Selective transport of polymeric immunoglobulin A in bile. Quantitative relationships of monomeric and polymeric immunoglobulin A, immunoglobulin M, and other proteins in serum, bile, and saliva.

In 17 adults, serum, hepatic bile, and saliva samples were analyzed for their sedimentation profile of IgA and secretory component (SC), and for their concentrations of albumin, orosomucoid, transferrin, IgG, IgA, alpha 2-macroglobulin (alpha 2M), IgM, and SC. Polymeric IgA(p-IgA) averaged 13% (50-700 micrograms/ml) of total IgA in serum, 70% (43-88%) in bile, and 93% (74-98%) in saliva. Most of the p-IgA in bile sedimented with SC, which also occurred free (8-44%), and with IgM. In bile, albumin (155-1,485 micrograms/ml) was the predominant protein, followed by IgG (32-480 micrograms/ml), and total IgA (37-209 micrograms/ml). In saliva, p-IgA (72-902 micrograms/ml) predominated, followed by albumin (16-385 micrograms/ml) and IgG (9-178 micrograms/ml). Secretion-to-serum albumin-relative concentration ratios (S/S-ARCR = 1 for albumin) in bile averaged 22 for p-IgA, 1.91 for IgM, 1.28 for monomeric IgA (m-IgA), 0.70 for IgG, and 0.57 for alpha 2M, indicating for p-IgA, IgM, and to a lesser extent for m-IgA, a selective excretion into bile. In saliva, a 16-fold greater selective excretion of p-IgA (mean S/S-ARCR = 354) was found. Labeled m- and p-IgA were injected intravenously into five patients. Specific activities indicated that for p-IgA 50% was serum derived in bile, as compared with 2% in saliva, and to 85% for m-IgA in bile. In the patient with the highest excretion of 125I-p-IgA in bile, only 2.8% of the injected dose was recovered in bile within 24 h after injection. Compared with rats and rabbits, the serum-to-bile transport of p-IgA in humans is much smaller.     

Secretion of immunoglobulins and plasma proteins from the jejunal mucosa. Transport rate and origin of polymeric immunoglobulin A.

Parameters of secretion of IgA and several other plasma proteins from the jejunal mucosa were investigated in 11 individuals who had a normal distribution of Ig-containing cells in the lamina propria and in one patient who was totally deficient in jejunal IgA and IgM plasmacytes. Jejunal samples were collected during segmental gut perfusion. The following results were obtained: (a) The secretion of polymeric IgA (p-IgA, mean equals 217 micrograms/40 cm per min) exceeded those of albumin (132 micrograms), IgG (35 micrograms), and monomeric IgA (m-IgA, 15 micrograms, or 6.4% of total IgA). About 35% of IgA was IgA2 in the jejunal secretion, compared with approximately 23% in serum. This closely corresponds to the 35 and 24% of IgA2 plasmocytes in jejunal mucosa and peripheral lymph nodes, respectively. (b) For each protein, a relative coefficient of excretion (RCE) was calculated (jejunum to serum concentration ratio expressed relative to that of albumin). RCEs of 1.41 for orosomucoid, 1.0 for albumin, 0.83 for IgG, and 0.74 for IgE and, in the deficient patient, of 0.64 for m-IgA and 0.016 for IgM were obtained. This was inversely related to the molecular weight of these proteins and indicated their predominantly passive transport into the jejunum. However, in normal individuals, the RCE of transferrin (approximately 1.11 greater than 1, P greater than 0.05), alpha 2-macro globulin (approximately 0.77), m-IgA (approximately 1.98), and p-IgA (approximately 218) exceeded the value expected from simple seepage from plasma, thus pointing to an additional role of either local gut synthesis and/or active transepithelial transport. (c) Approximately 98% of p-IgA, approximately 99% of IgM, and approximately 68% of m-IgA in jejunal secretions were derived from local production in the gut wall, as determined by 125I-p-IgA specific activities and/or by comparison between the RCE values of the deficient patient to the values of controls. Therefore, the jejunal production of p-IgA (approximately 312 mg/d per 40 cm vs. approximately 54 mg/d from bile) contributes the majority of upper intestinal IgA in humans. The active transport of plasma p-IgA across the intestinal mucosa (approximately 0.08 mg/40 cm per kg per d) contributes less than 2% of the total amount of p-IgA (4.5 mg/kg per d) that is cleared daily from plasma.     

High levels of secretory IgA and free secretory component in the serum of rats with bile duct obstruction

In the rat , ligation of the bile duct induces a rapid and progressive elevation of the IgA levels in serum. The increase is about 4-fold at 1 h, 15-fold at 1 day, and 30-fold at 1 wk after ligation. The additional IgA is of the secretory type. Free secretory component also appears in serum after bile duct obstruction; it does not continue to increase and occasionally disappears from serum after prolonged ligation. The increase in serum IgA levels is selective. These changes are totally reversible if the bile duct is reopened at 1 day after ligature. These findings confirm the role of the rat liver in the transfer of circulating IgA into the bile.     

The serum immunoglobulin levels in Down's syndrome and other diseases associated with mental disorder.

The serum levels of IgA, IgM, IgG and IgD were determined in patients with Down's syndrome (69 cases), Oligophrenia (101 cases) and Morbus Wilson (18 cases). In sera from Down's syndrome patients a significant increase in the levels of IgA, IgG and IgD were found. IgM levels were identical to those of healthy controls. The immunoglobulin levels in both the oligophrenia and Wilson's disease patients were not different from those of controls.     

兔胆红素钙结石成石过程中免疫复合物存在的意义

对正常对照组，胆道单纯不全梗阻组和胆道不全梗阻加感染组兔的血清和胆汁中免疫复合物进行了动态对比研究，结果发现ＢＯ组和ＢＯＩ组早期血清和胆汁中均未见ＩＣ的存在，随着成石率的逐步增加，ＩＣ的阳性率明显增高（Ｐ〈０．０５）。结果提示：在色素石形成过程中血清、胆囊和胆管胆汁均有ＩＣ的存在，为特异性抗原与Ｉｇ结合所致，ＩＣ的存在不是致石的直接原因，但促进了结石的形成。     

Rapid active transport of immunoglobulin A from blood to bile

Immunoglobulins were isolated from the serum or ascitic fluid of Lou/Wsl rats bearing plasmacytomas and labeled with 125I. When labeled IgA was injected i.v. it disappeared from the blood serum much more rapidly than IgG2 so that after 3 h less than 10% remained. This rapid disappearance of the injected IgA was not seen in rats with ligated bile ducts. In rats with cannulated bile ducts, the labeled IgA appeared rapidly in the bile so that 25% of the injected dose was recovered in 3 h; at the peak of this biliary excretion the specific radioactivity of the bile (cpm/milligram protein) was about 200 times greater than that of the blood serum. Thus much of the IgA which finds its way into the blood is rapidly and actively transported across the liver so that it enters the gut lumen via the biliary tract.     

The serum activities of AP, gamma-GT, GLDH, GPT and CHE after complete biliary obstruction and choledochocaval fistula in the rat

The activities in serum of alkaline phosphatase, gamma-glutamyltransferase, glutamate dehydrogenase, glutamic pyruvic transaminase and cholinesterase were compared after complete biliary obstruction (CBO) and choledochocaval fistula (CCF) in the rat. CCF was used as a model of complete biliary retention without bile stasis and without increased pressure in the biliary tract. The increases in AP, GLDH and gamma-GT within 24-h post-op. show no difference between the two experimental groups. The conclusion is that the retention of biliary constituents alone is responsible for the increase in the levels of serum activity and that other conditions like bile stasis and increased pressure in the biliary tract do not play an important role in the pathogenesis of these alterations. The rise of GPT activity in CCF is of a lesser degree than in CBO.     

Hypersialylated macromolecular serum immunoglobulin A1 in type 2 diabetes mellitus

OBJECTIVES: The origin of the elevation of serum immunoglobulin A1 (IgA1) in Type 2 diabetes mellitus (DM) is unsettled. The aim of this study was to address the carbohydrate changes of serum IgA1 from patients with Type 2 diabetes mellitus, as a possible cause of the elevation. DESIGN AND METHODS: IgA1 was purified from sera of 6 DM patients and 4 healthy matched controls by using highly acetylated-Sepharose 6B, anti-IgA-agarose, and jacalin-agarose columns, and further separated into jacalin low-affinity, medium, and high-affinity fractions. Hinge and Fc fragments from native IgA1 were obtained and analyzed by using Sambucus nigra, Maackia amurensis, Arachis hypogaea, Erythrina cristagalli, and Ricinus communis lectins. RESULTS: The jacalin high-affinity fraction, mostly constituted by macromolecular IgA1, was more abundant in DM patients than in controls and also more reactive to Sambucus nigra, and Maackia amurensis lectins. CONCLUSIONS: Macromolecular serum IgA1 from DM patients is hypersialylated and this probably contributes to the high level of IgA1 in DM patients.     

Serum secretory IgA, IgA1 and IgA2 subclasses in inflammatory bowel and chronic liver diseases

Healthy controls and patients with autoimmune chronic active hepatitis (CAH), primary biliary cirrhosis (PBC), coeliac disease (GSE), Crohn's disease (CD) and ulcerative colitis (UC) were examined for serum immunoglobulin A (IgA), secretory IgA (sIgA) and subclasses IgA1 and IgA2 concentrations separately. Elevated secretory IgA levels are found in CAH and PBC. IgA2 level as well as the proportional part of IgA2 out of the serum total IgA are significantly increased in GSE and in CD, while in UC IgA1 levels are significantly decreased as compared to controls. Serial determinations of IgA subclasses may provide a differential diagnostic tool in inflammatory bowel diseases and the findings support the view that increased sIgA levels in CAH and PBC probably have a different origin.     

Lactate dehydrogenase inhibition by immunoglobulin G in human serum

Low lactate dehydrogenase (LD; EC 1.1.1.27) activity and an abnormal LD pattern in electrophoretograms of LD isoenzymes in the sera of two patients were caused by inhibition of LD by immunoglobulin G. One of these showed inhibitor activity in the serum upon direct analysis, while the other showed activity only after the immunoglobulin was stripped from the LD. As judged from the LD isoenzyme patterns in serum, the LD inhibitor appeared to act against M subunits. However, quantification of binding affinities to each isolated isoenzyme showed that the LD inhibitor had a stronger effect on LD isoenzymes 2 and 3 (H3M1 and H2M2, respectively).     

Autoantibodies to lactate dehydrogenase in serum identified by use of immobilized protein G and immobilized jacalin, a jackfruit lectin

In this method for identifying autoantibodies to lactate dehydrogenase (anti-LDs) in serum, we used immobilized Protein G to bind IgG-complexed LD and immobilized jacalin to bind IgA-complexed LD, leaving non-complexed LD in solution. The non-complexed LD and total LD were kinetically measured. We report results as LD bound to immobilized Protein G and LD bound to immobilized jacalin. Using sera demonstrating IgG and IgA anti-LDs by immunoelectrophoresis (IEP), respectively, we optimized the method for incubation time and concentration of binding agents. We demonstrated concomitant binding of LD and greater than or equal to 98% of IgG and of LD and greater than or equal to 92% of IgA. For LD bound to immunobilized Protein G the detection limit was 10 U/L, within- and between-run CVs ranged from 2.9% to 9.1%, and values for normal sera were less than or equal to 3% of total LD. Results for LD bound to immobilized jacalin were similar. We tested 10 sera displaying aberrant LD electrophoretograms: In seven, LD bound to immobilized Protein G was increased (range: 26-99% of total LD), indicating IgG-complexed LD. This was confirmed by IEP, demonstrating IgG1,2, or IgG3 anti-LDs in these sera. In the other three sera, LD bound to immobilized jacalin was increased (range: 38-72% of total LD), indicating IgA-complexed LD. This was confirmed by IEP, demonstrating IgA anti-LDs in these sera. Evidently this method is an alternative to IEP for identifying anti-LDs in serum.     

Characteristics of the complex between alkaline phosphatase and immunoglobulin A in human serum

An abnormal band of alkaline phosphatase (ALP) activity was detected by electrophoresis in the serum of a patient with liver cirrhosis, and was shown to be a complex between ALP and immunoglobulin A (IgA) of the lambda type.

Physicochemical studies of ALP in the patient's serum showed properties of liver and bone isozymes. The patient's IgA and its F(ab')₂ fragment were prepared by column chromatography, and used in in-vitro reconstitution studies with various ALP isozymes. It was found that only the liver and bone ALP attached to the IgA, while the placental and intestinal ALP did not. The ALP was attached to the F(ab')₂ fragment of IgA. It is concluded that this complex is the result of an antibody-antigen reaction. Molecular weights of the two complexes, ALP-IgA and ALP-IgA-F(ab')₂, suggest that two molecules of monovalent ALP associated with one molecule of divalent IgA.     

Altered hepatic transport of immunoglobulin A in mice lacking the J chain

We have created J chain knockout mice to define the physiologic role of the J chain in immunoglobulin synthesis and transport. The J chain is covalently associated with pentameric immunoglobulin (Ig) M and dimeric IgA and is also expressed in most IgG-secreting cells. J chain- deficient mice have normal serum IgM and IgG levels but markedly elevated serum IgA. Although polymeric IgA was present in the mutant mice, a larger proportion of their serum IgA was monomeric than was found in wild-type mouse serum. Bile and fecal IgA levels were decreased in J chain-deficient mice compared with wild-type mice, suggesting inefficient transport of J chain-deficient IgA by hepatic polymeric immunoglobulin receptors (pIgR). The pIgR-mediated transport of serum-derived IgA from wild-type and mutant mice was assessed in Madin-Darby canine kidney (MDCK) cells transfected with the pIgR. These studies revealed selective transport by pIgR-expressing MDCK cells of wild-type IgA but not J chain-deficient IgA. We conclude that although the J chain is not required for IgA dimerization, it does affect the efficiency of polymerization or have a role in maintaining IgA dimer stability. Furthermore, the J chain is essential for efficient hepatic pIgR transport of IgA.     

病理程度不同IgA肾病患者血清代谢的差异性研究

目的寻找诊断IgA肾病潜在的生物标志物,并探讨其代谢途径。方法原发性IgA肾病患者35例(IgA肾病组),其中低危组23例,高危组12例,同期体检健康者23名为对照组,采用基于质谱核磁共振代谢组技术结合模式识别分析各组血清代谢物的差异。结果对照组与IgA肾病组血清代谢物比较差异有统计学意义(P<0.05);低危组和高危组血清代谢物比较差异无统计学意义(P>0.05);共筛选出24种IgA肾病的特征代谢物。结论应用质谱核磁共振代谢组技术成功建立了IgA肾病血清代谢诊断模型。     

Immunization of rabbits against a bacterial pathogen with an alginate microparticle vaccine.

Pasteurella multocida is an important bacterial pathogen of domestic rabbits. To evaluate the ability of a thiocyanate extract (PTE) of P. multocida to stimulate an immune response and protect against infection with P. multocida, rabbits were immunized subcutaneously or intranasally on Days 7, 21 and 35. Cholera toxin, a potent mucosal adjuvant, was included in one treatment group. Rabbits immunized subcutaneously (SC) or intranasally (IN) had significant increases in serum anti-PTE IgG but not IgA. In contrast, only rabbits immunized IN with PTE developed significant titers of nasal lavage anti-PTE IgA and cholera toxin significantly enhanced this response. In a second study rabbits were immunized via the drinking water with PTE incorporated into alginate microparticles on Days 7, 14 and 21. Mild increases in serum IgG were noted in rabbits immunized with PTE in microparticles, with or without cholera toxin, and this increase was significant (P相似文献   

Acute local inflammation alters synthesis, distribution, and catabolism of third component of complement (C3) in rabbits.

In order to evaluate the basis for changes in plasma concentrations of the third component of complement (C3) during inflammation, we injected purified radiolabeled C3 into normal New Zealand White rabbits and into rabbits with turpentine-induced pleurisy. In the normal animals, C3 was distributed between the intravascular compartment (75%) and the extravascular space (25%), with an exchange rate of 1.8 +/- 0.1% of the plasma pool per hour. The fractional catabolic rate (FCR) was 2.7 +/- 0.3% of the C3 plasma pool per hour, the synthesis rate was 1.0 +/- 0.2 mg C3/kg per h, and the plasma concentration was 1.23 +/- 0.3 mg C3/ml. Rabbits with turpentine-induced inflammation showed a shift of the volume of C3 distribution in favor of the extravascular compartment. In addition, the rate by which 125I-C3 was cleared from the circulation increased by 29% and was related to the appearance of 20% of the C3-bound circulating radioactivity in the affected pleural cavity at the zenith of inflammation. The FCR, calculated by measuring urinary excretion of radiolabel, increased by only 9% and was probably related to the C3 degradation that was observed in the pleural fluid during the early stages of inflammation. The plasma C3 concentration reached a peak at 230% of the baseline concentration, owing to an increase in the rate of synthesis by as much as 480%. The latter increase could be blocked by cycloheximide, an inhibitor of protein synthesis. We conclude that the increase of plasma C3 in the acute phase is due to stimulated synthesis, which is partially offset by a rise in FCR and by a shift of protein to the site of inflammation.     

Clinical significance of serum glutathione reductase in various clinical conditions, especially in liver diseases.

Serum glutathione reductase activity was measured in various conditions including acute hepatitis, chronic hepatitis, liver cirrhosis, malignant neoplastic diseases, and obstructive jaundice. A statistically significant elevation of the enzyme activity was found in all of these clinical conditions above normal value, especially in patients with acute hepatitis, some liver cancer, and malignant biliary obstruction. Comparison with other liver function tests showed the existence of statistically significant correlations of serum glutathione reductase with SGOT, SGPT and alkaline phosphatase in acute hepatitis, and with alkaline phosphatase in cirrhosis. In parenchymatous liver disease, serial determination was found to be important. High values in obstructive jaundice suggest the malignant obstruction.     

Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies.

Circulating immune complexes (CIC) containing IgA and C3 were elevated in 48% of IgA nephropathy patients; IgA1 was the predominant subclass. IgA1-IgG CIC were detected in 44%, IgA2-IgG CIC in 7%, and IgM-IgA1 CIC in 16% of the patients. No IgM-IgA2 CIC were detectable. Sucrose gradient ultracentrifugation indicated that IgG-IgA1 CIC were predominantly of intermediate (13-19S) size whereas IgA1-C3 CIC sedimented from 11S to 19S. At acid pH, isolated CIC revealed the presence of substantial amounts of 7S IgA. One third of the patients had elevated serum IgA rheumatoid factor (RF) of both polymeric and monomeric forms despite normal levels of IgM-RF; 87% of patients with elevated IgA-RF had IgA1-IgG CIC. These results indicate that the IgA1 component of CIC in patients with IgA nephropathy is not necessarily of mucosal origin and suggest that a portion of these CIC consists of IgA RF immunologically complexed with autologous IgG.     

Modified radioassay for measuring asialoglycoprotein in serum

Asialoglycoproteins are removed from the circulation by the carbohydrate-specific hepatic binding protein in the rat. Asialoglycoprotein in human serum can be detected by an inhibition assay in which the binding of 125I-labeled asialo-alpha 1-acid glycoprotein (ASAG) to purified hepatocyte membranes is inhibited by known amounts of ASAG or patient's serum. We were able to reproducibly measure inhibition equivalent to that of 1 to 20 ng of ASAG. The mean concentration of inhibitor in 11 healthy control patients was equivalent to 0.153 (SD = 0.051) mg of ASAG per liter, measured in 20 microL of serum. Significant increases of inhibitor were observed in patients with malignant extrahepatic biliary obstruction, alcoholic liver disease, viral hepatitis, or liver metastases, but not in those with benign biliary obstruction. For a set of six control sera the intra- and interassay CVs were 9.1% and 25.2%, respectively (n = 3 each).     

Alterations in lymphocyte subsets and serum immunoglobulin levels in patients with silicosis

The numbers of total lymphocyte and lymphocyte subsets in peripheral blood of patients with silicosis and their serum immunoglobulin (Ig) levels were studied to evaluate their immune status. The numbers of total lymphocytes and OKT4+ and OKT8+ cells tended to be decreased and the numbers of OKT3+ cells was significantly decreased (p less than 0.001), but that of OKIa-1+ cells was increased (p less than 0.001) in the patients. In the lymph nodes of the lung hilus, the ratio of OKT4+ cells to total lymphocytes was increased but that of OKT8+ cells to total lymphocytes was decreased. The serum levels of IgG and IgA were elevated in the patients with reduction in the numbers of total lymphocytes and OKT4+ cells in peripheral blood. The serum IgE levels in 17 of 82 patients were above 400 IU/ml. In 8 patients with serum IgE 82 patients were above 400 IU/ml. In 8 patients with serum IgE levels of more than 1,000 IU/ml, the numbers of total lymphocytes and OKT3+ and OKT4+ cells were decreased compared with those in controls. The following suggestions are proposed from the results: Increase and activation of helper T cells may be caused by the presentation of silica dust to macrophages in the lymph nodes, and these cells may then stimulate B cell proliferation and Ig production by B cells, resulting in increase in the serum Ig (IgG, IgA and IgE) level. Reduction in the number of OKT4+ cells helper/inducer T cells) in peripheral blood may be due to migration of helper T cells into the lymph nodes. These immunological events in patients with silicosis are probably due to the adjuvant effect of silica dust.