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1.
Polymeric immunoglobulin receptor (pIgR)-mediated polymeric immunoglobulin A (pIgA) transcytosis across mucosal epithelial cells plays an essential role in mucosal immunity. The general trafficking process has been well investigated, yet the elaborate regulatory mechanisms remain enigmatic. We identified a new pIgR interacting protein, the Rab11 effector Rab11-FIP1. Rab11-FIP1 and Rab11-FIP5 knockdown additively impaired pIgA transcytosis in both polarized and incompletely polarized cells. Moreover, Rab11-FIP1 and Rab11-FIP5 knockdown exhibited more significant inhibitory effects on pIgA transcytosis in incompletely polarized cells than in polarized cells. Interestingly, the trafficking process of pIgA in incompletely polarized cells is distinct from that in polarized cells. In incompletely polarized cells, the endocytic pIgR/pIgA was first transported from the basolateral plasma membrane to the vicinity of the centrosome where Rab11-FIP1 and Rab11-FIP5 bound to it, before the Rab11a-positive endosomes containing pIgR/pIgA, Rab11-FIP1 and Rab11-FIP5 were further transported to the apical plasma membrane via Golgi apparatus. During the trafficking process, TRIM21 mediated the K11-linked polyubiquitination of Rab11-FIP1 and the K6-linked polyubiquitination of Rab11-FIP5 to promote their activation and pIgA transcytosis. This study indicates that polyubiquitinated Rab11-FIP1 and Rab11-FIP5 mediated by TRIM21 cooperatively facilitate pIgA transcytosis and provides new insights into the intracellular trafficking process of pIgA in incompletely polarized cells.  相似文献   

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Immunoglobulin G (IgG) is currently the most studied immunoglobin class and is frequently used in antibody therapeutics in which its beneficial effector functions are exploited. IgG is composed of two heavy chains and two light chains, forming the basic antibody monomeric unit. In contrast, immunoglobulin A (IgA) and immunoglobulin M (IgM) are usually assembled into dimers or pentamers with the contribution of joining (J)-chains, which bind to the secretory component (SC) of the polymeric Ig receptor (pIgR) and are transported to the mucosal surface. IgA and IgM play a pivotal role in various immune responses, especially in mucosal immunity. Due to their structural complexity, 3D structural study of these molecules at atomic scale has been slow. With the emergence of cryo-EM and X-ray crystallographic techniques and the growing interest in the structure-function relationships of IgA and IgM, atomic-scale structural information on IgA-Fc and IgM-Fc has been accumulating. Here, we examine the 3D structures of IgA and IgM, including the J-chain and SC. Disulfide bridging and N-glycosylation on these molecules are also summarized. With the increasing information of structure–function relationships, IgA- and IgM-based monoclonal antibodies will be an effective option in the therapeutic field.  相似文献   

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Toll-like receptors (TLRs) are a large family of pattern recognition receptors. TLR signals are involved in the pathogenesis of systemic lupus erythematosus. Mouse and human B cells constitutively express most TLRs. Many B cell subpopulations are highly responsive to certain TLR ligation, including B-1 B cells, transitional B cells, marginal zone B cells, germinal center B cell and memory B cells. The B cell-intrinsic TLR signals play critical roles during lupus process. In this review, roles of B cell-intrinsic TLR2, 4, 7, 8 and 9 signals are discussed during lupus pathogenesis in both mouse model and patients. Moreover, mechanisms underlying TLR ligation-triggered B cell activation and signaling pathways are highlighted.  相似文献   

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目的探讨B族链球菌(GBS)表面免疫原性蛋白(Sip)的黏膜免疫效果。方法表达及纯化两种不同标签的Sip(Gp-Sip和pET-Sip),质谱分析法鉴定纯化蛋白。用Gp-Sip免疫BALB/c小鼠,pET-Sip检测免疫小鼠血清及阴道黏膜萃取液中特异性抗体水平,调理吞噬试验检测Sip抗血清的调理吞噬活性。结果经质谱分析和蛋白质库比较证实,纯化的Gp-Sip和pET-Sip为B族链球菌Sip的可能性分值分别为177和92。ELISA检测结果显示,Sip+CT经鼻内及直肠两种途径黏膜免疫后,均可诱发小鼠产生高水平的血清IgG及阴道黏膜IgA抗体,鼻内免疫效果优于直肠;不同剂量的Sip+CT鼻内免疫后,均可在血清及阴道黏膜中检出高水平的IgG和IgA抗体,组间比较差异无统计学意义;CT和CpG-ODN1826鼻内免疫均可促进Sip产生较好的黏膜免疫效果,二者之间差异无统计学意义。Sip抗血清可明显地促进吞噬细胞对GBS的吞噬作用。结论Sip具有较好的黏膜免疫原性,鼻内黏膜免疫效果优于直肠,CT和CpG-ODN1826两种佐剂均可有效提高Sip的免疫原性。  相似文献   

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The innate immune system of the skin is thought to depend largely on a multi-layered mechanical barrier supplemented by epidermis-derived antimicrobial peptides. To date, there are no reports of antimicrobial antibody secretion by the epidermis. In this study, we report the expression of functional immunoglobulin G (IgG) and immunoglobulin A (IgA), previously thought to be only produced by B cells, in normal human epidermal cells and the human keratinocyte line HaCaT. While B cells express a fully diverse Ig, epidermal cell-expressed IgG or IgA showed one or two conservative VHDJH rearrangements in each individual. These unique VDJ rearrangements in epidermal cells were found neither in the B cell-derived Ig VDJ databases published by others nor in our positive controls. IgG and IgA from epidermal cells of the same individual had different VDJ rearrangement patterns. IgG was found primarily in prickle cells, and IgA was mainly detected in basal cells. Both epidermal cell-derived IgG and IgA showed potential antibody activity by binding pathogens like Staphylococcus aureus, the most common pathogenic skin bacteria, but the microbial-binding profile was different. Our data indicates that normal human epidermal cells spontaneously express IgG and IgA, and we speculate that these Igs participate in skin innate immunity.  相似文献   

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目的分析重组弓形虫热休克蛋白70(rTgHSP70)鼻内或皮下免疫小鼠诱导的小肠黏膜IgA抗体分泌细胞(IgA antibody-secreting cells,IgA-ASCs)与小肠冲洗液sIgA抗体的动态变化及二者的相关性,探讨其上调小肠黏膜免疫应答的作用机制。方法 BALB/c小鼠90只,随机均分3组:鼻内组(20μg rTgHSP70/只,滴鼻,免疫2次,间隔2周)、皮下组(80μg rTgHSP70/只,背部皮下注射,免疫2次,间隔2周)、对照组(不免疫)。分别于末次免疫后第1、2、3、4、5、6周,每组取小鼠5只,脱颈椎处死,免疫组化法检测十二指肠、空肠及回肠黏膜IgA-ASCs数量,ELISA法检测小肠冲洗液sIgA水平。结果 IgA-ASCs分布于小肠黏膜的固有层中,且鼻内组小肠黏膜IgA-ASCs数量明显高于皮下组和对照组(P<0.001),鼻内组小肠冲洗液sIgA水平在免后1~4周均处于上升阶段,第4周达到高峰,显著高于皮下组和对照组,差异有统计学意义(P<0.001);鼻内组和皮下组小肠冲洗液sIgA水平与十二指肠、空肠、回肠黏膜固有层IgA-ASCs的数量呈正相关(P<0.05)。结论 rTgHSP70经鼻内或皮下免疫小鼠均可诱导小肠黏膜固有层IgA-ASCs和小肠冲洗液sIgA水平的持续高表达,且二者呈正相关,鼻内免疫上调小肠黏膜免疫的作用优于皮下免疫。  相似文献   

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Thymic stromal lymphopoietin (TSLP) contributes to asthmatic disease. The concentrations of protective IgA may be reduced in the respiratory tract of asthma patients. We investigated how homeostatic short TSLP (shTSLP) and asthma-associated long TSLP (loTSLP) regulate IgA production. B cells from healthy donors were stimulated in the presence or absence of shTSLP or loTSLP; the concentrations of IgA, IgM, IgE, and IgG antibodies were determined in cell culture supernatants; and B cells were analyzed by flow cytometry. LoTSLP, but not shTSLP, suppressed the secretion of IgA but not of IgE. The type 2 cytokine IL-4, which in addition to loTSLP contributes to asthmatic disease, did not affect the production of IgA or the frequency of IgA+ B cells. Instead, IL-4 increased IgG production, especially of the subclasses IgG2 and IgG4. LoTSLP inhibited IgA secretion by sorted memory B cells but not by naïve B cells. Although loTSLP inhibited IgA production, the vitamin A metabolite retinoic acid promoted the secretion of IgA, also in the presence of loTSLP, suggesting that vitamin A may promote IgA production in asthma. Our data demonstrate that asthma-associated loTSLP negatively regulates the secretion of IgA, which may negatively impact the surveillance of mucosal surfaces in asthma.  相似文献   

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Several freeze-drying and spray-drying methods were investigated in relation to the retention of immunoglobulins (Ig) A, IgG, and IgM. Spray drying produced human milk powders with 2% humidity and a good retention of IgG (>88%) and IgM (~70%). However, only 38% of IgA remained after spray drying. For freeze drying, only the highest heating plate temperature used in this study (40°C) brought IgA content down to 55% in powder with 1.75% residual humidity, whereas milk samples undergoing lower temperatures had higher preservation rates (75% for IgA and 80% for IgG and IgM) and higher residual moisture contents. From these results, it can be concluded that IgA is the most sensitive Ig lost during drying processing of human milk. The best method to generate human milk powders without a significant loss of Ig was thus freeze drying at 30°C heating plate temperature, which accelerated the process compared to lower processing temperatures, but still had good overall Ig retention.  相似文献   

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A new polymeric drug carrier system using amino acid‐based polymers was developed. Amino acid‐based polymers with controlled molar mass and narrow molecular weight distribution have been synthesized by reversible addition‐fragmentation chain transfer polymerization of four amino acid‐carrying monomers having different chirality and hydrophilicity. Metronidazole (MTZ) was immobilized onto the amino acid‐based polymers, and the release profiles of the polymer‐MTZ adducts were investigated in phosphate buffer solutions (pH = 2.0, 7.4, and 8.5). The model drug was released by the hydrolysis of the ester group, and the release rate and behavior of the polymeric prodrugs strongly depended on the configuration of the amino acid‐based polymers‐MTZ adducts and the pH of the release media. The release kinetics was determined using the Higuchi and Korsmeyer equations, which revealed the release mechanism of the polymeric prodrugs. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013  相似文献   

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目的观察母牛分枝杆菌制剂(商品名微卡)单独或与流感疫苗联合接种后,对小鼠血清中流感病毒特异性Ig产生的影响。方法将不同剂量微卡(11.25、22.5和45.0μg/只)与流感疫苗(11.25μg/只)联合接种BALB/c小鼠,或接种微卡22.5μg/只后,感染流感病毒(2LD50),检测小鼠血清中流感病毒特异性IgM、IgG、IgG1、IgG2a和IgA产生的时间和水平。结果微卡与流感疫苗联合首次接种后4d,小鼠血清中流感病毒特异性IgG与IgG2a水平较流感疫苗组均明显升高,接种后13d差异无显著意义,对IgM和IgG1的产生无明显影响。45.0μg和22.5μg剂量与11.25μg剂量微卡+流感疫苗组IgG、IgG1、IgG2a和IgM水平比较,差异均无显著意义。接种微卡的小鼠,在感染流感病毒后10d,血清中流感病毒特异性IgA水平显著升高。结论微卡单独或与流感疫苗联合接种,对流感病毒特异性IgG、IgG2a和IgA的产生均有促进作用。  相似文献   

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Mothers confer natural passive immunization to their infants through the transplacental pathway during the gestation period. The objective of the present study was to establish at birth the maternal and cord plasma concentration and relationship of immunoglobulins (Igs), cytokines (CKs), and adipokines. In addition, the impact of the maternal microbiota and diet was explored. The plasma profile of these components was different between mothers and babies, with the levels of many CKs, IgM, IgG2a, IgE, IgA, and leptin significantly higher in mothers than in the cord sample. Moreover, the total Igs, all IgG subtypes, IgE, and the Th1/Th2 ratio positively correlated in the mother–infant pair. Maternal dietary components such as monounsaturated fatty acids-polyunsaturated fatty acids and fiber were positively associated with some immune factors such as IgA in cord samples. The microbiota composition clustering also influenced the plasma profile of some factors (i.e., many CKs, some Ig, and adiponectin). In conclusion, we have established the concentration of these immunomodulatory factors in the maternal–neonatal pair at birth, some positive associations, and the influence of maternal diet and the microbiota composition, suggesting that the immune status during pregnancy, in terms of CKs and Igs levels, can influence the immune status of the infant at birth.  相似文献   

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Mice carrying human immunoglobulin transloci were immunised with HIV-1 gp140 antigen to gain insight into the range and nature of human monoclonal antibodies (mAbs) that can be elicited from such humanised mice. Using five-feature mice that harbour YAC-based germline-configuration human IgM, Igκ and Igλ transloci in a mouse background disrupted for endogenous mouse IgH and Igκ expression, gp140-specific human IgM mAbs were readily elicited following serial immunisation. These mAbs were converted to human IgG1 format and were found to bind diverse epitopes within gp140, exhibiting high functional affinity for the antigen-typically in the nanomolar or sub-nanomolar range. The number of specific, stable hybridomas per mouse was, however, low (typically around five) with the hybridomas within individual mice often being clonally related. Nevertheless, different mice used B cell clones expressing varied V(D)J combinations, with affinity maturation through somatic hypermutation making a critical contribution. Thus, a wide range of distinct high-affinity mAbs can be obtained by immunising multiple animals. The results confirm the utility of the translocus-mouse approach and give insight into strategies for possible future improvement.  相似文献   

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A novel (main‐chain)‐(side‐chain) vinyl polyperoxide, poly(dipentene peroxide) (PDP), an alternating copolymer of dipentene (DP) and oxygen, has been synthesized by thermal oxidative polymerization of DP. The PDP was characterized by 1H NMR, 13C NMR, FTIR, DSC, TGA, and EI‐MS studies. The overall activation energies of the degradation from Kissinger's method were 28 and 33 kcal/mol, respectively, for the endocyclic and acyclic peroxide units. The side‐chain peroxy groups were found to be thermally more stable than the main chain. Above 45°C the rate of polymerization increases sharply at a particular instant showing an “autoacceleration” with the formation of knee point. The kinetics of autoacceleration has been studied at various temperatures (45–70°C) and pressures (50–250 psi). © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 79: 1549–1555, 2001  相似文献   

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目的制备抗黄曲霉毒素B1(AFB1)的重链IgG2b亚型单克隆抗体,并建立黄曲霉毒素B1的间接竞争ELISA检测方法。方法采用AFB1-BSA偶联物为免疫抗原,AFB1-STI偶联物为检测抗原,利用间接竞争ELISA筛选分泌抗AFB1单抗的细胞株,并对抗体进行鉴定。结果筛选到1株能分泌特异性抗AFB1单克隆抗体的杂交瘤细胞株,其染色体数目为(90±10)条;所分泌的单抗亚类重链为IgG2b,轻链为λ;间接ELISA检测该株杂交瘤细胞分泌上清效价在1∶12800~1∶25600,纯化腹水效价为1∶105~1∶106。传30代及液氮中保存6个月,抗体效价稳定;建立的间接竞争ELISA检测方法的最低检出限为0.001ng/ml,校正曲线的线性范围为0.005~5ng/ml,IC50为0.01ng/ml;与AFB1的结构类似物AFM1和化学结构有差异的脱氧雪腐镰刀菌烯醇的交叉反应率分别为1.4%和<1%。结论所制备的抗黄曲霉毒素B1单克隆抗体具有高度特异性和稳定性,可应用于间接竞争ELISA检测方法。  相似文献   

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Effects of external conditions, solution concentration, solvent quality, added salt, and pH on the chain conformation dimension of two kinds of polyacrylamide (PAAm) flocculants, neutral‐PAAm, and cationic‐P(AAm‐DMC) (DMC, 2‐[(methacryloyloxy)ethyl] trimethylammonium chloride), in parent solutions and their flocculation performance for Kaolin suspensions have been investigated by Ubbelohde viscometer and spectrophotometer, respectively. It was found that a negative correlation existed between the flocculation performance of PAAm flocculants and their chain sizes in parent solutions. This was attributed to the expanded chain deformation of PAAm flocculants during the flocculation process from the flocculant parent solution to the Kaolin suspension and was interpreted in term of the competitive interaction among the polymeric flocculant, solvent, and Kaolin particle in the chain deformation process. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010  相似文献   

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