Functional and Immunoreactive Levels of IgG4 Correlate with Clinical Responses during the Maintenance Phase of House Dust Mite Immunotherapy

Mulin Feng, Qiujuan Su, Xuxin Lai, Mo Xian, Xu Shi, Peter Adler Wurtzen, Rundong Qin, Xiaohui Zeng and Jing Li
J Immunol June 15, 2018, 200 (12) 3897-3904; DOI: https://doi.org/10.4049/jimmunol.1701690

Abstract

Allergen-specific immunotherapy for house dust mite allergy is effective, but there are no validated biomarkers reflecting or predicting the clinical efficacy. We aimed to investigate the relationship between clinical outcomes and functional responses of allergen-specific IgG4 (sIgG4) and specific IgE (sIgE) during Dermatophagoides pteronyssinus s.c. allergen immunotherapy (SCIT) in allergic rhinitis and/or asthma patients. Combined symptom medication scores (SMS), D. pteronyssinus–sIgG4 levels, D. pteronyssinus–sIgE levels, and the serum inhibitory capacity against D. pteronyssinus–sIgE facilitated allergen binding to B cells (IgE-FAB) were determined during the updosing (week 0, 4, 12, and 16) and maintenance (week 52, 104, and 156) phase of SCIT. We found that SCIT patients had a significant improvement in SMS from week 52 to 156 compared with medication-treated control subjects (p < 0.05). Levels of D. pteronyssinus–sIgG4 in SCIT patients showed a significant increase from week 12 to 156 (p < 0.05). Serum obtained from SCIT patients significantly inhibited D. pteronyssinus–sIgE binding to B cells after 16 wk (p < 0.01). Significantly lower levels of D. pteronyssinus–sIgE were observed in SCIT patients after 52 wk (p < 0.05). A significant relationship was demonstrated between SMS and IgE-FAB or D. pteronyssinus–sIgG4 during the maintenance phase according to linear regression analysis. In conclusion, D. pteronyssinus–sIgG4 level and D. pteronyssinus IgE-FAB are associated with clinical efficacy in the maintenance phase rather than the updosing phase of SCIT. Immunologic tolerance can be induced with SCIT when maintenance phase is achieved.

Introduction

Allergen-specific immunotherapy (AIT) is an effective treatment for allergic rhinitis, allergic asthma, and other IgE-mediated allergic diseases (1). The mechanisms that are associated with successful immunotherapy involve Ab responses and cellular reactions (2). Cellular changes include the generation of allergen-specific T regulatory and B regulatory cells and suppression of allergen-specific Th2 cells (3). Allergen immunotherapy has been shown to reduce specific IgE (sIgE) production (4). Treatment is also associated with the induction of allergen-specific IgG Abs, in particular, specific IgG4 (sIgG4) Abs. IgG4 Abs are thought to compete with sIgE for binding to allergens, inhibiting allergen-IgE complex formation on mast cells, basophils, and other sIgE receptor–expressing cells (5). Indeed, studies have demonstrated serum IgG4 Abs were responsible for inhibiting allergen-IgE complex binding to B cells (6). However, the change of immunoreactive IgG4 levels has shown a poor correlation with clinical response as measured by symptom and medication scores (7, 8). One possible explanation for this discrepancy is that AIT may induce the production of new sIgG4 with augmented binding specificity and/or affinity. Several assays can be used to measure the functional activities of IgG involving competition between IgE and serum inhibitory Abs, such as IgE-facilitated allergen presentation (9), IgE-facilitated allergen binding to B cells (IgE-FAB) assay—which measures the serum inhibitory capacity of allergen-IgE complex binding to B cells (10, 11) and IgE-blocking factors (12). These functional assessments of IgG4 may be a more suitable surrogate than simple IgG4 concentration when studying immunologic efficacy.

Our previous studies have shown that house dust mites (HDM) such as Dermatophagoides pteronyssinus and Dermatophagoides farinae were the most prevalent allergens in patients with asthma and/or rhinitis in China (13). We also have demonstrated prominent IgG4 responses in D. pteronyssinus–specific immunotherapy (14). Other investigators demonstrated that depletion of IgG4 resulted in a reduction in serum inhibitory activity (15). In this study of D. pteronyssinus s.c. allergen immunotherapy (SCIT), we investigate the association of clinical outcomes with measured D. pteronyssinus–sIgG4 titers as well as functional assays. Because sIgE is a critical element of the IgE-FAB assay, we also observed the changes in the serum level of D. pteronyssinus–sIgE.

Materials and Methods

Study design and population

The study included a total of 83 subjects, 35 children (age ≤14 y) and 48 adults (age 15–57 y), with mild-to-moderate asthma and/or rhinitis; of these, 52 cases received D. pteronyssinus SCIT and 31 controls received standard medications (Table I). All patients came from the Allergy and Clinical Immunology Department of Guangzhou Institute of Respiratory Diseases, fulfilled the Allergic Rhinitis and its Impact on Asthma guideline for allergic rhinitis and/or the Global Initiative for Asthma guideline for mild-to-moderate asthma (16, 17), and had positive skin prick tests and sIgE to D. pteronyssinus. Patients visited the hospitals for treatments and clinical evaluations. Serum samples were collected before treatment and at specific time points during treatment (updosing phase: week 0, 4, 12, and 16; maintenance phase: week 52, 104, and 156). The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University and registered at http://www.chictr.org.cn (ChiCTR-OOC-15006207). Written informed consent was obtained from all adult patients and from parents of the children.

Skin prick tests

Sensitization to HDM aeroallergens including D. pteronyssinus and D. farinae (Soluprick SQ; ALK-Abelló A/S, Hørsholm, Denmark) was assessed. A positive skin reaction was defined as a wheal size ≥3 mm after subtraction of the negative control.

Detection of serum IgE and IgG4

The levels of total IgE and sIgE against D. pteronyssinus and D. farinae in all serum samples were measured by Pharmacia CAP fluorescence enzyme immunoassay system (Thermo Fisher Scientific) at week 0, 4, 12, 16, 52, 104, and 156. The sIgE results are reported as kilounits per liter, with a cut-off value of 0.35 kU/l and upper sIgE detection limit of 100 kU/l. Any sample with an sIgE level >100 kU/l was diluted and tested again. Serum D. pteronyssinus–sIgG4 levels were measured by a four-layer sandwich ELISA using methods we reported previously (14).

Spirometry and histamine bronchial provocation test

Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured (week 0, 4, 12, 16, 52, 104, and 156) using a MicroQuark Spirometer (Cosmed), which met the standards of the American Thoracic Society and the European Respiratory Society (18); the findings are presented as the percent predicted value (FVC% and FEV1%). The presence of airway hyperresponsiveness (AHR) was assessed by the rapid histamine inhalation provocation test (19). AHR was defined as provocative dose of histamine causing a 20% fall in FEV1 (PD20) when a ≤7.8 μmol cumulative dose of histamine had been administered. AHR classification was based on the decline of FEV1: 4 = severe AHR (PD20-FEV1 < 0.1 μmol), 3 = moderate AHR (0.1 μmol < PD20-FEV1 ≤ 0.8 μmol), 2 = mild AHR (0.8 μmol < PD20-FEV1 ≤ 3.2 μmol), 1 = very mild AHR (3.2 μmol < PD20-FEV1 ≤ 7.8 μmol), and 0 = normal (PD20-FEV1 > 7.8 μmol). Bronchial dilation tests were performed in those with FEV1 <70% of the predicted value. An increase of ≥12% and ≥200 ml from baseline in FEV1 in ∼10–15 min after administration of 400 mcg of salbutamol was considered positive and arbitrarily defined as class 5. Only those FEV1 ≥70% of the predicted value after dilation test were accepted to SCIT (20).

SCIT protocol

The patients were treated with s.c. injections of standardized aluminum-formulated D. pteronyssinus Alutard-SQ vaccine (ALK-Abelló A/S). The treatment protocol followed the recommended updosing schedule of 16 wk before reaching a maintenance dose of 100,000 Alutard-SQ, which was maintained to complete 3 y of SCIT (Fig. 1).

Clinical evaluations

The patients were requested to complete a symptom and medication diary during the whole course of treatment. Patients were asked to rate the symptoms of asthma (daytime: 0–5; nighttime: 0–4) and rhinitis (daytime or nighttime: 0–2) according to the severity and frequency of the symptoms in disturbing daily activities and sleep (21). The medication score is calculated by assigning a score of 1–160 μg of budesonide or the equivalent dose of inhaled corticosteroid or 130 μg of budesonide or the equivalent dose of nasal corticosteroid, each puff of salbutamol/terbutaline or the equivalent dose of another inhaled β2-agnoist, and 10 mg of oral loratidine or the equivalent dose of another oral antihistamine. Combined symptom medication scores (SMS) were defined as the sum of symptom scores and medication scores (22).

Serum IgE-FAB

Serum inhibitory activity against D. pteronyssinus–sIgE binding to B cells was performed as Shamji et al. (23) described. Specifically, stock indicator serum (10 μl) containing a high concentration of D. pteronyssinus–sIgE (192 kU/l) was preincubated with 2 μg/ml D. pteronyssinus extract (ALK-Abelló A/S) at 37°C for 1 h to form D. pteronyssinus–IgE complexes. To test for the inhibition of facilitated allergen binding, we mixed an equal volume of indicator serum (10 μl) with test serum (10 μl) or an equal volume of RPMI 1640 as a control. EBV-transformed B cells (10 μl, 1 × 107/ml) were then added to the D. pteronyssinus–IgE mixture and incubated for 1 h at 4°C. Cells were washed, and bound complexes were revealed using a polyclonal human anti-IgE Ab (AbD Serotec) and detected by flow cytometry (Beckman Coulter Epics XL-MCL). The calculation formula was as follows: percent relative allergen-IgE complex binding to B cells = (%IgE-FAB using indicator and immunotherapy serum / %IgE-FAB using indicator serum only) × 100.

Statistical analysis

Statistical analysis was performed using SPSS version 16.0. Student t tests for unpaired data were used to analyze between-group differences in FEV1, FVC, AHR, total IgE, and sIgE, and the Wilcoxon test was used to analyze within-group differences. The Mann–Whitney U test was used to analyze between-group differences in SMS, log D. pteronyssinus–sIgG4, and IgE-FAB. Values are shown as mean ± SE. Linear regression was employed to analyze the relationship between log D. pteronyssinus–sIgG4, IgE-FAB and SMS, and AHR. Differences were considered significant when p values < 0.05.

Results

Patient characteristics

The baseline demographic data, SMS, and Ab levels of all subjects are shown in Table I. There were no differences between the SCIT and medication group in gender, symptom and medication scores, AHR, FEV1, or serum IgE levels.

View this table:
Table I. The basic information of all patients in SCIT group and medication group

Changes of clinical outcomes

SMS of asthma and rhinitis decreased significantly from baseline after 12 wk of treatment in both groups (p < 0.05), with significantly more impressive decline in SCIT subjects than medication-treated subjects at week 52–156 (p < 0.05). FEV1% did not change significantly during treatment in either group. However, SCIT patients had greatly decreased AHR grades at week 52–156 (p < 0.05) (Figs. 1, 2).

FIGURE 1.
FIGURE 1.

Flow chart of dosing schedule of injection and visits for clinical evaluation and blood sampling.

FIGURE 2.
FIGURE 2.

Time course of mean SMS (A) AHR, (B) FEV1% predicted, (C) and FVC% predicted (D) in SCIT group and control group at visit time points. *p < 0.05, *' p < 0.01, *”p < 0.001 when compared with week 0. §p < 0.05, §’p < 0.01 when compared with control.

Changes of serum Abs

SCIT patients showed significant increases in D. pteronyssinus–sIgG4 concentrations beginning at week 12, with 37- to 73-fold increases from week 52 to 156 (p < 0.01). Serum samples obtained from SCIT patients revealed an increasing capacity to inhibit D. pteronyssinus–sIgE complex binding to B cells, but this began appearing at week 16 (IgE-FAB: 0 wk = 112.1 ± 2.9%, 4 wk = 112.1 ± 3.9%, 12 wk = 112.8 ± 3.0%, 16 wk = 71.7 ± 4.2%, 52 wk = 45.1 ± 3.1%, 104 wk = 35.7 ± 3.4%, 156 wk = 31.1 ± 3.8%, p < 0.01). The medication-treated subjects did not show these changes (Fig. 3A, 3B). Significantly lower levels of D. pteronyssinus–sIgE and D. farinae–sIgE were observed after 52 wk in SCIT subjects (D. pteronyssinus–sIgE: 0 wk = 97.0 ± 16.3 kU/l, 52 wk = 71.3 ± 14.5 kU/l, 104 wk = 71.8 ± 15.1 kU/l, 156 wk = 66.6 ± 15.5 kU/l; D. farinae–sIgE: 0 wk = 96.9 ± 14.5 kU/l, 52 wk = 75.6 ± 15.8 kU/l, 104 wk = 70.6 ± 15.5 kU/l, 156 wk = 64.4 ± 14.5 kU/l) when compared with baseline and to the medication-treated patients (p < 0.05) (Fig. 3C, 3D). No significant differences between or changes of total IgE were seen during the treatment in either group (p > 0.05) (Fig. 3E).

FIGURE 3.
FIGURE 3.

Time course of mean D. pteronyssinus–sIgG4 (A) IgE-FAB, (B) D. pteronyssinus–sIgE, (C) D. farinae–sIgE, (D) and total IgE (E) in SCIT group and medication group at visit time points. *p < 0.05, *’p < 0.01, *”p < 0.001 when compared with week 0. §p < 0.05, §p < 0.01, §’p < 0.001 when compared with control. #p < 0.05 when compared with week 52. Der f, D. farinae; Der p, D. pteronyssinus.

The linear regression between D. pteronyssinus–sIgG4, IgE-FAB, and clinical outcomes

SMS were found to have a significant but modest linear association with D. pteronyssinus–sIgG4 and IgE-FAB during the maintenance phase (the coefficient of determination is denoted as R2; D. pteronyssinus–sIgG4 at 52 wk: R2 = 0.13, p = 0.012; 104 wk: R2 = 0.18, p = 0.005; 156 wk: R2 = 0.16, p = 0.018; IgE-FAB at 52 wk: R2 = 0.12, p = 0.013; 104 wk: R2 = 0.16, p = 0.010; 156 wk: R2 = 0.18, p = 0.016), which was not present during the updosing phase (Fig. 4). IgE-FAB was found to have a significant (but modest) linear association with AHR only at week 156 (R2 = 0.18, p = 0.016) (Fig. 5).

FIGURE 4.
FIGURE 4.

The relationship between SMS and D. pteronyssinus–sIgG4 and IgE-FAB. (A) Week 4, (B) week 12, (C) week 16, (D) week 52, (E) week 104, (F) week 156, according to linear regression analyses. Der p, D. pteronyssinus.

FIGURE 5.
FIGURE 5.

The relationship between AHR and D. pteronyssinus–sIgG4 and IgE-FAB. (A) Week 4, (B) week 12, (C) week 16, (D) week 52, (E) week 104, (F) week 156, according to linear regression analyses. Der p, D. pteronyssinus.

Discussion

To our knowledge, this is the first study to assess the time course of the functional properties of serum IgG Abs, the so-called “blocking Abs,” during HDM SCIT in allergic rhinitis and/or asthma patients by using the IgE-FAB assay for CD23 binding in HDM allergy. Induction of these Ab isotypes has long been regarded as the characteristic immunological feature induced by SCIT, although there is some controversy regarding the correlation of these measures with clinical improvement.

Epidemiologic studies performed with a skin prick test, and serum sIgE showed that HDM is the most dominating perennial indoor allergen source in the country, whereas pollen allergy affected around 20% of Chinese patients, mainly located in the northern part of China (13). The majority of HDM-allergic patients are cosensitized to D. pteronyssinus and D. farinae with their high cross-reactivity, which enabled us to use a single allergen (D. pteronyssinus) for the HDM allergy treatment. In this study of SCIT with D. pteronyssinus extract, we found that HDM SCIT results in a significant improvement in asthma symptoms and a reduction in medication requirements starting after 12 wk of SCIT. We also found that levels of D. pteronyssinus–sIgE and D. farinae–sIgE decreased significantly after 52 wk of treatment. Furthermore, SCIT induced a substantial increase of allergen sIgG4 Abs. Importantly, their blocking function—as tested by IgE-FAB—significantly increased after 16 wk of SCIT. Further, we found that D. pteronyssinus–sIgG4 concentration and its inhibitory capacity against D. pteronyssinus–sIgE binding to B cells were both associated with clinical efficacy during the maintenance phase but not during the updosing phase.

AIT is an effective treatment for allergic disease. Although it was impracticable to perform a double-blind, placebo-controlled study in this 3-y-long clinical observation, current investigation is in agreement with our previous study (14, 21) and studies performed elsewhere (24, 25), which confirmed that HDM AIT can be effective in controlling asthma/rhinitis symptoms and reducing the needs for rescue medication. In addition, we observed an expected significant improvement of AHR after 1 y of SCIT, which confirmed that AIT results in an improvement of AHR to stimulations, as other studies have shown (26). However, Wang et al. (21) found that there was a significant improvement in a provocative concentration of histamine causing a 20% fall in FEV1 in both the AIT and the placebo group at 6 and 12 mo, respectively, when compared with baseline. This result could be explained by improved treatment compliance associated with study participation for all the patients who received positive/placebo injections in the double-blind, placebo-controlled study. Although Arvidsson et al. (27) found that FEV1% increased after AIT, our data showed no significant change of FEV1%. These differences may result from the differences in enrolled patients across different studies. In our study, FEV1% was ≥70% of the predicted value in all patients before SCIT.

AIT has been shown to reduce IgE production (4, 28). Yukselen et al. (29) found a significant decrease in HDM sIgE levels after 1 y of HDM AIT. Mastrandrea et al. (30) also found significant decreases in D. pteronyssinus 1 and D. pteronyssinus 2–sIgE values during long-term immunotherapy. In agreement with others, we found the levels of D. pteronyssinus–sIgE decreased significantly starting from week 52 of SCIT. Interestingly, in our D. pteronyssinus extract SCIT, D. farinae–sIgE also decreased. This might be because most of our study patients were both D. pteronyssinus– and D. farinae–sensitized, and SCIT with only D. pteronyssinus could also reduce D. farinae–sIgE levels based on cross-reactivity (31). Significant decreases of D. pteronyssinus 2, D. farinae, and D. farinae 2–sIgE levels after 1 y AIT in the positive clinical response allergy patients were also found in the study by Chen et al. (32). However, in some other studies, sIgE levels did not change after 1 y of AIT (33, 34), and Blumberga et al. (35) demonstrated that AIT induced an initial increase in serum HDM-sIgE values after 1 y of treatment, which then declined to baseline value.

Induction of sIgG4 has long been regarded as the characteristic immunological feature induced by AIT (34). In agreement with our previous finding and those of many other studies (10, 11, 14), we found that successful AIT could induce a substantial increase of allergen sIgG4 Abs. The magnitude of increase in D. pteronyssinus–sIgG4 concentrations is dependent on the concentration of the allergenic extract used for immunotherapy (36). IgG4 is a unique Ab with a heavy and attached light-chain exchange, also referred to as “Fab-arm exchange,” which results in monovalent and non–cross-linking Abs (37). sIgG4 has been shown to have blocking activities by competing with sIgE for allergen binding to sIgE receptor–expressing effector cells (5, 38–40) and interfering with IgE-facilitated Ag presentation, thereby preventing the allergen-dependent activation of T cells (8). Thus, sIgG4 is thought to be an important immunological marker for AIT when objectively assessing the clinical performance of the treatment.

However, quantitative assessments of IgG4 Abs have not necessarily correlated with the clinical efficacy of treatment (41–44). It has been found that AIT not only increases the level of serum IgG4 Abs but also alters their specificity (6, 10). Therefore, evaluation of blocking Abs in immunotherapy should not solely depend on the serum concentrations of IgG4 Abs but focus additionally on the Abs’ competing ability to block the binding between allergens and sIgE on the surface of effecter cells, which activates cytokine release (45). IgE-FAB represents an in vitro model of facilitated allergen presentation, in which allergen-IgE complexes are incubated with an EBV-transformed B cell line, bound to CD23, and assayed by flow cytometry (23). In a grass pollen immunotherapy study, IgE-FAB of postimmunotherapy serum inhibitory activity was found to be more predictive of the clinical response to immunotherapy than serum allergen sIgG4 levels (11). In our current HDM immunotherapy study, we found that IgE-FAB was significantly decreased and had a significant inverse correlation with sIgG4, which indicated that IgE-FAB reflected the function of sIgG4. We also found both HDM sIgG4 and IgE-FAB correlated with clinical efficacy in the maintenance phase rather than the updosing phase of SCIT.

Although SCIT could induce serum sIgG4 starting from week 12, we found that low concentrations of sIgG4 could not inhibit HDM allergen binding with sIgE at this early stage. At this point, medications were still more relevant in the control of symptoms. Shaikh (46) also found inhaled budesonide results in a faster and more striking improvement of asthma symptoms as compared with AIT during the first few months of treatment. In week 16, although sIgG4 started to increase significantly in AIT patients and its inhibitory capacity of IgE-allergen complex reached ∼30% as tested by IgE-FAB assay, no significant clinical improvements were found. This might result from D. pteronyssinus–sIgE levels remaining high enough to induce symptoms. After 52 wk of SCIT, as sIgG4 levels underwent 37- to 73-fold increases, the IgE-FAB revealed the inhibition of IgE activity reaching 50% or greater. As significant clinical improvement was achieved, the level of IgG4 and IgE blocking activities started to correlate with SMS. This correlation became evident when IgG4 reached a sufficiently high level to block the majority of IgE activity. Similarly, Zhao et al. (12) found that IgG4 and IgE blocking factors correlated with symptom improvements at 12 mo after the initiation of SCIT. Functional IgG4 Abs in serum from patients who received grass pollen immunotherapy were found to be responsible for the inhibition of IgE-FAB (6, 10). With this finding, we expect that induction of sIgG4 during AIT would be an important biomarker to correlate with clinical efficacy when AIT reached the maintenance phase. In Phl p extract SCIT, Shamji and his group (11) identified a significant inverse correlation between serum inhibitory activity immediately after updosing (at the first maintenance injection) and the subsequent SMS during the pollen season, which was not apparent for allergen-sIgG4 levels. In agreement with our study, data from both pollen and HDM SCIT suggest that to induce inhibitory Abs, an allergen-dose threshold needs to be reached, and the effect of immunotherapy might predict maintained efficacy on the basis of IgE-FAB measurements.

In summary, successful AIT is associated with a substantially increased allergen sIgG4 sufficient to provide measurable blocking function against sIgE activity. IgE-FAB correlated with clinical efficacy in the maintenance phase rather than the updosing phase of SCIT. Immunologic tolerance provided by SCIT occurs only when the maintenance phase is achieved.

Disclosures

The authors have no financial conflicts of interest.

Footnotes

  • This work was supported by the Breeding Program of Major Research Plan (91542104) of the National Natural Science Foundation of China, Precision Medicine Research of The National Key Research and Development Plan of China (2016YFC0905800) to J.L., and by the National Natural Science Foundation of China (81500024) to M.F.

  • Abbreviations used in this article:

    AHR
    airway hyperresponsiveness
    AIT
    allergen-specific immunotherapy
    FEV1
    forced expiratory volume in 1 s
    FVC
    forced vital capacity
    HDM
    house dust mite
    IgE-FAB
    IgE-facilitated allergen binding to B cells
    PD20
    provocative dose of histamine causing a 20% fall in FEV1
    SCIT
    s.c. allergen immunotherapy
    sIgE
    specific IgE
    sIgG4
    specific IgG4
    SMS
    combined symptom medication score.

  • Received December 6, 2017.
  • Accepted April 4, 2018.

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