现为细胞免疫功能低下,引起炎性介质分泌增多,导致多克隆B细胞活化及免疫球蛋白的分泌增加,介导了系统性微小血管炎,其中IgA介导的体液免疫紊乱在HSP的发病机制中起了主要作用;HSPN的IgA水平升高更为显著,可能是预测HSP发生肾脏损害的一个危险因素.     

Streamlined human antibody generation and optimization by exploiting designed immunoglobulin loci in a B cell line

Monoclonal antibodies (mAbs) are widely utilized as therapeutic drugs for various diseases, such as cancer, autoimmune diseases, and infectious diseases. Using the avian-derived B cell line DT40, we previously developed an antibody display technology, namely, the ADLib system, which rapidly generates antigen-specific mAbs. Here, we report the development of a human version of the ADLib system and showcase the streamlined generation and optimization of functional human mAbs. Tailored libraries were first constructed by replacing endogenous immunoglobulin genes with designed human counterparts. From these libraries, clones producing full-length human IgGs against distinct antigens can be isolated, as exemplified by the selection of antagonistic mAbs. Taking advantage of avian biology, effective affinity maturation was achieved in a straightforward manner by seamless diversification of the parental clones into secondary libraries followed by single-cell sorting, quickly affording mAbs with improved affinities and functionalities. Collectively, we demonstrate that the human ADLib system could serve as an integrative platform with unique diversity for rapid de novo generation and optimization of therapeutic or diagnostic antibody leads. Furthermore, our results suggest that libraries can be constructed by introducing exogenous genes into DT40 cells, indicating that the ADLib system has the potential to be applied for the rapid and effective directed evolution and optimization of proteins in various fields beyond biomedicine.     

IgG4相关性疾病泌尿系统损害的临床特点分析

目的 总结和分析IgG4相关性疾病(IgG4-RD)泌尿系统损害的临床特点.方法 收集24例IgG4相关性疾病泌尿系统损害患者的临床资料,回顾性分析患者肾脏受累、治疗前后Scr、Hb、炎性反应指标和IgG4亚类水平的变化情况.结果 2010年8月至2014年5月经北京协和医学院肾内科确诊的IgG4相关性疾病泌尿系统损害病例24例,平均受累器官数目(4.38±1.55)个.治疗前血清IgG4[M(范围)]为12 750(1 460～ 59 400) mg/L,均伴炎性反应指标明显升高.20例患者有检测尿蛋白量,其中19例尿蛋白量升高,6例伴肾病综合征.21例患者Scr升高,均值为(410.48±352.17) μmol/L,其中3例需接受透析治疗.14例患者伴贫血,8例伴单侧或双侧肾脏体积缩小.21例Scr升高的患者中,11例患者肾功能不全因肾后性梗阻所致,3例病理证实为肾小管间质肾炎.与治疗前相比,24例患者糖皮质激素联合或不联合免疫抑制剂治疗1周后Scr明显下降(P＜0.05),治疗1个月后Scr下降更为明显(P＜0.01),3例透析患者均脱离透析.血沉于治疗1个月后亦明显下降(P＜0.01).IgG4亚类水平在治疗1个月时无显著下降(P＞0.05),治疗2个月时明显下降(P＜0.01).结论 IgG4相关疾病合并肾功能不全并不少见,对中至大量糖皮质激素治疗反应良好,治疗后Scr下降早于血沉和IgG4亚类.     

Successful Treatment with Cyclosporine and High-Dose Gamma Immunoglobulin for Persistent Parvovirus b19 Infection in a Patient with Refractory Autoimmune Hemolytic Anemia

We describe a patient with persistent pure red cell aplasia due to human parvovirus B19 (HPVB19) infection during immunosuppressive therapy for refractory autoimmune hemolytic anemia (AIHA). The patient had been given corticosteroid (CS) and/or azathioprine for AIHA. During the course of treatment, reticulocyte count and hemoglobin levels decreased suddenly. Bone marrow aspirate showed erythroid lineage-specific aplasia with a few giant proerythroblasts, suggesting the presence of HPVB19 infection. The diagnosis of aplastic crisis due to HPVB19 infection was based on positive test results by polymerase chain reaction for HPVB19 immunoglobulin M (IgM) antibody and B19 DNA. Although splenectomy followed by administration of high-dose gamma globulin (HDIG) and plasma exchange were performed, the crisis and hemolysis recurred. Aplastic crises occurred several times when the B19 IgG result became negative and the CD4+ lymphocyte count was less than 300/microL. The patient showed complete recovery from anemia after CS was switched to cyclosporin A (CsA) and intermittent administration of HDIG. The result for B19 IgG antibody was continuously positive, and the DNA result became negative after these treatments. The results in this case indicated that concomitant administration of CsA and intermittent administration of HDIG can lead to cure of chronic anemia due to HPVB19 infection in patients with refractory AIHA.     

肾移植术后人类微小病毒B19感染致纯红细胞再生障碍性贫血2例并文献复习

目的探讨肾移植术后人类微小病毒(HPV)B19感染致纯红细胞再生障碍性贫血(纯红再障)的诊断和治疗特点。方法总结南方医科大学南方医院器官移植科收治的2例肾移植术后HPV B19感染致纯红再障的病例,结合文献复习讨论该病的临床特点、诊断方法、治疗过程及预后。结果两例肾移植受者术后早发严重贫血且进行性加重,输血治疗无效。排除导致贫血的其他原因,综合骨髓穿刺活检、荧光聚合酶链反应(PCR)检测HPV DNA等方法诊断为HPV B19感染致纯红再障。经调整免疫抑制方案、静脉注射用免疫球蛋白(IVIG)等治疗后2例患者贫血症状明显改善。结论对于肾移植术后早期不明原因、进行性加重的贫血患者,特别是伴随网织红细胞缺乏者,应考虑HPV B19感染致纯红再障的可能性。骨髓穿刺及荧光PCR检测结果是诊断纯红再障的主要依据,免疫抑制剂减量和应用IVIG治疗是主要治疗措施。经治疗后,患者预后较好,但易复发。     

26例IgG4相关性腹膜后纤维化的系统评价

目的 探讨IgG4相关性腹膜后纤维化的临床病理特点、治疗及预后情况.方法 联机检索中国期刊全文数据库、维普中文科技期刊数据库、Medlme/Pubmed及OVID全文数据库,检索截止至2013年11月,结合南京大学医学院附属鼓楼医院消化科诊治的1例患者,进行系统评价.结果 15篇文献进入本系统综述,共纳入26例诊断明确的病例.系统评价结果显示（1）该病好发于69岁左右男性,临床表现以腰背痛、腹痛及肾盂积水为主;（2）血清IgG4升高多见;CT或MRI提示腹膜后肿块;（3）组织病理学检查显示软组织纤维化和IgG4＋浆细胞聚集;（4）目前无标准化方案,糖皮质激素仍是治疗IgG4相关性腹膜后纤维化的首选方案.结论 IgG4相关性腹膜后纤维化是一新的疾病亚型,临床症状缺乏特异性,极易误诊,需进一步研究以提高对该病的认识.