Clinico-immunologic aspects of IgG subclass deficiency

Serum IgG contains 4 subclasses, IgG1 (60-66%), IgG2 (20-30%), IgG3 (less than or equal to 5%) and IgG4. Individual subclasses vary with respect to their physicochemical and biological properties. IgG subclass concentrations in serum are age dependent. IgG1 and IgG3 reach near to adult levels around the age of 3, IgG2 and IgG4 after the age of 6. Antibodies of certain specificities generally belong to a certain isotype (subclass) due to the isotype restriction. Patients with subclass deficiencies often suffer from recurrent infections. Those with IgG2 deficiency coften occurring with IgA and IgG4 deficiency) develop recurrent infection of the upper and lower respiratory tract often caused by pyogenic microorganisms (Haemophilus, Pneumo-(occus). Since early initiation of IVIG substitution therapy has a beneficial effect on long term prognosis the importance of early diagnosis is apparent.     

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.     

IgG subclass deficiency in asthma.

Total immunoglobulin G (IgG) and subclasses were measured in serum samples from 82 children with chronic asthma, aged 1.5 to 6.3 years, and 76 controls. Concentrations of IgG1, IgG2, IgG3, and total IgG were significantly lower in asthmatic children aged 1 to 5, and IgG2 concentrations were also significantly lower in asthmatic children over 5 years of age. Twenty eight asthmatic children had at least one value in the deficient range, and 26 had IgG2 deficiency alone or in combination. Five children had IgG2 and IgA deficiency. These 28 children were significantly younger and fewer had raised IgE concentrations than the remainder. IgG subclass deficiency, which may reflect delayed maturation of the immune system, is common in young asthmatic children, and may have a role in the pathogenesis of the disease.     

IgG subclass deficiency in children with recurrent bronchitis

We studied the incidence of IgG subclass deficiency in children with recurrent bronchitis. Recurrent bronchitis was defined as three or more episodes a year during at least 2 consecutive years, of bronchopulmonary infection, productive cough with or without fever and/or diffuse rales by physical examination in the absence of asthma or atopy. Fifty three children were selected, of whom 30 (57%) were deficient in one of the IgG subclasses. None had an IgG1 deficiency. Nine (17%) were deficient in IgG2, 9 (17%) in IgG3 and 20 (38%) in IgG4. Isolated IgG subclass deficiencies were most frequently seen for IgG4 (14, 26%), less for IgG3 (6, 12%) and even less for IgG2 (4, 7%). Nine (17%) children were IgA deficient and 8 (15%) IgG deficient with a combined IgG subclass deficiency in 8 and 7 of them respectively. By subdivision into different age groups most patients were encountered in the youngest group. The mean content of IgG2, IgG3 and IgG4 in 3- to 4-year-old children with recurrent bronchitis was significantly lower than in the age matched controls. The mean value for IgG4 in the 5- to 6-year-olds was significantly lower than in the control group. This study demonstrates the correlation between recurrent bronchitis in childhood and IgG subclass deficiency. IgG subclass deficiency and recurrent bronchitis are both quite prominent phenomena in young children but rare in older children, suggesting a transient immaturity of the immune system as one of the possible pathogenetic factors. An IgA or an IgG deficiency is highly suggestive for the existence of a combined IgG subclass deficiency.     

IgG subclass deficiency in children with congenital heart disease

This study of 66 children with congenital heart disease found 26 (39%) with IgG subclass deficiency, the majority being of the IgG₄ isotype. Conventional immunoiogical assessment (IgG, IgA, IgM, T cell) revealed 21 (32%) with immunodeficiency, while inclusion of IgG subclass assessment revealed a total of 35 (53%) of the 66 children had immuno-deficiency. Children with conotruncal lesions appeared to be predisposed to immunodeficiency affecting T cells and IgG subclasses (especially IgG₄) while those with shunt and stenotic lesions had a broad spectrum of immunoglobulin deficiencies. There was significant correlation between immunodeficiency and proneness to infection in these children (p < 0.01). These results suggest that immunodeficiency is a frequent occurrence in children with congenital heart disease, and that IgG subclass measurements should be added to the diagnostic work-up.     

Recurrent pneumococcal meningitis in a patient with transient IgG subclass deficiency

We report the case of a 3 year old boy who exhibited recurrent serious infections with a transient imbalance of IgG subclass in the second year of life. He suffered from pneumococcal meningitis at 3 months, hepatitis at 9 months, and purulent arthritis at 11 months of age. The second episode of pneumococcal meningitis occurred at 14 months. Serum IgG level was normal for age. Low level of IgG2, undetectable level of IgG4 and negligible level of pneumococcus-specific IgG1-G2 antibodies were found. No other primary immunodeficiency was apparent. Serum IgG2-G4 levels but not pneumococcus-specific IgG1-G2 titers increased by the age of 30 months. At that time, he was inoculated with a polyvalent pneumococcal vaccine along with acellular diphtheria-pertussis-tetanus vaccine. He acquired the immunity against these agents, and had no episodic infections in the following 2 years. This observation stresses the existence of transient IgG subclass deficiency associated with delayed development of the anti-polysaccharide antibody response.     

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.     

IgG2/IgG4 subclass deficiency in a patient with chronic mucocutaneous candidiasis and bronchiectases

A 22-year-old man with chronic mucocutaneous candidiasis (CMC) and hypothyroidism developed severe bronchiectases following recurrent bronchopneumonia. Immunological investigations revealed IgG₂/IgG₄ subclass deficiency and absence of antibodies against pneumococcal and Haemophilus polysaccharides. Under regular immunoglobulin substitution every 3 weeks pulmonary symptoms improved markedly.     

婴幼儿初次下呼吸道感染与血清IgG亚类缺陷

目的：研究婴幼儿初次下呼吸道感染患者中血清IgG亚类变化情况。方法：随机抽取185例初次下呼吸道感染病儿，用ELISA法检测血清IgG及IgG亚类浓度。并与该地区健康小儿血清浓度进行比较。以低于参考值下限(-1.96s)者为IgG或IgG亚类缺陷，而高于(+1.96s)者视为IgG亚类增高。结果：185例共检出43例IgG缺陷，均有IgG亚类缺陷，而余下的142例IgG正常者，发现IgG亚类缺陷120例，检出率高达 84.5%。其中0～3月4项、3项缺陷合计29例，占该年龄段缺陷总数的 85.3%，在各年龄段中为最高比例。而IgG亚类缺陷中以IgG3缺陷最高，占 47.6%。结论：婴幼儿初次下呼吸道感染伴有IgG亚类缺陷。年龄越小，越易出现IgG亚类联合缺陷。因而在检测Ig时，除注意总IgG外，还应注意IgG亚类水平。     

IgG subclass deficiency in childhood. Changes in the antigen specific immune response and significance of low IgG4 level

The definition of IgG subclass deficiency and the correlations between low IgG subclass serum concentrations and high incidence of infections in certain patients are still obscure. Therefore 260 children from 6 months to 18 years with severe recurrent infections or a known immunodeficiency were screened for IgG subclass deficiency. Nine patients with severe IgG2 deficiency (Ig2 less than 0.3 g/l) and 35 patients with non-detectable IgG4 in immunoprecipitation were detected. One of these patients had a concomitant IgA deficiency, eight revealed an additional IgA and IgG2 deficiency, two an IgA, IgG2, and IgG3 deficiency, eighteen an IgG2 deficiency and one patient an IgG2 and IgG3 deficiency. The proportion of patients with non-detectable IgG4 in immunoprecipitation was 13.5% and thus in the same order of magnitude as described in the literature for healthy people. Our data show that there is no relation between low IgG4 serum levels and the increased occurrence of severe infections. In all patients investigated with non-detectable IgG4 in immunoprecipitation the gene for the heavy chain gene constant domain C gamma 4 could be detected by Southern blotting. Using a sensitive ELISA method IgG4 could be directly demonstrated in all patients at a serum level of 0.5-29 micrograms/ml. Specific IgG4 antibodies against protein antigens could not be detected in IgG4-deficient patients. Nevertheless total IgG antibodies against diphtheria and tetanus toxoid reached protecting titers. Patients with IgG2 deficiency showed an impaired immune response against polysaccharides from pneumococci and haemophilus influenzae type b.     

IgG subclass level in healthy children

In 159 healthy German children aged 3 months to 16 years IgG subclass concentrations were measured by radial immunodiffusion using polyclonal antisera. IgG-4 levels were also determined by a monoclonal ELISA kit (Binding Site). Both methods for IgG-4 determination showed a significant correlation (r = 0.91); the WHO reference serum 67/97 was used for calibration. The mean range and percentiles for age are given. IgG subclass levels were correlated with the age of the children in the order IgG-2 greater than IgG-1 greater than IgG-4, but this was not the case for IgG-3. The normal ranges of IgG subclasses were in good agreement with those of previous studies. No IgG-4 was detected by RID in only 8.8% of all the children, but in all aged 7 years and above.