Antimitochondrial antibodies of immunoglobulin G3 subclass are associated with a more severe disease course in primary biliary cirrhosis
Eirini I. RigopoulouEdward T. DaviesDimitrios P. BogdanosChristos LiaskosMaria MytilinaiouGeorge Κ. KoukoulisGeorge N. DalekosDiego Vergani
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Abstract Background/Aims: Primary biliary cirrhosis (PBC) is characterised by the presence of immunoglobulin (Ig) G antimitochondrial antibodies (AMA), which are routinely detected by indirect immunofluorescence (IFL) using composite rodent tissue substrate. The IgG subclass distribution and clinical significance of IFL‐detected AMA in patients with PBC have not been previously studied in detail. Methods: We have examined IgG subclass‐specific AMA detected by IFL on rodent liver, kidney and stomach tissue substrate using affinity‐purified IgG subclass monospecific antisera as revealing reagents in 95 AMA‐positive PBC patients from Greece. Results: AMA of any of the IgG1, IgG2 or IgG3 subclasses were present in 89/95 (93.7%) patients. Among those 89, 55 (61.8%) had IgG1, 2, 3 AMA positivity; eight (9%) had IgG1, 2; seven (7.9%) had IgG2, 3; eight (9%) had IgG1, 3; nine (10.1%) had IgG1 subclass and two (2.2%) single IgG3 AMA reactivity. IgG4 AMA was absent. IgG3 titres were higher than IgG2 and IgG1 ( P <0.001) and IgG1 higher than IgG2 ( P <0.001). IgG3 AMA‐positive patients had a histologically more advanced disease ( P <0.01) and were more frequently cirrhotic compared with those who were negative ( P <0.01). There was a positive correlation between AMA IgG3 titre and Mayo risk score ( r =0.55, P =0.009, Spearman's correlation). Conclusions: Our findings suggest that AMA are not restricted to a specific IgG subclass. AMA of the IgG3 subclass are associated with a more severe disease course, possibly reflecting the peculiar ability of this isotype to engage mediators of damage.Keywords:
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Primary Biliary Cirrhosis
Immunoglobulin (Ig)M and IgG antibodies, prepared in the rabbit against the protective antigen of Pseudomonas aeruginosa P4, were compared as to their biological activities in vitro and in vivo. In vitro biological activities of these antibodies were determined by passive hemagglutination, bactericidal, and opsonophagocytic tests. Increased effectiveness of IgM over IgG on a molar basis was demonstrated in all of these tests. However, in mouse protection tests, in which the purified globulins were injected intraperitoneally 4 hr prior to challenge with P. aeruginosa suspended in hog gastric mucin, IgM anticapsular antibody was found to be less effective than IgG antibody. The exact mechanism whereby IgG antibody exerts more protective ability than IgM antibody is still unknown. We present evidence to suggest that the difference in activity between the two classes of antibody is due to the ability of the IgG antibody to enter the bloodstream more rapidly than the IgM antibody and also to the ability of IgG to diffuse rapidly through the tissues of the organs.
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Abstract Background/Aims: Primary biliary cirrhosis (PBC) is characterised by the presence of immunoglobulin (Ig) G antimitochondrial antibodies (AMA), which are routinely detected by indirect immunofluorescence (IFL) using composite rodent tissue substrate. The IgG subclass distribution and clinical significance of IFL‐detected AMA in patients with PBC have not been previously studied in detail. Methods: We have examined IgG subclass‐specific AMA detected by IFL on rodent liver, kidney and stomach tissue substrate using affinity‐purified IgG subclass monospecific antisera as revealing reagents in 95 AMA‐positive PBC patients from Greece. Results: AMA of any of the IgG1, IgG2 or IgG3 subclasses were present in 89/95 (93.7%) patients. Among those 89, 55 (61.8%) had IgG1, 2, 3 AMA positivity; eight (9%) had IgG1, 2; seven (7.9%) had IgG2, 3; eight (9%) had IgG1, 3; nine (10.1%) had IgG1 subclass and two (2.2%) single IgG3 AMA reactivity. IgG4 AMA was absent. IgG3 titres were higher than IgG2 and IgG1 ( P <0.001) and IgG1 higher than IgG2 ( P <0.001). IgG3 AMA‐positive patients had a histologically more advanced disease ( P <0.01) and were more frequently cirrhotic compared with those who were negative ( P <0.01). There was a positive correlation between AMA IgG3 titre and Mayo risk score ( r =0.55, P =0.009, Spearman's correlation). Conclusions: Our findings suggest that AMA are not restricted to a specific IgG subclass. AMA of the IgG3 subclass are associated with a more severe disease course, possibly reflecting the peculiar ability of this isotype to engage mediators of damage.
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The IgG subclass distribution of anti Rh antibodies (anti-D, 'anti-Du', anti-c, anti-E), anti-Kell and anti-Duffy (anti-Fya) antibodies was measured by two haemagglutination techniques on microtitre plates. The first technique involved rabbit subclass specific antisera which were used to agglutinate red cells previously reacted with the patients' antibodies at high concentration. The second, which was more sensitive, had an additional step by introducing sheep anti-rabbit antibodies (sandwich technique). By the sensitive sandwich technique we revealed, for anti-D antibodies: IgG1 8/19, IgG3 1/19, IgG1/IgG3 8/19, IgG1/IgG2/IgG3/IgG 41/19, IgG1/IgG4 1/19; for the Du reactive anti-D antibodies: IgG1 1/8, IgG1/IgG3 1/8, IgG1/IgG3/IgG4 6/8; for the anti-E antibodies: IgG1/IgG2/IgG4 2/3, IgG1/IgG2/IgG3/IgG4 1/3; for the anti-c antibodies: IgG1 2/5, IgG3 1/5, IgG1/IgG3 1/5; for the anti-Kell antibodies: IgG1 9/20, IgG1/IgG3 1/20, IgG1/IgG4 8/20, IgG1/IgG3/IgG4 2/20; and for anti-Duffy antibodies: IgG1 1/8, IgG1/IgG4 7/8. These results are partly at variance with previously published results.
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Abstract Anti‐GM1 immunoglobulin G (IgG) antibodies are frequently present in sera from patients with Guillain–Barré syndrome (GBS). A previous report on a patient who had a neuropathy with immunoglobulin M (IgM) M‐protein binding to a conformational epitope formed by phosphatidic acid (PA) and gangliosides prompted us to investigate the binding of IgG antibodies in GBS sera to a mixture of GM1 and PA (GM1/PA). Of 121 GBS patients, 32 had anti‐GM1 IgG antibodies. All 32 also had antibody activity against GM1/PA. Twenty‐five (78%) of 32 patients had greater activity against GM1/PA than against GM1 alone. Twelve patients who had no anti‐GM1 IgG antibodies had IgG antibody activity against GM1/PA. No GBS patient had IgG antibody against PA alone. In contrast, two rabbit anti‐GM1 antisera had greater activity against GM1 alone than against GM1/PA. IgG antibody with greater binding activity against a mixture of GM1 and a phospholipid than against GM1 alone may have an important role in the pathogenesis of GBS and has implications for diagnosis. Muscle Nerve 27: 302–306, 2003
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Serum obtained from normal human subjects contains antibodies reactive in an enzyme-linked immunosorbent assay with the glucuronoxylomannan (GXM) of Cryptococcus neoformans. The frequency of occurrence of class-specific antibodies among normal subjects was 28% for immunoglobulin G (IgG), 98% for IgM, and 3% for IgA. Anti-GXM antibodies with kappa light chains occurred in 98% of normal subjects, while the occurrence of lambda light chains was 28%. Each of five subjects with high levels of anti-GXM IgG antibodies had readily detectable antibodies of the IgG2 isotype; two of the five subjects had readily detectable IgG1 antibody. An examination of sera from human immunodeficiency virus-infected patients showed that human immunodeficiency virus infection was accompanied by a significant decrease in the occurrence of IgM antibodies and anti-GXM antibodies with kappa light chains; these decreases occurred early in infection when CD4 counts were still > or = 500 cells per microliter. A slight but not statistically significant decrease in the occurrence of anti-GXM IgG antibodies was seen only in patients with CD4 levels of < 200 cells per microliter. Sera from normal subjects with high levels of anti-GXM IgG antibodies were examined to identify any contribution of the antibodies to complement activation or to opsonization of the yeast cells. An analysis of the kinetics for activation and binding of C3 to the yeast cell showed no pattern of quantitative or qualitative differences between sera with high or low levels of anti-GXM IgG antibodies. Phagocytosis studies showed that the naturally occurring IgG antibodies did not contribute to opsonization of the yeast cells.
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Immunoglobulin G subclass measurements are important for the diagnostic work-up of immunodeficiencies and immunoglobulin G4 (IgG4) related diseases. It is currently unknown whether a single sampling is truly representative for an individual's IgG subclass concentrations. This study aimed to investigate whether IgG and IgG subclass concentrations in healthy individuals are stable over time.With a span of median 42 weeks, four samples from each of 54 (34M, 20F) healthy adult volunteers (24-66 years) were analyzed for IgG and IgG1-4 using turbidimetry. Concentrations were compared within and between individuals.IgG and IgG subclass concentrations followed either a normal (IgG, IgG1, and IgG3) or log normal (IgG2 and IgG4) distribution. Immunoglobulin 4 demonstrated by far the widest range of concentrations between individuals (670-fold: 0.004-2.68 g/L). Immunoglobulin G subclass variations within individuals were expressed as pooled standard deviations (PSD). These ranged from 0.056 (IgG4) to 0.955 g/L (IgG) and correlated with mean concentration of IgG or the particular IgG subclass. As a consequence, the relative PSDs (i.e., PSD divided by mean IgG or IgG subclass concentration) fell within a narrow range: 5.82%-10.1%. Based on these numbers, the 95%-upper one-sided confidence limits for intraindividual IgG and IgG subclass variation was calculated to range from 9.82% (IgG2) to 16.9% (IgG4).The study documents that IgG or IgG subclass concentrations within healthy individuals are very stable over at least 42 weeks. The expected variation for IgG4 concentrations at a 95% confidence level does not exceed ±16.9%.
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Immunoglobulin replacement therapy appears to benefit some patients who have IgG subclass deficiencies. Because some patients with subnormal trough concentrations of IgG subclasses remain well, because other patients who have borderline/low normal concentrations of an IgG subclass are abnormally infection-prone and helped by immunoglobulin therapy and because infection proneness in individual patients does not always appear to parallel their IgG subclass concentrations, it is evident that IgG subclass concentrations, while a helpful guide, are not an absolute determinant of the need for immunoglobulin replacement therapy in infection-prone patients. Low IgG subclass concentrations may indicate impaired ability to produce certain "specific" antibodies and antibody replacement is likely to be the crucial factor in treatment rather than merely maintaining concentrations of IgG subclasses at particular levels.
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To determine the effect of anti-immunoglobulin antibodies on the measurement of the humoral immune response in hepatitis C virus (HCV) infected patients. Anti-immunoglobulin antibodies were defined using sheep immunoglobulins as a target to characterize distinct changes in patterns of immunoglobulin levels. Serum immunoglobulin A, G and M concentrations were measured by ELISA in 45 patients with recent-onset HCV infection and 45 matched normal individuals. It was found that normal individuals had mean IgA, IgG and IgM levels of 2.67 mg/ml, 9.39 mg/ml and 1.77 mg/ml, respectively while HCV infected patients had mean levels of 3.19 mg/ml, 10.76 mg/ml and 1.94 mg/ml. These represented significant increases in immunoglobulin levels in the sera of HCV patients compared to normal individuals (p < 0.0001, p < 0.00004 and p < 0.0004). Anti-immunoglobulin antibodies lead to an overestimation of serum immunoglobulin levels in HCV patients. Interestingly, the mean levels of immunoglobulins A, G and M in HCV infected sera, determined after purification from anti-sheep immunoglobulins, was 2.73 mg/ml, 9.55 mg/ml and 1.79 mg/ml. Therefore, there was no significant difference in HCV patients compared to normal individuals (p < 0.42, p < 0.36 and p < 0.44). The presence of circulating immune complex in serum during the early phase of infection may contribute to immunopathological effects in the infected host and provide some new insights into antibody response to HCV.
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Abstract Antibodies against several self-glycans on glycosphingolipids are frequently detected in different neurological disorders. Their pathogenic role is profusely documented, but the keys for their origin remain elusive. Additionally, antibodies recognizing non-self glycans appear in normal human serum during immune response to bacteria. Using HPTLC-immunostaining we aimed to characterize IgM and IgG subclass antibody responses against glycosphingolipids carrying self glycans (GM1/GM2/GM3/GD1a/GD1b/GD3/GT1b/GQ1b) and non-self glycans (Forssman/GA1/“A” blood group/Nt7) in sera from 27 randomly selected neurological disorder patients presenting IgG reactivity towards any of these antigens. Presence of IgG2 ( p = 0.0001) and IgG1 ( p = 0.0078) was more frequent for IgG antibodies against non-self glycans, along with less restricted antibody response (two or more simultaneous IgG subclasses). Contrariwise, IgG subclass distribution against self glycans showed clear dominance for IgG3 presence ( p = 0.0017) and more restricted IgG-subclass distributions (i.e. a single IgG subclass, p = 0.0133). Interestingly, anti-self glycan IgG antibodies with simultaneous IgM presence had higher proportion of IgG2 ( p = 0.0295). IgG subclass frequencies were skewed towards IgG1 ( p = 0.0266) for “anti-self glycan A” subgroup (GM2/GM1/GD1b) and to IgG3 ( p = 0.0007) for “anti-self glycan B” subgroup (GM3/GD1a/GD3/GT1b/GQ1b). Variations in players and/or antigenic presentation pathways supporting isotype (M-G) and IgG-subclass pattern differences in the humoral immune response against glycosphingolipids carrying non-self versus self-glycans are discussed.
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