胆汁中的免疫球蛋白

人胆汁中的免疫球蛋白(Ig)由Tomasi在1963年首次测得。由于它在胆道、肠道免疫中的特殊作用,这一含量并不高的胆汁成分日益引起人们的重视。研究重点在于胆汁Ig的含量、来源、免疫学特性及其在肝胆乃至肠道免疫中的地位。胆汁Ig含量及免疫化学特性正常人和动物胆汁中均有Ig存在,啮齿类动物以IgA占优势,人胆汁中各类Ig含量由于测定方法及局部病理生理状态不同而有较大差异。Tomasi等报告胆汁各类Ig的含量顺次为IgG、IgA、IgM,IgG与IgA之比为2.6∶1;另一些作者报告胆汁Ig以IgA为主,约占Ig总量的50%,而IgG占35%,IgM占15%。免疫化学分析证明胆汁IgA与血浆IgA不同,以分泌型IgA占绝对优势,其中约60%是含分泌片(SC)的分泌型IgA(sIgA),不含SC的IgA二聚体(dIgA)占21～33%,其余     

IgA肾病尿液生物标记物的研究进展

IgA肾病是全世界最常见的原发性肾小球疾病,是引起终末期肾功能衰竭的重要原因之一。IgA肾病以蛋白尿和（或）血尿为主要表现,病情变化轻重不一。大量研究显示多种炎症因子,细胞因子等参与了IgA。肾病病理损伤过程,其在尿液中的表达及变化在评估IgA肾病疾病活动性,检测疾病进展程度及评价疗效,评估预后等方面有重要意义。现就近年来对IgA肾病尿液生物标记物的研究进展作一综述。     

胆外疾病与胆囊结石相关性的研究进展

胆囊结石是我国常见的消化系疾病之一,其发病机制复杂,多认为是在遗传背景下,由多种因素介导而成,包括胆汁胆固醇过饱和、肠道胆固醇吸收过多、胆汁中胆固醇成核异常、胆囊动力学功能障碍及胆汁淤积等。回顾性分析了上述机制对胆外疾病与胆囊结石形成之间的关系,着重探讨了代谢综合征、肝脏疾病、胃肠道疾病等与胆囊结石形成的相关性。基于目前的研究证据,以上疾病可能促进胆囊结石的形成,通过对以上胆外疾病的积极干预,可望为胆囊结石的防治拓展新的思路。     

胆汁淤积中多耐药相关蛋白作用

<正>胆汁主要由肝细胞和胆管细胞分泌产生,其形成机制十分复杂。在整个机制中最为关键的步骤就是顶端或毛细胆管膜上将胆盐、有机物质等大量溶质排入毛细胆管形成原始胆汁流的过程。这一步骤主要由具有ATP结合域的盒式跨膜转运蛋白(ABC转运蛋白)介导,毛细胆管胆汁酸盐输出泵(BSEP)和多耐药相关蛋白(MRP2)均属于ABC转运蛋白家族,其中BSEP负责胆汁盐排出,通过水解ATP,跨膜转运结合胆汁酸盐,形成毛细胆管内胆汁酸依赖性胆汁流;MRP2负责介导其     

IgA肾病40例的中西医结合治疗体会

IgA肾病是指肾小球系膜区以IgA或IgA沉积为主的原发性肾小球疾病。IgA肾病是肾小球源性血尿最常见的病因。亚太地区和西欧地区该病分别占原发性肾小球疾病的20％-40％和10％～30％，10年内约10％-20％IgA肾病患者进入尿毒症，在欧洲和澳洲慢性透析和肾移植患者IgA肾病占7％-20％。目前认为IgA肾病是肾小球肾炎中最常见的一种类型，也是导致终末期肾衰最常见的原因之一。该病在我国发病率占肾小球疾病的26％-40％，男性多于女性，好发年龄在10-30岁，我科从2000～2004年开始肾脏病理活检，总结40例IgA肾病患者运用中西医辨证治疗IgA肾病，取得较好疗效，将其体会介绍如下。     

胆结石患者血清和胆汁幽门螺杆菌相关蛋白免疫印迹检测

目的：研究幽门螺杆菌（HP）感染与胆石形成的关系。方法：采用聚合酶链免疫吸附法（ELISA）对胆结石患者的血清及胆汁免疫球蛋白IgG,IgA,IgM标本进行检测，对血清学及胆汁IgG均阳性患者的胆汁，采用免疫印迹法（Western blot)进行HP感染相关蛋白检测。结果：胆结石组50例患者中血清学及胆汁IgG均阳性者29例（58.0%)，另取非胆结石组13例作为对照，胆结石组与非胆结石组血清及胆汁HP免疫印迹检测，均可检出4种主要HP感染相关蛋白，但胆结石组血清及胆汁中UreA检出率较非胆结石组高。结论：胆汁中存在多种HP感染相关蛋白，并可能参与胆结石的形成。     

肝胆疾病患者的尿、血清及胆汁中的硫酸化和非硫酸化胆汁酸

众所周知,肝胆疾病患者血清中的胆汁酸浓度增高,并有大量的胆汁酸排入尿中。近来又注意到,肝胆疾病患者的血清和尿中含有一种新形式的结合胆汁酸,即硫酸化胆汁酸(Sulfated bile acid)。本文报道了在各种肝胆疾病患者的尿、血清及胆汁中硫酸化与非硫酸化胆汁酸的情况。     

日本医师国家考试内科题选答案与题解(二)(试题见1985年第11期)

一、E。题解:以肝内胆汁淤滞为主要表现的疾病有妊娠期复发性黄疸、原发性胆汁性肝硬变、原发性硬化性胆管炎及部分病毒性肝炎转为淤胆性肝炎等,但以药物所致的肝内胆汁淤滞者最为常见,其中C_(17)烷化皮质醇制剂最易使毛细胆管绒毛变性,发生胆汁淤滞。题中其他疾病均不引起肝内胆汁淤滞。二、E。题解:题中五种疾病的血清白蛋白都可减少。肾病综合征虽胆固醇合成正常,但其排泄迟缓,故血清胆固醇值升高。原发性胆汁性肝硬变     

补体活化异常与IgA肾病

IgA肾病(IgAN)是由半乳糖缺陷的IgA1结合抗体后形成病原免疫复合物所介导的自身免疫性疾病,以IgA在肾小球系膜区沉积为特点。系膜区沉积的IgA主要为多聚体IgA1,通过活化系膜细胞产生大量炎症因子,进一步激活补体系统。补体通过替代途径和凝集素途径活化,在IgAN发病机制中发挥重要作用。替代途径产物备解素、H因子(FH)及凝集素途径产物甘露糖结合凝集素(MBL)、MBL相关丝氨酸蛋白酶(MASP)1和2及C4d等参与形成系膜区免疫沉积物。补体H因子相关基因(CFHR)蛋白产物通过与FH竞争性调节替代途径,减弱FH对补体活化的抑制作用。全基因组关联分析显示CFHR 1和CFHR 3缺失对IgAN有保护作用。IgA参与形成的免疫复合物导致补体活化后补体因子及其片段可作为IgAN的血清、尿液及肾组织生物标志物。新近文献报道进展型IgAN患者受益于抗补体治疗,但其长期疗效有待于临床研究进一步验证。本文将补体活化异常对IgAN产生的影响加以综述。     

胆囊内胆汁与其粘膜的相互作用及其与胆结石形成之关系

胆囊在胆结石形成中起重要作用,故有必要了解胆囊及其与胆汁的相互作用。虽然源生于肝脏的胆固醇饱和性胆汁(称成石性胆汁)是胆结石形成的先决条件,但成石性胆汁也常存在于正常人,因而在胆汁或胆囊粘膜中肯定存在另一些因素。其中之一就是胆囊内胆汁的钙浓度。许多研究表明,在胆固醇或色素性胆结石患者,其胆汁中的钙常常是超饱和的,所以钙易沉淀。极大多数结石含有由钙酸盐组成的核心。当结石增大时,围绕核心沉积多层胆红     

The liver and IgA: immunological, cell biological and clinical implications

Secretory immunoglobulin A is the characteristic and predominant immunoglobulin of the mucosal immune system; it participates in immunological protection at the level of mucous membrane surfaces. During the past 10 to 15 years, a great deal of experimental and clinical evidence has shown that the liver is very much involved in the sIgA system. In certain animals (rats, mice, rabbits), polymeric forms of IgA are efficiently cleared by the liver and transported into bile by a receptor-mediated vesicular pathway across hepatocytes. Taking advantage of this easily accessible pathway, investigators have defined many of the events in the external secretion of pIgA, including details about the synthesis and secretion of its receptor, secretory component. In the rat hepatocyte, secretory component is synthesized as a transmembrane glycoprotein and is expressed preferentially on the sinusoidal plasma membrane; circulating pIgA that binds to secretory component is internalized into endocytic vesicles and transported across the hepatocyte to the bile canalicular membrane, where the pIgA is released into bile as a soluble complex with a portion of the secretory component, the complex being secretory IgA. In some other animals (dog, guinea pig, sheep) as well as man, biliary epithelial cells, not hepatocytes, express secretory component and perform the transcytosis and secretion of pIgA into bile. In those species, much of the pIgA that reaches bile is synthesized locally in plasma cells that populate the biliary tree; this design is analogous to the release of sIgA into various mucosae in the body. The major biological functions ascribed to the secretion of IgA into bile are enhancement of immunological defense of the biliary and upper intestinal tracts and the clearance of harmful antigens from the circulation as IgA-antigen complexes. However, the importance of biliary IgA antibodies is largely unclarified, and man lacks the capacity for effective clearance of IgA-antigen complexes via the secretory component-mediated transhepatocellular pathway; whether this deficit contributes to the propensity for man to develop IgA immune complex diseases should be clarified. Among liver diseases, alcoholic disease is most closely linked to alterations in IgA metabolism. This association is manifested principally by the deposition of IgA along the sinusoids in the livers of the majority of alcoholics and in the renal mesangium of many.(ABSTRACT TRUNCATED AT 400 WORDS)     

Changes in IgA following varying degrees of biliary obstruction in the rat

Polymeric IgA is rapidly transported from blood to bile by the rat liver. The effect of varying degrees of biliary obstruction on this transport process was studied. IgA concentrations were measured by radioimmunoassay. Serum IgA concentrations increased progressively, and IgA output in bile declined with increasing bile duct obstruction. The decline in bile IgA output was explained by both diminished bile flow and decreased concentrations of IgA in bile. Very little polymeric IgA was present in normal rat serum. In contrast, using column chromatography on Ultrogel AcA 22, increases in serum IgA associated with cholestasis were shown to be due to increments in polymeric IgA. Serum IgA was a more sensitive indicator of cholestasis than was serum alkaline phosphatase. IgA and secretory component were found, using indirect immunofluorescence, surrounding bile canaliculi and on or adjacent to the hepatocyte plasma membrane lining the sinusoids. With biliary obstruction, staining for IgA and secretory component intensified markedly near the bile canaliculi. We conclude that: (a) polymeric IgA must be efficiently removed from serum by the normal rat liver; (b) even minimal cholestasis impairs IgA output into bile, and (c) impairment of IgA transport during cholestasis appears to occur at or near the canalicular membrane.     

Effect of thermal injury on transfer of IR22 IgA myeloma protein into bile in the rat.

We previously observed a 75-90% decrease in concentration of biliary IgA after thermal injury to rat skin. Decrease in biliary IgA might result from an alteration in supply of polymeric IgA delivered to the hepatocyte or from an alteration in hepatocyte transfer of polymeric IgA into bile. In the present study, we examined the transfer of intravenously administered 125I-IgA into bile. Purified IR22 rat IgA myeloma protein consisting of both monomeric and polymeric IgA was labelled with 125I. Sprague-Dawley rats (140-180 g) received a 20-30% body surface area scald-burn or sham treatment. The bile duct was cannulated 18-24 h later and 125I-IgA preparations were injected into the tail vein. Bile was collected under light ether anesthesia for 3 h. In rats injected with 125I-IR22 IgA myeloma protein there were no significant differences in total, TCA-precipitable, or immunoprecipitable radioactivity in bile from burn-injured or sham-treated animals. On Bio-Gel A-1.5 m gel permeation, the radioactivity in bile from sham-treated animals eluted in the region of polymeric IgA as expected; the radioactivity in the bile from burn-injured animals eluted equally in the same regions as polymeric IgA and monomeric IgA. In sham-treated rats injected with isolated polymeric IgA only, bile contained primarily polymeric IgA. In burn-injured rats injected with polymeric IgA only, bile contained a mixture of polymeric IgA and monomeric IgA. These findings suggest that hepatocyte processing of polymeric IgA is altered after thermal injury, resulting in the transformation of some polymeric IgA into its monomeric form.     

Effect of thermal injury on transfer of IR22 IgA myeloma protein into bile in the rat

ABSTRACT— We previously observed a 75–90% decrease in concentration of biliary IgA after thermal injury to rat skin. Decrease in biliary IgA might result from an alteration in supply of polymeric IgA delivered to the hepatocyte or from an alteration in hepatocyte transfer of polymeric IgA into bile. In the present study, we examined the transfer of intravenously administered ¹²⁵I-IgA into bile. Purified IR22 rat IgA myeloma protein consisting of both monomeric and polymeric IgA was labelled with ¹²⁵I. Sprague-Dawley rats (140–180 g) received a 20–30% body surface area scald-burn or sham treatment. The bile duct was cannulated 18–24 h later and ¹²⁵I-IgA preparations were injected into the tail vein. Bile was collected under light ether anesthesia for 3 h. In rats injected with ¹²⁵I-IR22 IgA myeloma protein there were no significant differences in total, TCA-precipitable, or immunoprecipitable radioactivity in bile from burn-injured or sham-treated animals. On Bio-Gel A-1.5 m gel permeation, the radioactivity in bile from sham-treated animals eluted in the region of polymeric IgA as expected; the radioactivity in the bile from burn-injured animals eluted equally in the same regions as polymeric IgA and monomeric IgA. In sham-treated rats injected with isolated polymeric IgA only, bile contained primarily polymeric IgA. In burn-injured rats injected with polymeric IgA only, bile contained a mixture of polymeric IgA and monomeric IgA. These findings suggest that hepatocyte processing of polymeric IgA is altered after thermal injury, resulting in the transformation of some polymeric IgA into its monomeric form.     

An immunofluorescent study of the distribution of immunoglobulin-containing cells in the normal and the inflamed human gall bladder

Immunoglobulin-containing cells are present in the normal human gall bladder but they are much less numerous in this site than in the normal intestine. IgA-containing cells predominate in the mucosa but in the muscle layer IgM cells are the more numerous. In both acute and chronic inflammation of the gall bladder there is a marked increase in the number of immunoglobulin-containing cells. In all but the most severe cases of inflammation it is those cells containing IgA which show the greatest increase in numbers, but in severe cases there is a disproportionate rise in the number of IgG- and IgM-containing cells, these latter being possibly derived from the blood. IgA cannot be demonstrated in the epithelial cells of the gall bladder and positive evidence of secretion into the bile of locally produced immunoglobulin is lacking.It is suggested that the concentration of IgA normally present in bile is such that, irrespective of local production, some is derived from the serum or the intestine.     

Biliary transport of IgA: role of secretory component.

Biliary transport of rat immunoglobulin was studied by perfusion of isolated rat liver with blood containing radiolabeled immunoglobulin. Transport to bile was selective for polymeric IgA. Between 15 and 27% of polymeric IgA was transported from blood to bile during a 210-min perfusion period, and approximately 60% of the IgA transported to bile bore secretory component. Small quantities of IgM (0.12%) were transported; transport of IgG2 alpha, IgE, or monomeric IgA was not detected. Purification of radiolabeled polymeric IgA by affinity chromatography on human secretory component-Sepharose yielded a fraction that was transported more efficiently (i.e., up to 40% transported). In contrast, secretory IgA (colostral or biliary) was transported 1/25th to 1/12th as well as polymeric IgA myeloma protein. Complexes of 125I-labeled secretory component and polymeric IgA formed in vitro were transported poorly (0.1%) compared to polymeric IgA (26%). It was concluded that biliary transport of polymeric IgA requires combination of it with secretory component in the liver. In support of this hypothesis, rabbit IgG anti-rat secretory component antibodies were also transported to bile but normal rabbit IgG was not.     

The effect of bile duct obstruction on the clearance of circulating IgA immune complexes

The clearance of circulating IgA immune complexes following acute bile duct obstruction was investigated in this study. IgA immune complexes were formed in vitro from MOPC-315, an IgA M-component with anti-dinitrophenyl (DNP) specificity, and 125I-DNP10 bovine serum albumin (BSA). Eighteen hours after laparotomy during which the common bile duct was either identified only or identified and ligated, the IgA immune complexes were injected intravenously. Groups of bile duct-ligated and bile duct-patent rats were also injected intravenously with IgG anti-DNP-125I-DNP10BSA immune complexes and 125I-bovine liver beta-glucuronidase to assess the hepatic clearance of materials not dependent on an intact biliary system. Clearance of IgA immune complexes was delayed after bile duct ligation. Although the clearance of IgA immune complexes was delayed, only 10% of these complexes remained in the circulation at 3 hr. The clearance of IgG immune complexes and beta-glucuronidase was not affected by ligation. These experiments demonstrate the physiologic importance of a patent bile duct in the normal clearance of IgA immune complexes in the rat. The observation that clearance is delayed, but not completely inhibited by bile duct ligation suggests that alternate mechanisms exist for removing IgA immune complexes from the circulation.     

Is hepatitis B virus (HBV) the pathogenic antigen of IgA nephropathy

IgA nephropathy (IgA N) is one of the commonest glomerular diseases in China, where HBV carrier is not rare. In order to know whether HBsAg or HBcAg may induce IgA N, 105 cases of IgA N from most parts of China were studied. 8 of them were associated with HBs antigenemia. Neither HBsAg or HBcAg could be detected in the glomeruli of these 8 patients with and of 30 patients without HBs antigenemia by PAP method. IgA type anti HBc antibody was also negative in the serum of 21 cases of IgA N regardless of presence of absence of HBs antigenemia. It is concluded that HBsAg or HBcAg could not be confirmed to be pathogenic antigen of IgA N in our series.     

Selective immunoglobulin A deficiency associated with primary biliary cirrhosis in a family with liver disease

A family is described in which multiple members are afflicted with liver disease and primary biliary cirrhosis (PBC). In the third generation, one member died of PBC, and a second individual has both symptomatic PBC and selective immunoglobulin A (IgA) deficiency, an association not previously reported. By culturing this patient's lymphocytes in vitro it was shown that the IgA deficiency was due to a failure of B cells to secrete IgA. Two other siblings of this patient have multiple serum biochemical and serologic abnormalities that are sometimes associated with PBC, but they do not have histopathologically overt PBC or IgA deficiency. All three surviving family members have a diminished autologous mixed lymphocyte reaction, an immunologic abnormality that has previously been found in patients with PBC, selective IgA deficiency, and several autoimmune diseases. As there is an association between selective IgA deficiency and certain autoimmune diseases, it is possible that this immunodeficiency contributed to the development of PBC in the patient in whom the two diseases coexisted. Furthermore, the occurrence of PBC in a patient with selective IgA deficiency indicates that the pathogenesis of PBC does not require IgA-dependent immune mechanisms.     

Mucosal immunity and primary biliary cirrhosis: presence of antimitochondrial antibodies in urine

We have shown that IgA-class antimitochondrial autoantibodies (AMA) can be detected in the bile and saliva of patients with PBC, suggesting that AMA are secreted into the luminal fluid across bile ducts and salivary glands. These data prompted us to determine whether AMA of the IgA isotype may be transported across other epithelial mucosa. Therefore, we tested for the presence of AMA in the urine specimens of 83 patients with PBC and 58 non-PBC controls including healthy individuals and patients with other liver diseases. Patients enrolled in this study had no history of renal disease, and we confirmed there was less than 50 microgram/mL of protein in each of the urine specimens. Interestingly, we found that AMA were present in the urine of 71/83 (86%) of all patients with PBC and in 71/78 (91%) of patients with PBC that were serum AMA positive. In contrast, AMA were not detected in any of the 58 control urine specimens. Of particular interest, AMA of the IgA isotype was present in 57/83 (69%) of patients with PBC, and in 52 of these 57, we found secretory-type IgA. In a nested random subgroup of urine samples, the prevalence of the IgA2 AMA was 6/18 (33%), significantly lower than in matched serum samples, 13/16 (81%, P =.007). These data show that AMA of the IgA isotype is secreted into urine from the uroepithelium of patients with PBC, and support the thesis that PBC originated from either a mucosal challenge or a loss of mucosal tolerance.