Published online August 6, 2007
PEDIATRICS Vol. 120 No. 3 September 2007, pp. e543-e547 (doi:10.1542/peds.2006-3613)
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ARTICLE

Low Serum Immunoglobulin G2 Levels in Infancy Can Be Transient

Adelle R. Atkinson, MD and Chaim M. Roifman, MD

Division of Immunology and Allergy, Canadian Centre for Primary Immunodeficiency, Jeffrey Modell Research Laboratory for the diagnosis of Primary Immunodeficiency, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. The immunoglobulin G2 subclasses contain predominantly antipolysaccharide antibodies. It was therefore believed intuitively that low immunoglobulin G2 levels could predispose individuals to infections with encapsulated bacteria. Although many reports initially supported this notion, more recent studies challenged it. Regardless of the biological significance, the natural history of low immunoglobulin G2 levels has not been carefully studied.

METHODS. We studied the outcome of low serum immunoglobulin G2 subclass levels in children. Thirteen patients who were referred because of recurrent infections were found to have low immunoglobulin G2 levels. Laboratory evaluation at presentation and follow-up visits included total serum immunoglobulins, immunoglobulin subclasses, and specific antibodies to protein antigens and to pneumococcal vaccine.

RESULTS. Low immunoglobulin G2 levels resolved completely within 0.6 years to 6 years (median: 1.5 years) in all patients. All 13 patients responded adequately to vaccination with protein antigens such as tetanus toxoid and polio as well as to immunization with pneumococcal vaccine. Four of 13 patients had a previous history of transient hypogammaglobulinemia, raising the possibility that the other cases may simply represent the tail end of this condition.

CONCLUSION. We have demonstrated that low immunoglobulin G2 detected in early infancy and childhood is likely to resolve completely within several months and up to 6 years from the time of presentation.

Key Words: primary immunodeficiency • immunoglobulin IgG subclasses • childhood • infections

Abbreviations: IgG—immunoglobulin G • IgA—immunoglobulin A • IgM—immunoglobulin M • PCP—pneumococcal capsular polysaccharide

Immunoglobulin G (IgG) comprises 4 distinct subclasses that differ in structure and function.1,2 IgG1 is better than IgG2 and IgG3 in fixing complement by the classical pathway, whereas IgG4 does not bind C1q and therefore does not fix complement. IgG1 and IgG3 also bind Fc receptors at higher affinity than IgG2 or IgG4.1–9

Antibodies to protein antigen are predominantly in the IgG1 and IgG3 subclasses, whereas antibodies to polysaccharide antigens are mostly of the IgG2 subclass.3,4 Unfortunately, IgG2 antibodies are the least efficient in crossing the placenta to the disadvantage of the newborn.5,6 This disadvantage continues because production of IgG2 is sluggish, reaching adult levels only during adolescence, whereas IgG1 levels reach adult levels at 3 to 4 years of age.7–10 Acquisition of antipolysaccharide antibodies is also inefficient in the first 2 to 3 years of life.

Beyond these physiologic variations, low levels of IgG2 with or without low IgG4 and in the presence or absence of immunoglobulin A (IgA) deficiency have been linked to repeated infections.1,2 Patients with low IgG2 have been initially reported to have infections with organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and other encapsulated bacteria.11–14 Some of these patients were also reported to have impaired responses to polysaccharide antigens.15,16 However, subsequent studies went on to identify asymptomatic individuals who had reduced IgG2 but normal responses to vaccines that contained polysaccharide antigens.17 Furthermore, there have been descriptions of patients who experienced recurrent bacterial infections and had a reduced ability to produce antipolysaccharide antibodies despite normal IgG subclasses.18,19 Thus, the significance of low IgG2 levels in children and its natural history remain unclear.20

We previously reported that low IgG2 levels may follow the resolution of total IgG levels in a patient with transient hypogammaglobulinemia. IgG2 levels in this patient subsequently normalized.21 Here we followed the outcome of patients with low IgG2 levels in the face of normal total IgG levels. We found that all cases that were diagnosed in infancy or early childhood with low IgG2 levels eventually resolved.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
All patients who were referred to the immunology clinic at the Hospital for Sick Children for evaluation between 1987 and 2005 were considered. Patients with normal quantitative IgG and below-normal IgG2 in the presence or absence of low IgG4 subclass were included in the study when they were available for appropriate follow-up. Patients with a diagnosis of a well-defined primary immunodeficiency such as chronic mucocutaneous candidiasis, combined immunodeficiency, Wiskott Aldrich syndrome, or ataxia telangiectasia were excluded from the evaluation.

The following was collected on patients who met the inclusion criteria: gender; age at presentation; reason for first referral; duration of follow-up; and serum IgG, IgA, and immunoglobulin M (IgM) and IgG subclasses at presentations and at each subsequent visit. Titers to polio, tetanus, measles, mumps, and rubella were determined at presentation and periodically thereafter. Responses to pneumococcal vaccine were also measured. The study protocol was approved by the Hospital for Sick Children Research Ethics Board.

Lymphocyte Markers and T Cell Proliferative Responses
The surface phenotypes of blood mononuclear cells obtained by Ficoll-Hypaque density gradient centrifugation were determined by direct immunofluorescence with fluorescein isothiocyanate–conjugated goat anti-human immunoglobulin antibody (Tago, Burlingame, CA) or fluorescein isothiocyanate–conjugated monoclonal antibodies anti-CD3, CD4, CD8, CD20, and CD56 (Coulter Instruments, Mississauga, Ontario, Canada). Analysis was performed on a Coulter EPICS V flow cytometer. Lymphocyte proliferative responses to mitogens including phytohemagglutinin were determined by tritiated thymidine incorporation using the microtiter plate technique. All assays were performed in triplicate and were compared with those simultaneously performed on normal controls.22

Serum concentration of Immunoglobulins and IgG Subclasses
Serum concentrations of immunoglobulins were measured by nephelometry. Quantification of IgG subclasses was done by using the BINDARIO kit (The Binding Site Ltd, Birmingham, United Kingdom). The kit is based on single radial immunodiffusion methods that were derived from the work of Fahey et al23 and Mancini et al.24 In short, the method detects a protein diffusing radially from a cylindrical well through an agarose gel that contains the appropriate antibody. The resulting immune complexes form a precipitin ring. Once the ring size reaches equilibrium, a linear relationship exists between the square of the ring diameter and the concentration of the IgG subclass. The concentration of an IgG subclass in an unknown sample may be determined by measurement of the ring diameter and reading off the calibration curve. Normal range was determined according to evaluation of 40 to 50 normal infants and children for each age group: 0 to 2 years, 2 to 4 years, 4 to 6 years, 6 to 8 years, 8 to 10 years, 10 to 12 years, 12 to 14 years, and 14 to 18 years. Mean and SDs were determined using least-squares regression analysis.23,24

Determination of Specific Antibodies
Levels of serum antibodies to tetanus, measles, mumps, and rubella were measured by enzyme-linked immunosorbent assay (Vacczyme anti–tetanus toxoid IgG enzyme immunoassay kit, Euroimmune Mumps EIA kit, Euroimmune Measles kit, and Euroimmune rubella kit; Euroimmune, Gross-Groenau, Germany). Polio antibody titers were determined by complement fixation according to the manufacturer's instructions and as previously described.21,22 Antipneumococcal antibodies were assessed using 2 kits, according to the manufacturer's instructions. Anti–pneumococcal capsular polysaccharide (PCP) IgG enzyme immunoassay kit and anti-PCP IgG2 enzyme immunoassay kit both were manufactured by The Binding Site Ltd. The assays are designed for the in vitro measurement of specific IgG antibodies against PCP present in human serum. The kits are designed to measure antibody responses to pneumococcal vaccines incorporating 23 polysaccharides that are isolated from Streptococcus pneumonia.25 The PCP antigens used include 1 to 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F according to Danish nomenclatures.

In short, the principle of assay includes microdisks precoated with PCP antigens. Calibrators, controls, and diluted patient samples are added to the wells, and antibodies that recognize the PCP antigens are allowed to bind during the incubation. Purified peroxidase sheep-labeled anti-human IgG or IgG2 conjugate is added. The bound conjugate is visualized with tetramethylbenzidine substrate, which gives a blue reaction.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
Thirteen patients who met the study inclusion criteria were 1.0 to 4.5 years of age at presentation (mean: 4 years; median: 3.7 years) and were followed for a period that ranged from 0.6 to 6.0 years (mean: 2.5 years; median: 1.5 years; Table 1).


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  		TABLE 1 Patients Features

 
Clinical Features
Patients were referred to the immunology clinic because of repeated infections (Table 1). Most common, recurrent otitis media (7 patients) and repeated upper respiratory infections (4 patients) were reported. Two patients had >1 episode of pneumonia, 3 patients had a history compatible with recurrent sinusitis, and 4 were referred because of recurrent diarrhea. One patient presented with recurrent varicella infections. In addition to the history of infections, 2 patients had asthma and 1 of them also had eczema. During follow-up, no major invasive infection was registered in the patients. Specifically, no episodes of pneumonia, acute sinusitis, abscesses, or meningitis were recorded. However, normal frequency of upper respiratory infection or otitis media were reported in 5 patients during the follow-up period. In addition, patient 4 continued to have repeated episodes of sinusitis even after IgG2 levels normalized. He experienced 3 episodes in a period of 4.5 years of follow-up.

Evaluation of the Immune System
Serum IgG and IgM levels were normal in all studied patients. IgA levels that were below normal but still detectable were found in 1 of 13 patients at presentation.

Specific antibody response to tetanus vaccine was normal in 12 of 13 patients tested at presentation. The remaining patients responded normally after reimmunization. Responses to polio vaccine were also normal in all patients. Isohemagglutinin levels when examined at the age of 2 years or older were also normal in 12 of 13 patients (1 patient had an AB blood group). Responses to vaccination with Pneumovax was also normal in all 13 patients.

Four patients had additional laboratory evaluation, including lymphocyte markers as well as in vitro responses to mitogens and antigens. All 4 patients had normal markers and mitogenic responses.

IgG Subclasses
All patients had low IgG2 level, and 3 also had a reduced IgG4 level. For the purpose of this study, only patients with extremely low IgG2 levels were included. All patients had IgG2 levels <95th percentile range (Fig 1); 3 of 13 had undetectable IgG2 levels at presentation.


Figure 1
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  		FIGURE 1 Serum IgG2 levels. Triangles represent the values of IgG2 at presentation in 13 patients who completed follow-up; their IgG levels eventually normalized. Ovals represent IgG2 values in 13 patients at the end of their follow-up periods. The mean normal values per age as well as the lower limit (2 SDs) are depicted.

 
Within 0.6 years to 6.0 years (mean: 2.24 years; median: 1.5 years), IgG2 levels returned to the reference range in all 13 patients who were available for follow-up (Fig 1). All 3 patients who had low IgG4 levels also normalized by the end of follow-up.

Transient Hypogammaglobulinemia and Low IgG2 Levels
Three of 13 patients had a history of transient hypogammaglobulinemia. Although IgG levels normalized, the IgG2 fraction remained low for a period that ranged from 1.0 to 4.5 years. This finding raises the possibility that the other patients with low IgG2 in our study may have gone through a similar course.


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We studied here the outcome of low IgG2 in 13 infants and children. The pathogenesis of "IgG2 deficiency" remains unknown. A delay in IgG2 production in infants seems physiologic, because IgG1 but not IgG2 reaches near adult normal levels by 3 to 4 years of age.7–10 It is possible that in the cases reported here, there may be an exaggeration of this physiologic process.

Alternatively, the low IgG2 levels observed in these patients may be part of and perhaps the end of transient hypogammaglobulinemia. Thus, despite normalizing total IgG levels, IgG2 subclass levels remain low for a while until they reach normal values.21 Indeed, 3 patients in this series had a history of transient hypogammaglobulinemia. It is conceivable that in the rest of the patients, transient low IgG levels may have been missed before the identification of IgG2 subclass deficiency. Such a scenario is plausible because both transient hypogammaglobulinemia and low IgG2 subclass levels have been detected in asymptomatic individuals.17

Throughout the 1980s, a variety of publications cited the association of low subclasses with recurrent sinopulmonary infections.11–16 The link was based on the assumption that reduced IgG2, which contains predominantly polysaccharide antibodies,1,2 should intuitively be associated with an increased susceptibility to infection caused by encapsulated bacteria. Subsequent studies severely challenged this theory. First, asymptomatic children with low IgG2 levels were found to have normal responses to polysaccharide antigens after vaccination.17 Furthermore, children who have some inability to produce antipolysaccharide antibody have been found to have normal serum levels of IgG2 in isolation18,19 or as a feature of Wiskott-Aldrich syndrome.26 Finally, heavy-chain deletion of various IgG subclasses was identified in asymptomatic individuals.27,28 Together, these findings question the causative link between IgG2 deficiency and susceptibility to infections.

Patients in this study were referred to us because of a history of recurrent infection. Assessment of responses to polysaccharide antigens was limited to children who were older than 2.5 years because studies in younger children are inconsistent and lack reliability. Evaluation that was performed in patients who were older than 2.5 years at presentation or later during follow-up showed normal responses to unconjugated polyvalent pneumococcal vaccine. These results are consistent with the observation that during follow-up, patients did not report severe invasive infections. One patient continued to have repeated episodes of sinusitis after IgG2 normalized, suggesting that infections in these patients may not have been related to the level of serum IgG2 subclass. It is possible that these patients had a history of infections because of a previous condition of transient hypogammaglobulinemia, or, alternatively, the clinical history was part of a normal pattern of infections in this age group.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This unique follow-up of patients with low IgG2 subclass levels demonstrates that this phenomenon could be transient and is therefore of limited biological significance. In most cases, it may reflect an exaggeration of an already existing maturational delay in producing IgG2 subclass, possibly as the last stage in resolution of transient hypogammaglobulinemia.


   ACKNOWLEDGMENTS
 
This work was supported by the Canadian Immunodeficiency Society, the Jeffrey Modell Foundation, and the Donald and Audrey Campbell Chair in Immunology.

We thank Ms Rena Roifman for collecting the data.


   FOOTNOTES
 
Accepted Mar 22, 2007.

Address correspondence to Chaim M. Roifman, MD, Division of Immunology/Allergy and Infection, Immunity, Injury and Repair Program, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: chaim.roifman{at}sickkids.ca

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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