Background
Immunoglobulin (Ig) G (IgG) is the predominant of five classes of Ig (IgG, IgA, IgM, IgE, and IgD). Igs differ in heavy chain structure and effector function [
1]. IgG1, the largest IgG subclass, represents ~ 60% of IgG [
1,
2] and has a half-life of 21 days [
3]. Antibody responses to soluble protein and membrane antigens primarily induce IgG1 [
1,
4], although polysaccharides and allergens also elicit IgG1 responses [
1]. In two studies, adults with frequent or severe respiratory tract infection had subnormal IgG1 (< 2 standard deviations (SD) below respective means) in the absence of subnormal levels of other IgG subclasses, subnormal IgA, or subnormal IgM [
5,
6].
In normal adults, IgG2 represents ~ 30% of serum IgG [
1,
2]. IgG2 activates complement less readily than IgG1 and IgG3 [
1], has low affinity for Fc receptors on phagocytes (FcγR) [
1], crosses the placenta less freely than other IgG subclasses [
7,
8], and has a half-life of 21 days [
3]. IgG2 is the predominant antibody that responds to bacterial polysaccharide antigens [
9‐
12]. Some persons with frequent or severe respiratory tract infection have subnormal IgG2 (< 2 SD below respective means) [
13‐
16].
In normal adults, IgG3 represents ~ 4% of serum IgG [
1,
17]. IgG3 activates complement more readily than other IgG subclasses [
1], has high affinity for Fc receptors on phagocytes (FcγR) [
1], crosses the placenta less readily than IgG1 and IgG4 but more so than IgG2 [
18], and has an overall half-life of ~ 7 days [
1,
3]. Some adults with frequent or severe respiratory tract infection have subnormal IgG3 (< 2 SD below respective means) [
19‐
21].
IgG subclass deficiency (IgGSD) is characterized by frequent or severe upper or lower respiratory tract infection, one or more subnormal IgG subclass level(s) (≤ 2 SD below respective means) unexplained by other causes, and decreased IgG response to pneumococcal polysaccharide vaccination (PPSV) [
20‐
25]. The predominance of women with IgGSD [
21,
24,
25] becomes evident at ages ≥ 16 y [
22]. IgGSD occurs in ~ 1 in 10,000 persons [
26]. In two studies, IgG levels were subnormal in 38% and 46% of adults with IgGSD who had subnormal IgG1 only [
5,
6] and in three adults with IgGSD and subnormal IgG2 in whom IgG1 levels were not subnormal [
16]. These observations suggest that both IgG1 and IgG2 are determinants of IgG in adults with IgGSD.
We sought to identify factors associated with IgG levels in adults at diagnosis of IgGSD. We performed a retrospective chart and data review to identify adults diagnosed with IgGSD in a hematology clinic who had subnormal IgG1 only, combined subnormal IgG1/IgG3, or subnormal IgG3 only at diagnosis without other subnormal IgG subclasses, subnormal IgA, or subnormal IgM. We compiled these data: age at diagnosis; sex; autoimmune condition(s) (AC); atopy; serum levels of IgG, IgG subclasses, IgA, IgM; IgGsum (IgG1 + IgG2 + IgG3 + IgG4); and the D-parameter (D), the percentage difference between IgGsum and IgG [
27]. In subnormal IgG1 only or combined subnormal IgG1/IgG3 subclass groups, we compared clinical and laboratory attributes of patients with and without IgG < 7.00 g/L. In each of the three subnormal Ig subclass groups, we analyzed relationships of IgGsum and IgG, performed backward stepwise regression on IgG and D using appropriate variables, computed correlations of IgG1 and IgG2, and determined IgG subclass proportions of IgGsum. We discuss the present results in the context of factors that influence IgG and IgG subclass levels in adults with IgGSD.
Discussion
This study of adults with IgGSD demonstrates that both IgG1 and IgG2 are major determinants of IgG in patients with subnormal IgG1, combined subnormal IgG1/IgG3, or subnormal IgG3, after adjustment for other variables. In patients with subnormal IgG1 or combined subnormal IgG1/IgG3, we also demonstrate that median IgG2 levels are significantly lower in those with IgG < 7.00 g/L than those with IgG ≥ 7.00 g/L. In the present study, IgG < 7.00 g/L occurred in 39% of patients with subnormal IgG1 only and 60% of patients with combined subnormal IgG1/IgG3. These latter observations are consistent with two respective reports that IgG was subnormal (< 7.00 g/L) in 38% and 46% of adults with IgGSD who had subnormal IgG1 only without other subnormal IgG subclasses, subnormal IgA, or subnormal IgM [
5,
6], contradicting previous suggestions that patients with low IgG1 will most likely be identified without IgG subclass testing [
31,
32].
In the present patients with subnormal IgG1 subclass patterns, mean IgG1 was significantly lower in those with IgG < 7.00 g/L than IgG ≥ 7.00 g/L. Regressions on IgG revealed significant positive associations of IgG1, both in patients with subnormal IgG1 only and patients with combined subnormal IgG1/IgG3, after adjustment for other variables. In 12 adult patients with IgGSD and subnormal IgG2 and subnormal IgG, nine also had subnormal IgG1 [
16]. These observations demonstrate that IgG1 is a major component of IgG in adults with IgGSD as it is in subjects unselected for subnormal IgG subclass levels [
2,
4,
28‐
30].
IgG2 levels in the present patients were within reference limits, by definition. Regardless, mean or median IgG2 levels in patients with subnormal IgG1 subclass levels were significantly lower in patients with IgG < 7.00 g/L than in patients with IgG ≥ 7.00 g/L. Regressions on IgG revealed significant positive associations of IgG2 in both subnormal IgG1 subclass groups, after adjustment for other variables. In 12 adults with IgGSD selected for subnormal IgG2 levels who also had subnormal IgG, three had normal IgG1 [
16]. These observations demonstrate that IgG2 is also a major component of IgG in adults with IgGSD as it is in normal subjects [
1,
2,
4,
28‐
30]. In contrast, none of 115 adults with IgGSD and subnormal IgG3 only had subnormal IgG [
20].
In patients with subnormal IgG1, the prevalence of AC was significantly greater in those with IgG ≥ 7.00 g/L than IgG < 7.00 g/L. This suggests that preferential synthesis of IgG1, IgG2, or both may occur as a consequence of one or more AC. In another study, respective mean serum levels of IgG1 were significantly higher and mean serum levels of IgG2 were significantly lower in patients with primary Sjögren syndrome (pSS), systemic lupus erythematosus (SLE), and systemic sclerosis than in healthy controls [
33]. Two other studies found that serum IgG1, IgG2, and IgG3 levels were significantly higher in patients with pSS [
34] and SLE [
35] than in normal control subjects.
IgG1 percentages of IgGsum were significantly lower and IgG2 percentages of IgGsum were significantly higher in patients with subnormal IgG1 subclass levels than in patients with subnormal IgG3 only. Correlations of IgG1 and IgG2 values in patients with subnormal IgG1 subclass levels were not significant. Although the correlation of IgG1 and IgG2 was significant in patients with subnormal IgG3 only, the strength of the Pearson correlation coefficient was low. Taken together, these observations suggest that a) IgG1 and IgG2 subclass proportions of IgGsum and absence of significant correlation of IgG1 and IgG2 in the present patients with subnormal IgG1 subclass levels are consequences of the subnormal IgG1 selection criteria we used; and/or that b) that synthesis of IgG1 and IgG2 in adults with IgGSD and subnormal IgG1 subclass levels is not regulated in tandem.
IgG1, IgG2 and IgG3 molecules have polymorphic antigens known as Gm (gamma marker) allotypes on the constant regions of their respective γ1, γ2, and γ3 heavy chains encoded in
IGHG loci (chromosome 14q32.33
) [
36,
37]. Some Gm allotypes are associated with different serum Ig levels. For example, the “normal” IgG2 range for persons with allotype G2m(23)- is 35% lower than that of persons with G2m(23) + [
38]. There was a three-fold difference across mean serum IgG3 levels of normal adults grouped by G3m allotypes [
29]. Few persons have deletions or other structural changes in
IGHG loci that decrease the level of one or more IgG subclasses [
39‐
43]. Most patients with IgGSD have dysfunctional regulation of IgG subclass production [
44]. Intravascular distributions, fractional catabolic rates, and average biologic half-lives of IgG1 and IgG2 are similar [
3].
All patients in this study presented with frequent or recurrent upper or lower respiratory tract infection and some of them were discovered to have subnormal IgG1 subclass levels. Adults in two other studies also had frequent or recurrent upper or lower respiratory tract infection and subnormal IgG1 only [
5,
6]. In a California cohort of 78 adults with IgGSD, 27 (35%) had subnormal IgG1 (< 3.42 g/L), alone or in combination with subnormal IgG3 or IgG4 [
21]. In a study of 3005 persons ≥ one year of age who had frequent or severe episodes of infection (and their relatives) and other patients without infection discovered incidentally to have hypogammaglobulinemia, 119 (4%) had subnormal IgG1 only [
45]. Of these 119 patients, 83% had infections, especially sinusitis [
45]. These and related observations [
46] suggest that the proportion of adults with subnormal IgG1 who have or eventually develop frequent or severe respiratory tract infection is high.
Mean IgG2 was significantly lower in patients with IgG < 7.00 g/L than IgG ≥ 7.00 g/L in this study, although the IgG2 level of each patient was within the reference limit. Subnormal IgG2 is associated with frequent or severe respiratory infection in some persons [
13‐
16], whereas other persons with subnormal or absent IgG2 are healthy [
30,
40,
41,
47,
48]. Thus, it is unknown whether quantitative differences in IgG2 levels in the present patients contributed to their frequent or severe respiratory tract infection.
IgG3 exerts multiple effector functions against many viral and bacterial pathogens [
1,
49]. Subnormal IgG3 only is the most common IgGSD pattern in adults [
19‐
21,
25]. Nonetheless, IgG3 levels < 2 SD between population means are common in ostensibly healthy adults [
2,
28‐
30] and in some patient groups unselected for frequent or severe respiratory tract infection or subnormal Ig [
50‐
52].
The mean difference in IgG and IgGsum in the present adults with subnormal IgG1 only subgrouped by IgG1 levels (< 7.00 g/L vs. IgG ≥ 7.00 g/L) was ~ 16%. In another study, IgG and IgGsum differed by > 15% in 11% of 571 consecutive clinical samples [
53]. The difference between IgG and IgGsum correlated with the proportion but not level of IgG1 [
53]. After dilution of samples with differences > 15%, repeat testing did not reduce the differences significantly [
53]. In the present study, we did not observe significant mean differences in D in adults with combined subnormal IgG1/IgG3 subgrouped by IgG1 levels (< 7.00 g/L vs. IgG ≥ 7.00 g/L).
Infection susceptibility was increased in persons with common AC [
54‐
58] and atopy [
59‐
62] who were unselected for IgGSD. The odds of respiratory tract infection were significantly increased in male Finnish military recruits with mannose-binding lectin levels below the median, after adjustment for asthma status [
63]. In contrast, the prevalence of mannose-binding lectin ≤ 50 µg/L in white adults with IgGSD did not differ significantly from that in general European white populations [
64]. In persons with subnormal IgE, the prevalence of frequent or severe respiratory tract infection [
65,
66], other subnormal Ig isotypes [
65,
67], and autoimmune conditions [
66,
67] was significantly greater than that of control subjects. Hypogammaglobulinemia E in adults with IgGSD was negatively associated with bronchitis, allergic asthma, IgG1, and levels of blood CD4 + lymphocytes, after adjustment for other variables [
68].
In this study, there was a predominance of women in all IgGSD groups, consistent with other reports of IgGSD in adults [
6,
16,
19‐
21,
24,
45,
69]. The predominance of females among persons with IgGSD becomes evident at puberty [
70]. AC are common in adults with IgGSD [
6,
16,
19‐
21,
45] and women predominate among adults with AC [
71,
72]. The prevalence of chronic rhinosinusitis in women, the most common respiratory tract infection in adults with IgGSD [
21,
64], is twice that of men [
73]. Taken together, it is plausible that factors related to the X-chromosome, X-chromosome inactivation, or hormonal differences between women and men could explain the predominance of women in cohorts of adults with IgGSD, although this is unproven.
Elevated IgA occurred in 5% of 187 women and no men in this study, although the difference in prevalence was not significant. Elevated IgA occurs in some patients with AC [
74,
75] and others with cirrhosis due to chronic hepatitis B [
76]. In healthy women and men grouped by age, there was no significant difference in mean IgA levels [
77].
Elevated IgM occurred in 15% of 187 women and none of 20 men in this study. Elevated IgM levels are common in AC [
78]. In 404 adults in the U.S. ages 20–89 y without conditions known to affect Ig levels, women had significantly higher IgM levels than men, regardless of age [
77]. In a population-based survey of 460 adults in Spain, there was a significant negative association of male sex with IgM levels, after adjustment for other variables [
79]. Serum IgM levels in adults are directly related to the number of X-chromosomes [
80].
The present regression analyses demonstrate that IgG1 and IgG2 levels account for 71–82% of the variance of IgG levels in 207 adults with IgGSD. Thus, we infer that other factors not included in our analyses also influence IgG levels. We cannot exclude the possibility that AC, atopy, IgA, or IgM levels also influence IgG, although that possibility is not suggested by the results of the present univariate analyses. IgG subclass data from individual age- and sex-matched control subjects unselected for frequent or severe upper or lower respiratory tract infection or IgGSD were not available for analysis. Results in other IgGSD cohorts could vary due to referral differences and between-laboratory variation in methods of analysis, control data, and consequent IgG and IgG subclass reference limits. Ascertaining Gm allotypes, studying specific antibody activity, quantifying IgGSD responses to PPSV, and measuring IgE and mannose-binding lectin levels were beyond the scope of this work.
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