Increased IgG2 and IgG3 Concentration Is Associated with Advanced Pseudomonas Aeruginosa Infection and Poor Pulmonary Function in Cystic Fibrosis

ABSTRACT. The concentrations of IgG subclass immunoglobulins were determined by radial immunodiffusion in serum from 126 patients with cystic fibrosis (CF). The results were compared to values from age-matched healthy children and adults and correlated to patients age, duration of chronic Pseudomonas aeruginosa infection and lung function parameters. Fifty-two percent of the patients had an elevated concentration of at least one of the IgG subclasses; IgG1 28%, IgG2 16%, IgG3 18% and IgG4 48%. There was significant correlation between elevated serum levels of IgG2, and to a lesser extent IgG3, with decreased lung function (for FEV₁; p =0.0001, and p =0.001 respectively) and high levels of antipseudomonas precipitins ( p =0.008, and p =0.002). A similar correlation was not found for IgG1 and IgG4. IgG subclasses vary in their ability to promote phagocytosis and to activate complement and it is possible that individual differences in the IgG subclass pattern could explain the variable course of this disease.     

反复呼吸道感染患儿IgG亚类及维生素A水平的关联研究

目的：反复呼吸道感染（RRTI）是儿科的常见病之一。目前研究发现其发病与维生素A缺乏,免疫功能异常有关。该研究检测了RRTI患儿IgG 亚类及维生素A水平,并对该类病人维生素A缺乏与IgG亚类缺陷之间的关系进行了初步的探讨。方法：采用ELISA方法检测血清IgG 亚类;采用高效液相色谱分析Miller改良法进行维生素A的测定。结果：RRTI患者血清IgG2,4水平及维生素A水平均低于健康对照组,差异具有显著性（P<0.05）。结论：RRTI患者虽IgG正常,但是可能存在IgG亚类异常。RRTI患者存在维生素A水平低于正常儿童,而且IgG2,4水平的降低可能与维生素A水平有关。［中国当代儿科杂志,2007,9（6）：557-558］     

IgG subclasses in wheezing infants

The wheezing infant is a common but difficult patient to approach diagnostically. The prevalence of IgG subclass antibody deficiency in wheezing infants is still controversial. We studied serum concentration of IgG subclasses in 38 wheezing infants (aged 6–24 months who had not received systemic steroids before investigation) and in 30 healthy age matched control (aged 6–24 months). The prevalence of one or more IgG subclass deficiency was 31.6% in wheezing infants and 26.7% in controls. There was no significant difference in prevalence of IgG subclass deficiency between patients and controls (p>0.05). The mean concentration of IgG subclasses in patients were compared with controls. There was no significant difference in mean serum concentration of IgG1, G2 and G3 subclasses. But there was a trend towards higher concentrations of IgG4 in wheezing infants and this difference for IgG4 was significant (p<0.01). However, IgG subclass deficiency was found in 25% and 36.4% of wheezing infants who had experienced from two to four and five or more wheezing episodes in two years, respectively (p>0.05). These findings suggest that wheezing in infancy is not associated with IgG subclass deficiency and in wheezing infants low IgG subclass levels do not increase the frequency of wheezing.     

IgG2 deficiency in children with human immunodeficiency virus infection

Infection with the human immunodeficiency virus (HIV) induces a polyclonal B-cell activation. Despite elevated serum immunoglobulin levels, a significant deterioration of the antigen specific humoral immune response exists in most cases. We studied the influence of HIV infection on the serum levels of IgG subclasses in children. We investigated 76 children (aged 15 months to 18 years) with HIV-1-infection. Most children (88%) showed elevated serum immunoglobulin levels. IgA (87%) and IgM (74%) were more often above normal levels for age than IgG (60%). IgG subclass serum levels were significantly altered. The increase in total IgG was mainly due to a marked augmentation of the IgG1 fraction. In most cases IgG3 was simultaneously elevated. Ten children (13%) had very low IgG4 levels (<0.03 g/l). Out of 61 patients older than 2 years 8 (13%) had a profound IgG2 deficiency with normal or elevated total IgG. Four of them also had low IgG4 levels (<0.03 g/l). A correlation between IgG2 deficiency and HIV infection according to the Centres for Disease Control classification for acquired immunodeficiency syndrome could not be demonstrated (three patients with symptomatic and five with asymptomatic infection).     

IgG SUBCLASS LEVELS IN INFANCY AND CHILDHOOD

Abstract. Oxelius, V. (Department of Paediatrics, University Hospital, Lund, Sweden). IgG subclass levels in infancy and childhood. Acta Paediatr Scand, 68: 23, 1979.—The concentrations of IgG1, IgG2, IgG3 and IgG4 were determined by electroimmunoassay in 10 pairs of maternal and cord sera and in sera of 162 healthy children, aged 6 weeks to 15 years. Specific rabbit antisera against the IgG subclasses were used. The content of the normal serum pool WHO 67/97 was used as reference. The mean value, standard deviation and normal range of each IgG subclass were calculated for each age group and compared with the adult values. All IgG subclasses were present in cord serum except for IgG4 in those cases where also the maternal serum lacked demonstrable IgG4. The IgG subclasses followed the pattern of total IgG with a fall during the first 3–6 months and a subsequent gradual rise with age. The IgG1 and IgG3 levels rose faster with age than IgG2 and IgG4. Adult levels were not reached before puberty. No IgG4 was detectable in 12–21% of the children above 7 years of age.     

Effect of Anti-Epileptic Drugs on Serum Level of IgG Subclasses

Objective

There are some controversial studies on effects of anti-epileptic drugs (AEDs) on serum IgG subclasses; however, the role of these medications is still unclear. The aim of this study was evaluation the effects of anti-epileptic drugs on serum concentration of IgG and its subclasses

Methods

Serum IgG and IgG subclasses of 61 newly diagnosed epileptic patients were measured at the beginning of monotherapy with carbamazepine, sodium valproate, and phenobarbital, and 6 months later. Measurement of IgG and its subclasses was performed using nephlometry and ELISA techniques, respectively.

Findings

Reduction of at least one IgG subclass was found in 6 patients 6 months after treatment with AEDs. Among 27 patients receiving carbamazepine, decrease in at least one serum IgG subclass level was found in 5 patients. Among 20 patients using sodium valproate, only one patient showed decrease in IgG2 subclass. None of the 14 patients using phenobarbital revealed significant decrease in IgG subclasses. No infection was seen in the patients with reduction of subclasses.

Conclusion

Although in our study, children with selective IgG subclass deficiency were asymptomatic, assessment of serum immunoglobulin levels could be recommended at starting the administration of AEDs and in serial intervals afterward in epileptic patients.     

Increased IgG2 and IgG3 concentration is associated with advanced Pseudomonas aeruginosa infection and poor pulmonary function in cystic fibrosis

The concentrations of IgG subclass immunoglobulins were determined by radial immunodiffusion in serum from 126 patients with cystic fibrosis (CF). The results were compared to values from age-matched healthy children and adults and correlated to patients age, duration of chronic Pseudomonas aeruginosa infection and lung function parameters. Fifty-two percent of the patients had an elevated concentration of at least one of the IgG subclasses; IgG1 28%, IgG2 16%, IgG3 18% and IgG4 48%. There was significant correlation between elevated serum levels of IgG2, and to a lesser extent IgG3, with decreased lung function (for FEV1; p = 0.0001, and p = 0.001 respectively) and high levels of antipseudomonas precipitins (p = 0.008, and p = 0.002). A similar correlation was not found for IgG1 and IgG4. IgG subclasses vary in their ability to promote phagocytosis and to activate complement and it is possible that individual differences in the IgG subclass pattern could explain the variable course of this disease.     

IgG subclasses in children with recurrent respiratory tract infections in an allergy practice

Isolated or combined deficiencies of immunoglobulin G (IgG) subclasses have been recognized in children with recurrent infections. In our allergy practice, there are a subset of children with recurrent respiratory tract infections. To investigate the presence of immunoglobulin G subclass deficiency (IgGSD), 60 children with atopy and 14 children without atopy suffering from recurrent respiratory tract infections were studied in an attempt to determine whether atopy is associated with a certain IgG subclass pattern. Ten atopic children were found to have isolated or combined IgG subclass deficiencies: one with IgG1, two with IgG2, four with IgG3 and three children had IgG2–IgG3. Neither IgG subclass concentration nor the frequency of children with high or low IgG subclasses showed any difference between atopic and non-atopic groups. Except for a week correlation with IgG3, no correlation existed between IgE and other IgG subclasses. It was concluded that childhood respiratory diseases complicated by recurrent respiratory tract infections may be associated with IgG subclass deficiencies. Although there have been reports noting some IgG subclass patterns in atopic disorders, in the present study, no distinctive feature between atopics and non-atopics with respect to IgG subclass concentrations and patterns was observed.     

Normal levels of IgG subclass in childhood determined by a sensitive ELISA

Normal values of all IgG subclasses were determined using a sensitive ELISA in children aged from newborn to 14 years. The upper and lower limits of normal values of all IgG subclasses were obtained in all the age groups using 29 umbilical cord blood samples from full-term newborns and 308 venous blood samples from normal infants and children. The trends in the levels of IgG1, IgG2 and IgG3 with age were almost similar to previous reports. IgG4 levels decreased gradually until reaching the lowest level at 7 to 12 months and increased gradually with age, reaching a plateau at 12 to 14 years of age. Thus, the lower limit of serum IgG4 levels was determined using our method.     

IgG Subclass Imbalance in Children with Acute Lymphoblastic Leukemia Receiving Maintenance Chemotherapy

Serum levels of IgG subclasses were measured in 18 children with acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy and in 36 age-matched controls in order to attempt to analyse the effects of chemotherapy. The IgG subclasses were measured by enzyme linked immunosorbent assay. Serum IgG₁, IgG₂ and IgG₄ levels in the patients were significantly (p<0.01, p<0.005, p<0.005) lower than in the controls, but serum IgG₃ levels in patients were as high as in controls. Suppression on IgG₂ and IgG₄ were more profound than IgG₁. In six children, the levels of the IgG subclasses were measured at diagnosis, during maintenance chemotherapy and one year after cessation of chemotherapy. The levels of the four IgG subclasses at diagnosis and after cessation of chemotherapy were as high as those in control children except for the IgG₄ levels in the postchemotherapy group. IgG₂ and IgG₄ may be more susceptible to suppression by chemotherapy than IgG₁ and IgG₃ may not be suppressed by chemotherapy.     

Transfer of specific IgG and IgG subclasses to herpes simplex virus across the blood-brain barrier and placenta in preterm and term newborns

The kinetics of virus-specific IgG subclasses (IgG 1-4) among newborns and their mothers has not yet been determined. In this report, we examined anti-herpes simplex virus IgG activities (HSV-IgG) and its subclasses in CSF and serum of premature or term newborns without HSV infection and in the serum of their mothers using ELISA. We found that CSF/serum ratios of HSV-IgG and IgG subclasses (IgG 1-4) in newborns with a gestational age less than 38 weeks were higher than those of term newborns. These findings indicate that the blood-brain barrier against HSV-IgG and IgG subclasses is insufficient in newborns. Furthermore, we found that HSV-IgG subclasses, which were transferred across the placenta and later transferred across the blood-brain barrier had a tendency to be proportional to each of the maternal HSV-IgG subclasses.     

IgG subclass deficiency

The different biological properties of human IgG subclasses make each subclass unique in its functional role in either resistance to infection, autoimmune diseases or allergy. Not only are there marked differences in the relative concentrations of IgG subclasses in serum (IgG₁ > IgG₂ > IgG₃/IgG₄) but the distribution of the antibody responses in the 4 subclasses of IgG can vary markedly depending on the nature of the antigen, the type of infection, the degree of antigen exposure, the immunization regimens, the age of individual, the immune disorder and the allotype of the individual. Measurement of the IgG subclass distribution of antibodies can be informative in identifying an immunological deficiency, evaluating the production of host protective antibodies, and assessing pathophysiology. Determination of IgG subclass concentrations is essential in the diagnosis of immunodeficiencies. However, there is still uncertainty about the accuracy of measurements in relation to standards, monoclonal antibodies and assay types. For the paediatric population, a sensitive assay, such as an enzyme linked immunoabsorbent assay, is essential. A standardised definition of IgG subclass deficiency is yet to be accepted; however, values substantially below the 5th percentile for a normal healthy population of appropriate age measured by a defined assay system may be indicative of significant abnormality. There is emerging evidence that some subclass deficiencies are associated with increased susceptibility to infection. Such IgG subclass deficiencies may be amenable to treatment with intravenous gammaglobulin preparations, but further carefully designed and controlled studies are needed to ascertain treatment efficacy.     

Reduced levels of IgG subclasses and IgA in young children with asthma

Serum immunoglobulins including IgG subclasses were measured in 73 unselected children with asthma. The results showed that 22 (30%) had partial IgA and/or IgG₄ subclass deficiency. Clinical assessment showed that 21 children were infection-prone, and 52 were not. Further analysis showed that infection-prone children were significantly different from non-infection-prone children with regard to familial history of allergy (29% vs 60%, p = 0.015), elevated IgE (62% vs 33%, p = 0.021), IgA deficiency (38% vs 15%, p = 0.38) and IgG subclass deficiency (24% vs 4%, p = 0.018). These results suggest that there may be subgroups of children with asthma who are also immunodeficient.     

Undetectable IgG4 in immunoprecipitation: association with repeated infections in children?

A total of 210 patients with repeated infections were screened for IgG4 deficiency. In 30 patients (14%) IgG4 was undetectable by radial immunodiffusion (<30 mg/l). Of these patients 17 (57%) were less than 2 years of age. Concomitant IgA deficiency (IgA<0.05 g/l) was demonstrated in 11 cases (37%). IgG2 serum levels below the normal range were found in 26 children. IgG4 could be demonstrated at a concentration of 0.5–29 mg/l in all 30 patients using a more sensitive enzymelinked immunosorbent assay technique. Although a highly selected group of patients was investigated, the percentage of individuals without detectable IgG4 by immunodiffusion was in the same range as reported in the literature for healthy control persons. It is thus concluded that IgG4 serum reference levels have to be defined using more sensitive methods and that the observed severe infections are more likely to be connected with low serum IgG2 and/or IgA levels than undetectable IgG4 as measured by immunodiffusion.This work was supported by a grant from the Deutsche Forschungsgemeinschaft BA 872/1-1     

IgG subclasses in nonallergic children with chronic chest symptoms

Immunoglobulin and IgG subclass measurements were made on sera from 37 children thought to have asthma whose chronic chest symptoms were unexplained by allergy. There was a higher proportion of low or low-normal levels of IgG subclasses 1, 2, and 4 in these children than in normal children. Those who had low serum IgG values on initial measurement had a higher proportion of low or low-normal levels of IgG1, IgG2, and IgG4; those who had normal IgG values had a higher proportion of low or low-normal levels of IgG2 and IgG4. Thus a normal serum concentration of IgG did not exclude the possibility of an abnormal level of IgG2 or IgG4. Our experience suggests that abnormal levels of IgG subclasses might play an etiologic role in the chronic chest symptoms in some of these children.     

Serum IgG subclass concentrations in healthy subjects at different age: Age normal percentile charts

IgG subclass levels were determined in 448 normal children from 6 months to 18 years of age and in 141 healthy adults by radial immunodiffusion using monoclonal antibodies. Age-normal percentile values were calculated for each year of age up to 18 years for IgG1, IgG2, IgG3 and in adults for all four subclasses. The broad spread of IgG4 values in children did not permit calculation of reference values.     

IgG subclass deficiencies in children: Facts and fiction

The chance to analyse the four IgG subclasses arose with the publication of Terry and Fahey¹. Since then, a lot of new information on the role of subclasses and their deficiency states in humans has been obtained. This review tries to analyse critically our current knowledge of subclass deficiencies in children.     

Correlation of allergen‐specific IgG subclass antibodies and T lymphocyte cytokine responses in children with multiple food allergies

Scott‐Taylor TH, Hourihane J, Strobel S. Correlation of allergen‐specific IgG subclass antibodies and T lymphocyte cytokine responses in children with multiple food allergies.
Pediatr Allergy Immunol 2010: 21: 935–944.
© 2010 John Wiley & Sons A/S Cytokines can affect the quantity and class of allergen‐specific immunoglobulins through the T cell polarization that accompanies atopy. Antigen‐specific IgG subclasses and IgE antibodies were compared with intracellular T cell cytokine changes to sensitizing antigens in 23 children with multiple food allergies and 20 healthy controls. Allergic children showed higher levels of total and food‐specific IgE, IgG1 and IgG4 to peanut, milk and egg than non‐atopic children or adults, coinciding with a TH2 cytokine response to sensitizing antigens. IgG1 and IgG4 antibodies specific to milk and egg and peanut protein were elevated relative to age‐matched healthy children (p ≤ 0.05) and, in milk‐ and egg‐sensitized children, correlated with cytokine responses (p < 0.05). Peanut‐sensitized children additionally had elevated levels of IgG2 and IgG3 also which correlated inversely (p < 0.003 and p < 0.04, respectively) with IFNγ production. Elevated allergen‐specific IgG subclass antibodies in sensitized children correlated with total IgE levels (p ≤ 0.05) in all three food allergen groups. The ratio of specific IgG1 to IgG4 was highest in those with high IgE, inverted with resolution of allergy, and correlated with total IgE levels (p ≤ 0.01) in milk‐ and egg‐sensitized children. The correlation of TH2 responses with allergen‐specific antibodies would implicate polarized T cells in food allergic children in IgE hypersensitivity and overproduction of particular IgG subclasses alike. IgG1:IgG4 ratio declines with allergy sensitization and may denote emerging tolerance.     

Immunoglobulin G subclass concentrations and infections in children and adolescents with severe asthma

It was the aim of this study to investigate possible dysfunctions of the humoral immune system in asthmatic children with frequent respiratory infections. Forty‐one severe asthmatics (7–15 years of age), classified according to the Second Brazilian Consensus in Asthma (1998), were divided into two groups: group I (n = 12) had recurrent respiratory infections; and group II (n = 29) were without recurrent respiratory infections. Immunoglobulin (Ig)G, IgA and IgM levels (nephelometry), and IgE (radioimmunoassay) and IgG subclasses (enzyme‐linked immunosorbent assay), were evaluated using standard methods. Asthmatics with recurrent infections presented with worse clinical evolution, an increased number of hospital admissions, and a higher need of medication than the children without recurrent infections. There were no significant differences between the mean values of IgG, IgA or IgM levels, or IgE or IgG subclasses, in patients of both groups. A complete IgA deficiency was detected in two patients of group I (one was associated with IgG subclass deficiency). Deficiency of one or more IgG subclasses was verified in eight of 12 (66%) children from group I and in 16/29 (55%) from group II. The following deficiencies were found in both groups: IgG₃ (10/41), IgG₄ (three of 41), IgG₂ (two of 41), IgG₁ (one of 41), IgG₃‐IgG₄ (four of 41), IgG₁‐IgG₃ (two of 41), and IgG₁‐IgG₃‐IgG₄ (one of 41). There were a higher proportion of children with low IgG₄ levels in group I than in group II (p = 0.01). To conclude, IgA and IgG subclass deficiencies were detected in both severely asthmatic groups, with a predominance of IgG₃ subclass deficiency. However, low IgG subclass levels appear not to be a suitable predictor of the development of infections in asthmatic children.     

Comparison of IgG subclasses in foetal serum, maternal serum at delivery and milk in IgA-deficient and control women

Immunoglobulin G subclass concentrations were measured in paired foetal (cord) and maternal serum specimens at delivery from 27 IgA-deficient (serum IgA < 0.01 g/l) and 15 control women. IgA-deficient women had significantly higher serum IgGl and IgG3 concentrations than control women but 2 of the group had concomitant IgG2/IgG4 deficiency and a further 12 had low IgG4 concentrations (serum IgG4 < 0.025 g/l). Foetal serum also had significantly higher IgGl concentrations than control foetal serum but lower IgG2 and IgG4 levels. Concentrations of IgG subclasses and IgM were measured in breast milk collected on the fifth day postpartum from 19 of these IgA-deficient and 18 control women. Between-group differences in IgG subclass levels resembled those in serum. Compared with serum, proportionally less IgG3 was present in milk in both groups although the contribution of IgG3 to total IgG was not less than that of IgG4. Slightly higher IgM was found in milk from the IgA-deficient mothers.