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Biomedical subjects

V A Oxelius

Publications and source records attributed to V A Oxelius.

At least 19 recordsLinked to original sources

IgG subclass antibodies to dietary antigens in IgA deficiency quantification and correlation with serum IgG subclass levels.

IgG subclasses of antibodies to the dietary antigens ovalbumin, beta-lactoglobulin, casein, bovine IgM, and glycgli (a gluten component) were quantified in 20 adults and 10 children with IgA deficiency and healthy controls (21 adults and 7 children). In the IgA-deficient subjects the levels of IgG subclasses in serum were determined. Detectable antibody levels were observed in the majority of the subjects in IgG1 and IgG4 for anti-ovalbumin and beta-lactoglobulin, and in IgG1, followed by IgG2, IgG3, and IgG4 for antibodies to casein, bovine IgM, and glycgli. Levels of IgG1 and IgG2 antibodies to bovine IgM were higher in the IgA-deficient adults than in controls (P less than 0.00005, P = 0.0007, respectively), whereas the other antibody levels did not differ significantly between the two groups. An analysis of correlation between the IgG subclass antibody levels did not provide evidence for a particular IgG subclass antibody response pattern against different protein antigens within the single individual. Serum IgG4 levels correlated positively with the summed IgG4 antibody levels (Spearman's p = 0.673, P = 0.0051). The IgA-deficient subjects, when compared with healthy controls, did not show a particular IgG subclass pattern or restriction of antibodies to dietary antigens.

Adolescent

Lack of the G2m(n) allotype in IgG subclass deficiency, in IgG2 deficiency together with lack of G1m(a) and G3m(g), and in IgG3 deficiency together with lack of G1m(f) and G3m(b).

Lack of G2m(n) was demonstrated in both IgG2-deficient and IgG3-deficient Caucasian patients. Lack of G2m(n) or G2m(",") was found together with homozygosity for both G1m and G3m allotypes as the dominant finding, i.e. for IgG2-deficient patients together with G1m (f,f) and G3m(b,b), constituting the Gm(f,",b) phenotype, and for IgG3-deficient patients together with G1m(a,a) and G3m(g,g), constituting the Gm(a,",g) phenotype. The group with IgG2 deficiency and the selected patients with the Gm(f,",b) phenotype expressed characteristically very low or undetectable IgG4, significantly increased IgG3, and normal IgG1. The group with IgG3 deficiency and the selected patients with the phenotype Gm(a,",g) expressed instead normal IgG4 and nearly normal IgG2 and IgG1 levels. The lack of G2m(n) together with lack of one or the other of the alternative G1m genes and corresponding G3m genes give different IgG2 levels and different IgG subclass patterns. The frequency of G1m allotypes and corresponding G3m allotypes also deviated significantly when the IgG2 deficiency and IgG3 deficiency groups were compared with each other. Most IgG subclass-deficient patients are homozygous in the Gm system and lack genetic variants in the three IgG subclasses, IgG1, IgG2, and IgG3.

Antibodies, Monoclonal

Correlation between atopy and Gm allotypes.

In 50 consecutive atopic Caucasian patients with increased IgE greater than 600 kU/l, the phenotypic Gm allotype constellation deviated from that to be expected, with significantly increased frequency of patients with the phenotype Gm(f,n,b). There was an increased frequency of the G2m(n) allotype, more frequent in patients with IgE greater than 1,000 kU/l, and in patients with IgG4 greater than 1 g/l. In patients with IgE greater than 1,000 kU/l the phenotype Gm(a,f,n,b) was significantly increased and in patients with IgG4 greater than 1 g/l the phenotype Gm(f,n,b) was significantly increased. Those atopic patients with increased IgE and increased IgG4, according to earlier studies known to have the most severe forms of the disease, were thus mainly found to have the m(f,n,b) phenotype.

Adolescent

Gm allotype genes and gene dosage affecting both IgG subclass and IgE levels in atopic patients.

The imbalanced IgG subclass levels of 50 atopic patients with IgE greater than 600 kU/l reflected the Gm expression of the patients. IgG1 was significantly increased but only in patients with the phenotypes Gm(f,f,n,n) and Gm(a,a,'',''). The typical IgG4 increase was found in the most frequent Gm(f,f,n,n) and Gm(a,f,n,'') phenotypes. Significant increase of IgG2, IgG3 and IgG4 was found in patients homozygous for G2m(n) compared to those lacking this allotype. IgG2 decrease was found in those with the Gm(f,f,'','') phenotype and IgG3 decrease in those with the Gm(a,a,'','') phenotype. Also the IgE levels were influenced by the Gm allotypes with increased IgE levels in the G1m(f,f) patients compared to the G1m(a,a) patients.

Adolescent

Pneumococcal serum antibody concentrations during the first three years of life: a study of otitis-prone and non-otitis-prone children.

One hundred and thirteen children were followed prospectively from birth until the age of 3, serum being obtained from cord blood, and at the ages of 3, 6, 12, 18, 24, 30 and 36 months. Thirteen children developed recurrent acute otitis media (rAOM), 29 remained very healthy and the remaining children formed an intermediate group. Cord serum concentrations were determined of total IgG class, of IgG1 and IgG2 subclasses, as well as of specific IgG antibodies against the pneumococcal capsular types, 3, 6A and 19F. The specific pneumococcal IgG as well as IgA and IgM antibodies were also followed in the sequential serum samples up to the age of 3 in the rAOM and healthy children. Despite total IgG class and IgG1 and IgG2 subclass concentrations being of the same magnitude in cord serum of rAOM (median: 11.15, 7.48 and 2.16 g/l for IgG, IgG1 and IgG2, respectively) as in that of healthy children (median: 10.21, 8.16 and 2.16 g/l, respectively), both in cord serum and in most serum samples drawn during the first year of life, specific IgG antibodies against types 6A and 19F, but not against type 3, were significantly lower in the rAOM group than in the healthy children. In the intermediate group, cord serum concentrations of specific IgG antibodies to type 6A were of the same magnitude as in the healthy children. The only significant difference in specific IgM and IgA antibody concentrations against types 3, 6A and 19F between the two groups was noted for type 6A antibodies at 36 months of age where rAOM children exhibited lower values. The results indicate an association between pre-existing low specific IgG antibody levels against AOM-associated pneumococcal types and the development of rAOM.

Acute Disease

Immunoglobulin G subclass distribution in three human intravenous immunoglobulin preparations.

In immunodeficiency patients the lack of immunoglobulins (Ig) can be total or partial with a specific IgG subclass imbalance masked by normal values for total IgG. In the latter case therapy with intravenous IgG preparations (IVIG) is generally beneficial, provided the IVIG preparations used originate from large pools of normal blood donors and exhibit a normal IgG subclass distribution. We have analyzed the subclass distribution of three IVIG products: Sandoglobulin (SAGL), GamimuneN (GI), Gammagard (GG), 6-10 lots each, in four different laboratories. The competitive enzyme immunoassays and radial immunodiffusion methods used different monoclonal and polyclonal antibodies specific for IgG1, IgG2, IgG3, and IgG4, respectively. Despite minor interlaboratory differences, the results show that the slightly lower IgG1 content of SAGL versus GI and GG was quantitatively compensated by a higher proportion of IgG2, that no differences existed in IgG3 levels, but that one preparation (SAGL) contained 2-3% of IgG4 compared to 0.5-1.5% in GI and below 0.5% in GG. This difference was significant, the two latter preparations being at or below the lower limit of what are considered to be normal values found in human adults. Such differences may have important clinical consequences.

Antibodies, Viral

The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin.

With the increased use of immunoglobulin for intravenous use (IGIV) as replacement therapy for patients with primary immunodeficiencies, a natural concern is whether such preparations demonstrate a normal turnover rate with regard to total IgG, individual IgG subclasses, and specific antibody titers. We have conducted such a pharmacokinetic study on a cohort of eight patients with an IGIV preparation, Gammagard. For total IgG, the half-life found was 25.8 days; for IgG1 it was 29.7 days; for IgG2 it was 26.9 days; and for IgG3 it was 15.7 days. The results are similar to those reported for endogeneous IgG. Half-lives for antibodies to S. minnesota (Re 595 mutant), cytomegalovirus, and S. pneumoniae were of the same order of magnitude as that for total IgG. We conclude that this IGIV preparation is catabolized in patients with primary immunodeficiency at a rate similar to that of native IgG in normal individuals.

Adolescent

C2 deficiency, moderately low IgG2 concentrations and lack of the G2m(23) allotype marker in a child with repeated bacterial infections.

C2 deficiency was demonstrated in an 11-year-old boy with a past history of recurrent purulent otitis media, pneumonia, H. influenzae meningitis and S. pneumoniae septicaemia. The major histocompatibility complex haplotypes present, A10, B18, DR2, BF*S, C2*QO, C4*A4, C4*B2 and A28, B18, DR2, BF*S, C2*Q0, C4*A4, C4*B2, were in accord with previous observations in C2 deficiency. The concentrations of C1q, C5, factor B and factor D were in the low normal range and the hemolytic activity of the alternative pathway was slightly decreased. In addition, the patient showed moderately low IgG2 concentrations and lacked the IgG2 subclass marker G2m(23). The findings indicate that the patient's susceptibility to bacterial infections may be due to C2 deficiency in combination with the presence of an IgG allotype associated with impaired antibody responses to carbohydrate antigens.

Bacterial Infections

Correlation between deficiency of immunoglobulin subclass G3 and Gm allotype.

Gm allotypes were investigated in 63 Swedes: 46 females and 17 males, in whom serum IgG3 was below 0.35 g/l. Both monoclonal antibodies and polyclonal antisera were used for the quantification. Concentrations of the other IgG subclasses were within the age-related normal ranges. The distribution of the IgG1 genetic markers G1m(a,x,f) differed markedly from that observed in normal Swedes (p less than 0.001). Thus G1m(a) was present in 60 subjects as compared to an expected 36, and phenotype G1m(-f) in 34 subjects as against an expected 8. The mean IgG3 concentration was numerically lower in the G1m(-f) group than in the G1m(+f) cohort, and individuals with IgG3 levels 0.10 g/l were more frequent in the G1m(-f) group. Among Caucasians, G3mg is in linkage disequilibrium with G1ma and our interpretations is that the haplotype G1ma;ax G2m-n G3mg is markedly increased in individuals with IgG3 deficiency.

Dysgammaglobulinemia

IgG subclass deficiency in children with IgA deficiency presenting with recurrent or severe respiratory infections.

A group of 22 children presenting with recurrent or severe respiratory tract infections who had low IgA levels (more than 2 SD below the mean for age) were examined for IgG subclass deficiency. Patients were screened for possible defects in neutrophil chemotaxis, bactericidal, fungicidal, and quantitative iodination activity, as well as for complement function. The majority of the patients showed IgG subclass levels below the mean for age. Nine of the children showed definite IgG subclass deficiency and at least two showed definite deficiency of more than one IgG subclass. The predominant subclass deficiency was found to be IgG1. While nine children showed IgG4 levels below the level detectable by the technique used, it is not possible to assess whether these patients are deficient in this isotype since some healthy subjects also give values below the level of detection. Most of the patients who had very low (1-6 mg/dl) or undetectable (less than 1 mg/dl) levels of serum IgA did not show IgG subclass deficiencies, while IgG subclass deficiencies were common among those with borderline low IgA levels (slightly more than 2 SD below the mean for age). Nine children showed total IgG levels close to 2 SD below mean for age, and at least six of these showed IgG subclass deficiency. The result suggests that patients with recurrent and/or severe respiratory infections who have borderline IgA and IgG levels may have IgG subclass deficiencies and if they do could benefit from immunoglobulin therapy.

Blood Bactericidal Activity

IgG3 deficiency: common in obstructive lung disease. Hereditary in families with immunodeficiency and autoimmune disease.

Among 313 patients with serum IgG deficiency, selective IgG3 deficiency was found in 59.5%, combined IgG3 deficiency together with IgG1 deficiency in 36% and combined IgG3-IgG2 deficiency in only 4.5%. Most of the patients with IgG3 deficiency suffered from upper respiratory tract infections, but many also from recurrent bronchitis, bronchopneumonias and asthma bronchiale. Those with combined IgG3-IgG1 deficiency often suffered from obstructive lung disease and chronic lower respiratory tract infections. Other diagnoses found in patients with IgG3 deficiency were diabetes mellitus, Henoch-Schönlein, recurrent herpes simplex infections and recurrent erysipelas. IgG3 deficiency was also found in relatives of patients with common variable immunodeficiency and IgA deficiency. In one family both parents and all four children showed IgG3 deficiency, some of them also C2 deficiency. In another family 2 siblings with diabetes mellitus showed IgG3 deficiency. In still another family the mother and her daughter both with asthma bronchiale showed IgG3 deficiency. Patients with IgG3 deficiency could respond to pneumococcal vaccine and seemed to respond to immunoglobulin substitution given every or every other week.

Autoimmune Diseases

Symptoms in patients with lowered levels of IgG subclasses, with or without IgA deficiency, and effects of immunoglobulin prophylaxis.

Several patients with subnormal levels of IgG subclasses have repeated infections. Further controlled studies are required to better define the relation between the level of the various subclasses and the possible clinical consequences. It may be important to determine whether or not IgG subclass deficiency can lead to infections which cause lung damage as was suggested in a few patients with IgA deficiency combined with low IgG subclass levels. An open study of the effect of immunoglobulin prophylaxis in 38 patients with subnormal levels of one or two of the IgG subclasses 1, 2 or 3 during altogether 1,524 months of observation suggested that many of them improved. This must be further substantiated in carefully controlled studies. Immunoglobulin prophylaxis could be given in IgG subclass deficient patients with IgA deficiency and anti-IgA antibodies, provided a preparation poor in IgA was used and the patients' anti-IgA titres did not increase during the prophylaxis.

Dysgammaglobulinemia

IgG subclass levels in the serum of patients with primary immunodeficiency.

Serum IgG subclass levels are reported on 70 patients with known primary immunodeficiency syndromes. Analysis of the data on the 28 patients with common variable immunodeficiency suggest that the deficit in subclasses is not generally proportionate. Some subclasses appear to be more strongly affected than others. The pattern suggests a hierarchical involvement with the order: IgG4 greater than IgG2 greater than IgG1 greater than IgG3. There appears to be a closer relationship between IgG1 and IgG3 levels than between IgG2 and IgG3 or IgG1 and IgG2 levels. The data are consistent with the hypothesis that there is a sequential increasing impediment of the programmed cascade for downstream heavy chain constant region gene rearrangements.

Agammaglobulinemia