Serum immunoglobulin levels and the risk of bladder cancer in the AMORIS Cohort

BackgroundThe anti-tumour T-cell response in bladder cancer has been shown to correlate with response to treatment and prognosis. However, little is known about the role of humoral immunity in this highly immunogenic human cancer, which is characterised by a high mutation-associated neoantigen load and a strong response to immunotherapy. In the present study, we interrogated the Swedish Apolipoprotein Mortality Risk Study (AMORIS) to explore the relationship between pre-diagnostic serum immunoglobulin levels and the risk of developing bladder cancer.MethodsOur analysis included all AMORIS participants aged 20 years or older, who had all three major serum immunoglobulins (IgA, IgM, IgG) recorded at the same baseline measurement (n = 29,876). All participants were free from bladder cancer at the time of measurement. Samples were obtained between 1985–1996, with follow-up information until 2011. Multivariate Cox proportional hazards regression was used to investigate the association between bladder cancer risk and different levels of pre-diagnostic serum immunoglobulins.ResultsDuring a mean follow-up period of 15.31 years, 163 (0.5%) individuals were diagnosed with bladder cancer. Multivariate Cox regression showed an inverse association between pre-diagnostic serum IgM levels ≥ 1.4 g/L and bladder cancer risk compared to serum IgM levels < 1.4 g/L [HR: 0.68 (95% CI 0.45–1.03)]. Corresponding associations could not be established for serum IgA or IgG.ConclusionOur findings implicate serum IgM in the pathogenesis of bladder cancer and suggest that the concept of humoral immune surveillance against cancer warrants further mechanistic investigation.     

Age-related changes of immunoglobulin levels in African green monkeys (Cercopithecus aethiops)

Serum IgG, IgA, and IgM levels were measured in domestically bred African green monkeys (Cercopithecus aethiops) ranging in age from 0 day to 49 months as well as in adult (5 years or older) animals of wild origin. Transplacental transfer of IgG was observed. IgG, IgA, and IgM levels increased with increasing age except for a temporal decrease of IgG level in the first month of life.     

Multi-isotype Glycoproteomic Characterization of Serum Antibody Heavy Chains Reveals Isotype- and Subclass-Specific N-Glycosylation Profiles

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Highlights

• •nLC-MS/MS method to analyze immunoglobulin (Ig) N-glycopeptides from human serum.
• •Multi-isotype, site-specific characterization of immunoglobulin N-glycosylation.
• •IgA2 sequence and glycosylation-site variant analyses.
• •Platform to define disease-specific N-glycan signatures for different Ig isotypes.

     

The role of oxygen radicals in immune complex injury

In this review we will summarize our current understanding of the mediation of immune complex induced tissue injury. Comparisons will be made between the mediation of IgG versus IgA immune complex injury with emphasis on the role that reactive oxygen products derived from leukocytic phagocytic cells play in the initiation of the tissue injury.     

Fugu immunoglobulin D: a highly unusual gene with unprecedented duplications in its constant region

We have isolated and characterized the cDNA that encodes IgD of fugu (Takifugu rubripes). Though the splicing of 1 with the 1 domain was similar to those reported for teleost IgDs, highly unusual and unprecedented domain duplications were found in the constant region of the fugu IgD. The structure of the fugu IgD is like VDJ-1-(1-2-3-4-5-6)₂-7-m1-m2. Genomic sequence analysis of the fugu IgD gene supported the results of cDNA sequencing that the first six domains in the constant region are duplicated. Such a novel duplication pattern has not been reported in any other vertebrates. However, IgD secretory domains could not be identified in this study. The deduced amino acid sequence of the fugu IgD constant region showed high identity (35–55%) to the sequences of previously reported teleost IgDs. Gene expression analyses based on RT-PCR demonstrated that the IgD gene is preferentially expressed in presumptive lymphoid tissues; moreover, in situ hybridization showed that IgD-positive cells are distributed throughout the spleen and head kidney. The expression pattern is similar to that of IgM, corroborating the hypothesis that IgD plays an important role in the humoral immune system of this species.The nucleotide sequence data reported in this paper will appear in the DDBJ/EMBL/GenBank nucleotide sequence databases with the accession numbers AB159481 and AB159482.     

IgY: a key isotype in antibody evolution

Immunoglobulin Y (IgY) is central to our understanding of immunoglobulin evolution. It has links to antibodies from the ancestral IgM to the mucosal IgX and IgA, as well as to mammalian serum IgG and IgE. IgY is found in amphibians, birds and reptiles, and as their most abundant serum antibody, is orthologous to mammalian IgG. However, IgY has the same domain architecture as IgM and IgE, lacking a hinge region and comprising four heavy‐chain constant domains. The relationship between IgY and the mucosal antibodies IgX and IgA is discussed herein, in particular the question of how IgA could have contributed to the emergence of IgY. Although IgY does not contain a hinge region, amphibian IgF and duck‐billed platypus IgY/O, which are closely related to IgY, do contain this region, as does mammalian IgG, IgA and IgD. A hinge region must therefore have evolved at least three times independently by convergent evolution. In the absence of three‐dimensional structural information for the complete Fc fragment of chicken IgY (IgY‐Fc), it remains to be discovered whether IgY displays the same conformational properties as IgM and IgE, which exhibit substantial flexibility in their Fc regions. IgY has three characterised Fc receptors, chicken Ig‐like receptor AB1 (CHIR‐AB1), the chicken yolk sac IgY receptor (FcRY) and Gallus gallus Fc receptor (ggFcR). These receptors bind to IgY at sites that are structurally homologous to mammalian counterparts; IgA/FcαRI for CHIR‐AB1, IgG/FcRn for FcRY and IgE/Fc?RI and IgG/FcγR for ggFcR. These resemblances reflect the close evolutionary relationships between IgY and IgA, IgG and IgE. However, the evolutionary distance between birds and mammals allows for the ready generation of IgY antibodies to conserved mammalian proteins for medical and biotechnological applications. Furthermore, the lack of reactivity of IgY with mammalian Fc receptors, and the fact that large quantities of IgY can be made quickly and cheaply in chicken eggs, offers important advantages and considerable potential for IgY in research, diagnostics and therapeutics.     

Immunomodulatory effect of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in allergic conditions in vitro and in vivo

Cytotechnology - We found that strawberry extract suppressed immunoglobulin (Ig) E production in vitro and in vivo, and identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as one of the IgE...     

Echinococcus multilocularis: Immunoglobulin and antibody response in C57BL6J mice

Each of 50 male C57BL/6J mice was infected intraperitoneally with 50 cysts of Echinococcus multilocularis. At 2, 4, 6, 8, and 14 weeks after infection, 10 mice were sacrificed, their larval cyst masses weighed, and their sera collected. Each serum sample from uninfected control and infected mice was adsorbed twice with two batches of E. multilocularis antigen conjugated to Sepharose beads. The concentrations of IgG1, IgG2a, IgG2b, IgM, and IgA in unadsorbed and IgG1, IgG2b, and IgM in adsorbed sera were quantified by the radial immunodiffusion technique. Hydatid mice produced increasingly large amounts of IgG1 and IgM; small measurable increases of IgG2b and no significant increases of IgG2a and IgA were observed during the course of infection. During the rapid growth phase of the cysts (6 to 14 weeks) IgG1 antibodies were found to range from 86 to 93% and IgM antibodies from 17 to 33% of the total IgG1 and IgM. However, the actual protein concentrations of IgM antibodies (761 and 1215 mg/dl) were higher than the sum of the protein concentrations of IgG1 and IgG2b antibodies (411 and 779 mg/dl). The significance of the relative concentrations of IgM, IgG1, IgG2a, and IgG2b antibodies is discussed with reference to their effectiveness in antibody-dependent cellular cytotoxicity and complement-mediated lysis in the control of alveolar hydatid disease.     

Measurement of serum levels of natalizumab, an immunoglobulin G4 therapeutic monoclonal antibody

Human immunoglobulin G4 (IgG4) is a poor trigger of effector functions and, therefore, is the preferred subclass for therapeutic monoclonal antibodies that merely aim to block their in vivo targets. An example is natalizumab, a recombinant IgG4 antibody directed against α4-integrin and used for treatment of multiple sclerosis. Efficient treatment requires that the pharmacokinetics of therapeutic monoclonal antibodies can be accurately monitored. For natalizumab, this requires special precautions due to recently reported structural peculiarities of human IgG4. Here we describe the development of an assay to determine serum levels of natalizumab. Compared with other IgG subclasses, human IgG4 possesses unique structural properties that influence its interactions in both in vivo and in vitro settings. Thus, IgG4 undergoes Fab arm exchange in vivo, resulting in effectively monovalent antibodies. Furthermore, IgG4 is able to bind to other human and nonhuman IgG via Fc interactions. We demonstrate how these features can interfere with measurement of specific IgG4 and describe how we addressed these issues, resulting in an assay that is not sensitive to Fab arm exchange by natalizumab or to IgG4 Fc interactions.     

Herpes Simplex Virus-Specific IgM,IgA and IgG Subclass Antibody Responses in Primary and Nonprimary Genital Herpes Patients

To clarify the humoral immunity in herpes simplex virus (HSV) infection, HSV-specific IgM, IgA and IgG subclass antibody responses were studied in patients with genital herpes: 17 primary, 13 recurrent and 6 nonprimary first episode. A total of 181 serum samples serially collected from the patients, 5 per patient until 213 days after the onset of disease (on average), were analyzed by an enzyme-linked immunosorbent assay. IgGl, IgG3 and IgA were detected in all patients with primary and nonprimary infections, whereas IgG4 was detected in 74% of only those with nonprimary infections and IgG2 was detected in none. IgM was detected in 100% of the patients with primary infections, but also in 68% of those with nonprimary infections. IgA showed a peak similar to that of IgM in patients with primary infections. No significant difference was observed in the detection rate or pattern of antibody responses between the recurrent and nonprimary first episode infections, nor between the HSV-1 and HSV-2 infections. These findings may be useful to improve the diagnostic potential of HSV serology.     

Immunologic aspects of human colostrum and milk—A misinterpretation

Interpretations of the demographic impact of Western diseases are frequently clouded by a failure to appreciate the complex nature of immune responses. It is commonly assumed that epidemic diseases are generally characterized by both transplacental and lacteal transmission of maternal antibodies. This is not, however, the case for viral diseases, such as measles, smallpox, and influenza–-all of which reached epidemic proportions during the post-Columbian era. In this paper I review the nature of the immune response for viral diseases, with emphasis upon measles, a disease that contributed heavily to the demise of native peoples. © 1994 Wiley-Liss, Inc.     

严重急性呼吸综合征(SARS)病人血清抗体水平的初步探讨

为了了解严重急性呼吸综合征(SARS)病人血清中的抗体产生规律,对56份病人血清和36份健康人血清,分别采用间接酶联免疫吸附试验(EIA)检测IgG抗体和捕获法检测IgM抗体。结果显示：56份病人血清中有48份IgG抗体阳性,7份IgM抗体阳性。     

Gene conversion in human rearranged immunoglobulin genes

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V(H) segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V(H) replacements with no addition of untemplated nucleotides at the V(H)-V(H) joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V(H) replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion.     

The first report on immunoglobulins A,E, G and M levels in cystic fibrosis patients in Saudi Arabia

BackgroundPrevious reports have shown that pulmonary and systemic hypergamma-globulinemia in CF patients is a reflection of chronic pulmonary infection. Infection with Pseudomonas aeruginosa is known to have major prognostic significance in patients CF. This study aims to identify the incidence of immunoglobulins (especially: IgG, and IgE) in a cohort of CF patients.MethodsA total of 297 patients recruited all over the country’s region for this study were a as part of the CF registry data from 1st January 1984 to 1st June 2016. All patients had their immunoglobulin levels measured by enzyme link immunosorbent assay (ELISA) in 3 stages, at presentation and two follow-ups.ResultsOf the 297 patients recruited, 139 (46.8%) were males while 158 (53.2%) were females. IgA and IgM levels were found not to have risen above the previously reported levels in healthy individuals in all stages. On the contrary, IgE level increased from 209.51 ± 32.30 KU/L to 303.58 ± 37.11 KU/L from baseline to stage 3 while IgG level rose from 12.26 ± 0.43 mg/mL to 17.17 ± 1.68 mg/mL for baseline and stage 3 respectively all above previously reported levels in healthy individuals.ConclusionThis study establishes a potential for the use of IgE and IgG in disease diagnosis as well as the prognostic implications. However, further study is needed to identify the role of infection or medications in relation to the rise of both IgE and IgG with advancement of age and progression of disease severity which may inherently confound the observed results.     

Structural changes of immunoglobulin G oligosaccharides with age in healthy human serum

Age-related changes of IgG N-linked oligosaccharides isolated from normal human serum are reported for 403 individuals (male 227 and female 176), varying in age from 0 to 85 years. The IgG N-linked oligosaccharides were released from the protein by digestion with a glycoamidase and reductively aminated with the fluorescent reagent, 2-aminopyridine. The mixture of pyridylaminated oligosaccharides was separated at high resolution by HPLC using a reverse-phase column. From the results of neutral oligosaccharide analysis, agalactosyl glycoform and bisecting GlcNAc-containing glycoform were shown to increase with increasing age. Spearman's correlation coefficients were 0.503 and 0.473, respectively. Thus, in healthy people, an increase of both types of glycoforms correlates weakly with age. In addition, differences were demonstrated between male and female groups in their twenties. The quantity of agalactosyl glycoform was found to be lower in females than in males. No significant differences, however, were observed in the quantity of bisecting GlcNAc-containing glycoforms between males and females. Abbreviations: Gal, D-galactose: GlcNAc, N-acetyl-D-glucosamine; Man, D-mannose; Fc, C-terminal half of the heavy chain dimers of IgG; HPLC, high-performance liquid chromatography; IgG, immunoglobulin G; ODS, octadecylsilyl; PA, pyridylamino This revised version was published online in November 2006 with corrections to the Cover Date.     

A simultaneous electrochemical impedance and quartz crystal microbalance study on antihuman immunoglobulin G adsorption and human immunoglobulin G reaction

The quartz crystal microbalance (QCM), in combination with electrochemical impedance spectroscopy (EIS), has been utilized to monitor in situ antihuman IgG (hIgG) adsorption on bare poly(o-phenylenediamine) (PPD)- and 1-dodecanethiol (C12SH)-modified Au electrodes and succeeding human IgG reaction, respectively. The resonant frequency (f) and the motional resistance (R(1)) of the piezoelectric quartz crystal (PQC) as well as electrochemical impedance (EI) parameters were measured and discussed. The standard heterogeneous rate constants of the ferricyanide/ferrocyanide couple before and after the antibody adsorption and antibody-antigen reactions were determined. The results show that the amount for antibody adsorption was the greatest on the most hydrophobic (1-dodecanethiol-modified) surface, while the antibody bioactivity was almost identical on the three kinds of surfaces. Two parameters simultaneously obtained, Deltaf and DeltaC(s) (interfacial capacitance), have been used for the first time to estimate both the association constant of the immunoreaction and the valence of antigen with satisfactory results. The proposed method may find wide application in interfacial biochemistry studies for its advantages in providing real-time multidimensional piezoelectric and electrochemical impedance information.     

Effects of bile acids and lectins on immunoglobulin production in rat mesenteric lymph node lymphocytes

Summary We investigated the effect of bile acids either alone or in combination with lectins on immunoglobulin (Ig) production in vitro of rat mesenteric lymph node (MLN) lymphocytes to examine their immunoregulatory activities. Among free bile acids examined, chenodeoxycholic acid stimulated IgE production by MLN lymphocytes and inhibited IgA production at the concentration of 0.3 mM, whereas cholic and deoxycholic acids exerted the comparable effect at 3 mM. Among conjugated bile acids, deoxycholic acid derivatives stimulated IgE production more strongly than cholic acid derivatives. On the other hand, free and conjugated bile acids did not affect IgG production. The IgE production by MLN lymphocytes was stimulated by concanavalin A and inhibited by pokeweed mitogen, and the effect of phytohemmagglutinin and lipopolysaccharide was marginal. These lectins did not affect IgA and IgG production by the lymphocytes. In the presence of lectins, free bile acids affected IgE production at 0.03 mM. These results suggest the possibility that bile acid is a stimulant for food allergy.