The Subclass Nature and Clinical Significance of the IgG Antibody Response in Patients Undergoing Allergen-Specific Immunotherapy

The purpose of this paper is to discuss the methodological difficulties in quantitation of human IgG subclass antibodies to allergens, to describe the subclass nature of the IgG antibody response in patients undergoing allergen-specific immunotherapy, and to discuss the possible immunological functions and clinical significance of allergen-specific IgG antibodies of different subclasses. Based on results obtained by use of assays with documented specificity it is concluded that the IgG antibody response during allergen-specific immunotherapy is IgG1 and IgG4 restricted, although low levels of IgG2 and IgG3 antibodies to some allergens may occur. In most patients the early IgG antibody response is IgG1 dominated and the late IgG4 dominated. A too early or too pronounced IgG4 dominated antibody response seems to indicate a poor clinical outcome of immunotherapy with inhalant allergens, whereas a pronounced early IgG1 antibody production has been found to be associated with a decrease in synthesis of IgE antibodies to an insect venom. It is therefore proposed that an early IgG1 dominated response is necessary to induce suppression of the ongoing IgE antibody production, which in its turn may be a prerequisite for long-lasting clinical effect. The possibility of induction of an early IgG1 dominated response in every patient by use of alternative immunotherapy procedures is discussed.     

Increased IgG Antibody-Induced Cytotoxicity Against Airway Epithelial Cells in Patients with Nonallergic Asthma

Background  IgG autoantibodies to airway epithelial cell proteins have been detected in patients with nonallergic asthma. Objective and Methods  To evaluate the functional significance of these autoantibodies, we examined the presence of IgG antibody-induced cytotoxicity against airway epithelial cells (A549) by the microcytotoxicity assay using IgG antibodies purified from patients with nonallergic asthma. Results  IgG antibody-induced cytotoxicity (expressed as percent cell lysis) was significantly increased in nine patients with nonallergic asthma (mean ± standard deviation; 30.6 ± 7.3%) as compared with eight healthy controls (13.9 ± 5.1%) and nine patients with allergic asthma (20.3 ± 10.4%; p < 0.05). In addition, IgG antibody-induced cytotoxicity was significantly inhibited when IgG antibodies from patients with nonallergic asthma were pre-incubated with recombinant human airway epithelial cell autoantigens (cytokeratin 18 or alpha-enolase proteins; p < 0.05). Conclusion  These results suggest a possible involvement of IgG autoantibody-induced cytotoxicity against airway epithelial cells in the pathogenesis of nonallergic asthma.     

IgG Subclass Antibody Response in Grass Pollen-Allergic Patients Undergoing Specific Immunotherapy

All four subclasses of IgG antibodies to timothy grass pollen extract were measured by a three-layer immunoradiometric assay in sera from 20 grass pollen-allergic patients who underwent specific immunotherapy in a 3-year prospective study. Both IgG1 and IgG4 antibody levels rose significantly during the first 8 weeks of immunotherapy. IgG1 antibody level passed its peak (median 5.4 U/ml) after 12 weeks. At this time, the ratio between the medians of IgG1 and IgG4 antibodies was 2.25. IgG4 antibody level reached its peak (median 11.6 U/ml) just before termination of immunotherapy. At this time IgG1/IgG4 ratio was 0.43. Two years after the end of immunotherapy, IgG1 and IgG4 antibody levels were 0.0 and 1.8 U/ml in median, respectively. The amounts of IgG2 and IgG3 antibodies detected in the sera were less than 1.6 U/ml and were considered insignificant. Preseasonal serum IgG1 and IgG4 antibody levels did not correlate significantly with symptom scores in the subsequent season. Serum IgG4 level obtained after 12 weeks of immunotherapy was significantly correlated to symptom score in the third season, i.e. the season just after termination of therapy (rs = 0.529, t = 2.567, P = 0.02). In this work, a serum IgG4 antibody level higher than 8.0 U/ml after 12 weeks of therapy predicted poor clinical result at the end of immunotherapy with 100% sensitivity and 87% specificity. An IgG4/IgG1 ratio greater than 1.0 after 12 weeks' therapy had the same predictive value.     

Specific Antibody Deficiency in Adult Patients With IgG or IgG Subclass Deficiency

PurposeSpecific antibody deficiency (SAD) involves a deficient response to a polysaccharide vaccine despite having normal immunoglobulin levels. The failure of the polysaccharide response can be observed as a component of various primary antibody deficiencies. However, only a few studies have described the clinical and immunological profiles in SAD and/or other primary immunodeficiencies (PIDs) in adults.MethodsA total of 47 patients who had a clinical history suggestive of antibody deficiency or had already been diagnosed with various antibody deficiencies were enrolled. Polysaccharide responses to 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) were measured using the World Health Organization enzyme-linked immunosorbent assay (WHO-ELISA), and postvaccination immunoglobulin G (IgG) titers were compared to clinical and laboratory parameters.ResultsBased on the American Academy of Allergy, Asthma, and Immunology (AAAAI) criteria for the WHO-ELISA, 11 (23.4%) patients were diagnosed as having SAD. Sixteen-three percent of them had combined with other types of PID, such as IgG subclass deficiency and hypogammaglobulinemia. Postvaccination IgG titers for the serotypes 4/9V/18C correlated with IgG2 (P = 0.012, P = 0.001, and P = 0.004) and for 6B/9V/14 with IgG3 (P = 0.003, P = 0.041, and P = 0.036, respectively). The IgG3 subclass levels negatively correlated with forced expiratory volume in 1 second (FEV1, %) and FEV1/forced vital capacity (P < 0.001 and P = 0.001, respectively).ConclusionSAD can be diagnosed in patients with normal IgG levels as well as in those deficient in IgG or the IgG3 subclass, implicating that restricted responses to Streptococcus pneumoniae polysaccharide antigens commonly exist in patients with predominantly antibody deficiency.     

A Human-Mouse Hybridoma which Secretes Monoclonal Thyroglobulin Autoantibody with Properties Similar to those of the Donor Patient's Serum Autoantibody

Human monoclonal antibodies produced by Epstein Barr (EB) virus transformation and/or cell fusion are frequently IgM antibodies which tend to cross react with a range of antigens and often bear little relationship to the highly specific IgG antibodies associated with human autoimmune disease. By fusing EB virus transformed B lymphocytes from a Hashimoto patient with a mouse myeloma line and selecting for synthesis of IgG class thyroglobulin (Tg) antibody, we have developed a hybridoma (VB/5) secreting Tg antibody of IgG2 subclass and lambda light chain type which has the characteristics of a monoclonal antibody on isoelectric focussing. The antibody has a high affinity for human Tg and recognises Tg from other primates but not non-primate Tg. However, it does not react with human thyroid peroxidase or a panel of other autoantigens.

In terms of affinity constant, functional affinity and affinity heterogeneity, the antibody closely resembles the IgG2 lambda Tg antibody present in the serum of the Hashimoto patient whose B lymphocytes were used to develop the hybridoma. In addition to providing a useful reference standard for Tg antibody IgG subclass assays, VB/5 antibody and the hybridoma line provide a valuable starting point for detailed studies of Tg autoantibodies and the genes coding for the variable regions of their heavy and light chains.     

Circulating levels of IgG1 and IgG4 Anti-IgE antibodies and asthma severity

In this paper, we have determined the levels of IgG1 and IgG4 anti-IgE in the sera of 66 asthma patients suffering from mild ( n = 24), moderate ( n = 23), or severe ( n = 19) symptoms, and 20 nonatopic, healthy subjects. The study has revealed that although asthma patients have significantly elevated levels of IgG1 and IgG4 anti-IgE antibodies, the concentration of these autoantibodies is not related to the severity of asthma. This conclusion may be related to the known heterogeneity of autoanti-IgE antibodies in terms of their ability to trigger basophil histamine release.     

Isotype distribution of mucosal IgG-producing cells in patients with various IgG subclass deficiencies

The subclass distribution of IgG-producing immunocytes was examined by immunohistochemistry in nasal and rectal mucosa of infection-prone patients with untreated IgG subclass deficiencies. Biopsy specimens from the two sites were obtained in 18 clinically and serologically well-characterized adult subjects; only a nasal or rectal sample was available from nine similar patients. Chronic lung disease was common in the patient groups with selective serum IgG1 deficiency and combined IgG1 and IgG3 deficiency, whereas the other categories of patients had mainly upper airway and other mild infections. Serum IgG2 or IgG3 deficiency was usually expressed also at the cellular level in rectal mucosa, and the proportion of rectal IgG1 cells was significantly correlated with the IgG1 level (r = 0.90, P less than 0.001). Likewise, there tended to be a decreased expression of the actual subclass at the cellular level in nasal mucosa of patients with serum IgG1 or IgG2 deficiency. Conversely, the median nasal proportion of IgG3 cells was remarkably unaffected by a deficiency of this subclass in serum and rectal mucosa. Interestingly, these patients rather tended to have raised IgG3 and reduced IgG2 cell proportions in their nasal mucosa, although this apparent local IgG3 compensation was nevertheless strongly correlated with the serum IgG3 level (r = 0.87, P less than 0.002). These disparities may reflect different antigenic and mitogenic exposure of the two tissue sites; for example, a persistent protein bombardment of the nasal mucosa that could conceivably override locally a B cell maturation defect. The possible clinical consequences of such variable mucosal expression of IgG subclass deficiencies remain to be studied.     

Hyper-response of serum IgG1 to Staphylococcus aureus peptidoglycan in patients with hyper-IgE syndrome.

The hyper-IgE (HIE) syndrome is characterized by high IgE serum levels, chronic dermatitis and recurrent infections. To determine whether an impairment of the antibody response to Staphylococcus aureus contributes to infections in this syndrome we measured total serum IgG subclass, specific IgG1 and IgG2 levels against peptidoglycan (PG), the immunodominant cell wall component of S. aureus and serum opsonic activity to PG. Of the 14 patients with HIE syndrome, nine had increased level of serum IgG1 and six had IgG2 subclass deficiency. In regard to specific response of IgG1 and IgG2 antibodies to PG, patients were divided into five groups related to ages and compared with 10 control subjects for each age cohort. Patients with HIE syndrome had significant high levels of serum-specific IgG1 to PG and significant decreased levels of serum-specific IgG2 to PG in all five groups. Additionally, serum opsonic activity in patients was significantly higher than that in normal control subjects. It is concluded that IgG2 deficiency or poor IgG2 antibody response to S. aureus is not the explanation of the abnormal susceptibility to S. aureus infections of HIE patients.     

Immunoglobulin subclass distribution of specific antibodies in allergic patients

The IgG and IgA subclass distribution of specific antibodies against a variety of protein and polysaccharide antigens was determined in sera from individuals with high levels of IgE. No shift of the antibody pattern could be observed, suggesting that the aberrant regulation of responses against allergens noted in these patients is limited, encompassing selected antigens only. Antibodies against protein antigens are mainly of the IgG1 subclass. In addition, low levels of specific IgG3 or IgG4 antibodies may be formed. Our data suggest that a given antigen induces either IgG3 or IgG4 and that potential allergens, in addition to IgG1 and IgE, elicit a response restricted to IgG4.     

Characterization of Human Immunoglobulin (Ig) Isotype and IgG Subclass Response to Bartonella henselae Infection

Serologic parameters of cat scratch disease (CSD) were evaluated by Western blot analysis. Sera from patients with serologically confirmed CSD antigen were screened for immunoglobulin (Ig) isotype-specific as well as IgG subclass-specific reactivity against Bartonella henselae whole-cell antigen. Bartonella-negative control sera were used to determine baseline antibody activity. Heterogeneous B. henselae-specific IgG reactivity with numerous protein bands, ranging from >150 to <17 kDa, was observed. Though individual banding patterns were variable, one approximately 83-kDa B. henselae protein (Bh83) was immunoreactive with all CSD sera tested, suggesting it is a conserved antigen during infection. Bh83 was not recognized by reference human antisera against Rickettsia rickettsii, Chlamydia group positive, Treponema pallidum, Orientia tsutsugamushi, Fransciscella tularensis, Ehrlichia chaffeensis, Mycoplasma pneumoniae, and Escherichia coli, although other cross-reactive proteins were evident. Significantly, CSD sera failed to recognize the 83-kDa protein when tested against Bartonella quintana antigen, though sera from B. quintana-infected patients did react to Bh83. This cross-reactivity suggests epitope conservation during infection with B. henselae or B. quintana. Western blot analysis further revealed similar banding patterns when B. henselae was reacted against the Ig isotypes IgG and IgG₁ and both secretory and alpha chains of IgA. Neither IgM nor IgE reacted significantly to Bartonella antigen by our Western blot analysis. Dissection of the antibody response at the IgG subclass level indicated that prominent antigen recognition was limited to IgG₁. These observations provide insight into induced immunity during CSD and provide evidence for conserved epitope expression during infection with B. henselae or B. quintana.

The spectrum of human disease and pathologic syndromes observed to be associated with Bartonella henselae, an alpha-2 proteobacterium, has been progressively expanding since its identification in 1992 (18, 27). Granulomatous and vasculoproliferative diseases stemming from this emerging pathogen have since been described in both immunosuppressed and immunocompetent patients. Implicated in the etiology of cutaneous bacillary angiomatosis, bacillary hepatic peliosis and its parenchymal variant, endocarditis, and fever with persistent bacteremia (2, 9, 10, 12, 23, 24, 28), B. henselae is most notably recognized for its role as the primary etiologic agent of cat scratch disease (CSD) (5, 14). Afflicting an estimated 24,000 persons in the United States annually (8), CSD is characterized by a broad range of clinical symptoms manifested in varying degrees of severity depending largely on the immune status of the host. Infected patients present with subacute regional lymphadenopathy after inoculation, low-grade fever, anorexia, and malaise. Such manifestations are typically self-limiting and resolve untreated within several weeks in the immunocompetent host. It has become clear, though, that individuals with a depressed cellular immune response succumb to more-severe, atypical manifestations of CSD, including systemic complications of multiorgan involvement, particularly of the spleen and liver, and involvement of the central nervous system (2, 21, 28). Although B. henselae is a cause of human disease with a wide spectrum of severity, little is known regarding pathogenicity and immunity induced during infection.B. henselae is a fastidious, gram-negative bacillus that may require an incubation period as long as 5 weeks to culture axenically. Consequently, serologic methods, such as indirect fluorescent-antibody assay (IFA) and enzyme immunoassay (EIA), have been the most-practical and least-invasive means of clinical diagnosis (3, 19). Widely accepted as a diagnostic assay, IFA is routinely used to confirm B. henselae infection (4). However, when the whole bacterial cell antigen is used, IFA is unable to differentiate species-specific serologic reactivity from cross-reactivity with other antigens of phylogenetic proximity, namely, Bartonella quintana (4, 11). Modifications to improve the efficacy of serologic detection methods are pending a more-comprehensive understanding of the factors influencing both the pathogenesis of infection due to B. henselae and the evoked human immune response.The purpose of this study was to dissect the humoral immune response to B. henselae antigen in patients with clinically and laboratory-diagnosed CSD (positive by IFA) by Western blot analysis. In evaluation of the B. henselae proteins recognized following infection, an 83-kDa immunodominant protein was identified that was recognized by all seropositive patient samples tested. Furthermore, we have provided an in-depth characterization of the immunoglobulin (Ig) isotype and IgG subclass response in CSD patients. The findings, which elucidate serologic responses to B. henselae infection, provide insight into the immunity induced by this pathogen.(This work was presented in part at the 13th Sesqui-Annual Meeting of the American Society for Rickettsiology [abstract 14], September 1997, Champion, Pa.)     

Differences in titres of IgE, IgG4 and other IgG subclass anti- Der p 2 antibodies in allergic and non-allergic patients measured with recombinant allergen

Background The mite allergens are recognized as major causes of allergic disease such as bronchial asthma, allergic rhinitis and atopic dermatitis. The functions of allergen-specific IgG subclass antibodies are not defined.
Objective In order to clarify the relationship between IgE and IgG subclasses, we examined scrum levels of the Dermatophagoides pteronyssisus group 2 (Der p 2)-specific antibodies of IgH. IgG total and IgG subclasses in children with mite allergy.
Methods We prepared a recombinant Der p 2 fusion protein and examined serum levels of Der p 2 antigen-specific antibodies by enzyme-linked immunosorbent assay (FLISA) systems developed in our laboratory using a recombinant Der p 2 as target antigen. Sera from 240 children with mite allergy and 25 controls were measured.
Results The serum levels of specific IgE and, to lesser degree, lgG4 were higher in allergic children than non-allergic controls, while in the levels of the other IgG subclasses there was no difference between the two groups. There was no correlation between levels of specific IgF and IgG4 or in those between specific IgG4 and other IgG subclasses.
Conclusion Results indicate that the induction of Der p 2-specific lgG4 in allergic diseases is independent to IgE as well as other IgG subclasses.     

A Case of IgG4-Related Disease with Bronchial Asthma and Chronic Rhinosinusitis in Korea

IgG4-related disease (IgG4-RD) is characterized by a systemic involvement of tumor-like lesions with IgG4-positive plasmacytes. We experienced a case of IgG4-RD developed in a patient with bronchial asthma (BA) and chronic rhinosinusitis (CRS). A 55-yr-old female patient with BA and CRS complained of both eyes and neck swelling as well as a recurrent upper respiratory infection in recent 1 yr. The serum levels of IgG4, creatinine, and pancreatic enzymes were elevated. A biopsy of the submandibular gland showed an abundant infiltration of IgG4-positive plasmacytes. Her symptoms remarkably improved after the treatment of a systemic steroid that has been maintained without recurrence. We report a rare case of IgG4-RD developed in a patient with BA and CRS.

Graphical Abstract

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Impaired IgG Antibody Production to Pneumococcal Polysaccharides in Patients with Ataxia–Telangiectasia

Various factors seem to be etiologic in the susceptibility to sinopulmonary infections in ataxia–telangiectasia (A-T) patients, i.e., low serum and salivary IgA, low serum IgG2, and even aspiration of saliva. S. pneumoniae is a common pathogen responsible from pulmonary infections and impaired antibody response to polysaccharide antigens is seen in patients with IgG2 and IgA deficiency as well as patients with CVID and WAS. We studied IgG-type antibody production to six pneumococcal serotypes in 29 A-T patients by ELISA before and 3–4 weeks after pneumococcal vaccine. The response was considered positive when the antibody titer was >10 U/ml but weak when the titer was 10–20 U/ml. Twenty-two of 29 (76%) patients did not respond to any of the serotypes, 5 (17%) showed a positive response to one serotype, 1 (3.4%) to two serotypes, and 1 (3.4%) to four serotypes. With conversion to gravimetric units (ng IgG/ml) and >1800 ng/ml (300 ng Ab N/ml) considered a positive response, 5 of 29 (17.2%) patients showed a positive response (300 ng ab N/ml) to two or fewer serotypes. All patients tested produced IgG antibody to tetanus toxoid. Sixteen of 27 (59.3%) patients had low IgG2 and four (14.8%) had low IgG3 levels, while 18 (62.1%) of 29 patients had low serum IgA. No correlation was found either between serum Ig isotype levels and antipolysaccharide antibody response or between susceptibility to infection and antibody production. The mechanism responsible for disturbed antipolysaccharide (TI-2 antigen) antibody production in patients with A-T needs to be investigated. It may provide additional information on the function of the ATM gene product and be helpful in clarifying the role of B cells and contribution of T cells in TI-2 responses     

Risk Factors Predicting Severe Asthma Exacerbations in Adult Asthmatics: A Real-World Clinical Evidence

PurposeMinimizing the future risk of asthma exacerbation (AE) is one of the main goals of asthma management. We investigated prognostic factors for risk of severe AE (SAE) in a real-world clinical setting.MethodsThis is an observational study evaluating subjects who were diagnosed with asthma and treated with anti-asthmatic medications from January 1995 to June 2018. Risk factors for SAE were analyzed in 2 treatment periods (during the initial 2 years and the following 3–10 years of treatment) using the big data of electronic medical records.ResultsIn this study, 5,058 adult asthmatics were enrolled; 1,335 (28.64%) experienced ≥ 1 SAE during the initial 2 years of treatment. Female sex, higher peripheral eosinophil/basophil counts, and lower levels of forced expiratory volume in 1 second (FEV1; %) were factors predicting the risk of SAEs (P < 0.001 for all). Higher serum total immunoglobulin E levels increased the risk of SAEs among the patients having ≤ 2 SAEs (P = 0.025). Patients with more frequent SAEs during the initial 2 years of treatment had significantly higher risks of SAEs during the following years of treatment (P < 0.001, for all) (patients with ≥ 4 SAEs, odds ratio [OR], 29.147; those with 3 SAEs, OR, 14.819; those with 2 SAEs, OR, 9.867; those with 1 SAE, OR, 5.116), had higher maintenance doses of systemic steroids, and showed more gradual decline in FEV1 (%) and FEV1/forced vital capacity levels maintained during the following years of treatment (P < 0.001 for all).ConclusionsAsthmatics having risk factors for SAEs (female sex, higher peripheral eosinophil/basophil counts, and lower FEV1) should be strictly monitored to prevent future risk and improve clinical outcomes.     

Ovalbumin-specific immunoglobulin G and subclass responses through the first 5 years of life in relation to duration of egg sensitization and the development of asthma

BACKGROUND: Egg sensitization, particularly persistent sensitization, is a risk factor for later asthma. However, little is known about accompanying IgG and subclass responses and how they might relate to asthmatic outcome. OBJECTIVE: To characterize hen's egg ovalbumin (OVA) IgG and subclass responses through the first 5 years of life in relation to duration of egg sensitization and later asthma. SUBJECTS and METHODS: The subjects (n=46) formed part of a larger cohort, born to atopic parents, who had been evaluated prospectively for the development of asthma. Egg sensitization was classified as transient (positive egg skin prick test at 1 year only) or persistent (positive skin test for at least 2 years). Plasma OVA IgG, IgG1 and IgG4 concentrations at birth (cord), 6 months, 1 and 5 years of age were measured by ELISA. RESULTS: The kinetics of OVA IgG and IgG1 responses, but not IgG4, differed between egg sensitized and non-egg sensitized (NES) children. Only persistently sensitized children had a rise in OVA IgG1 concentration through the first year of life, and at 1 year of age they had significantly higher OVA IgG and IgG1 than either transiently sensitized or NES children. High OVA IgG1 was associated with later asthma: at 1 year of age, OVA IgG1 greater than 14,500 U predicted asthma with a sensitivity 64% and specificity 74%. CONCLUSION: OVA IgG and subclass responses relate to the duration of egg sensitization. Measurement of OVA IgG1 concentration in infancy might offer a useful adjunct to identify those at an increased risk of asthma.     

Subclass composition and J-chain expression of the 'compensatory' gastrointestinal IgG cell population in selective IgA deficiency.

The subclass distribution of IgG-producing immunocytes was examined by two-colour immunohistochemistry in gastrointestinal mucosa of 14 patients with selective serum IgA deficiency providing the following biopsy material: gastric (n = 1); jejunal (n = 12); colonic (n = 1); and rectal (n = 2). All except two patients suffered from various infections, and coeliac disease was observed in six of them. Control reference data were based on biopsies from immunologically intact subjects, including histologically normal jejunal (n = 10) and large bowel (n = 10) mucosa and stomach mucosa with slight chronic gastritis (n = 8). The total mucosal population of immunoglobulin-producing cells per 500 microns gut length unit was only slightly decreased in IgA deficiency because of an increased number of IgG (30%) and especially IgM (71%) immunocytes. The IgG1 immunocyte proportion in the proximal gut (median 87%) was higher than that in the comparable controls (gastric 69%, jejunal 66%). A similar trend was seen in the distal gut (69%) compared with controls from the large bowel mucosa (55%). Conversely, IgG2 and IgG3 cell proportions were significantly decreased compared with the respective controls from the proximal gut. The same was true for IgG4, which also was significantly reduced in jejunal mucosa. Paired staining for cytoplasmic J chain and immunoglobulin isotype showed 71% positivity for jejunal IgG-producing cells in IgA deficiency, which was somewhat reduced compared with comparable controls (89%). J chain appeared to be preferentially expressed by IgG1 cells (75%), but was also found in IgG2 (70%), IgG3 (32%) and IgG4 cells (33%). IgM-producing cells showed a J-chain positivity (99%) in IgA deficiency similar to normal (100%). Our results suggested that the block in mucosal B cell differentiation to IgA expression in the proximal gut is mainly located immediately upstream to the CH alpha 1 gene, giving excessive terminal maturation of J-chain-positive IgG1 immunocytes.     

Association of autoimmunity with IgG2 and IgG4 subclass deficiency in a growth hormone-deficient child

An association between humoral immune deficiency and childhood autoimmune disease has been previously established. We describe a 7-year-old male with severe autoimmune disease, recurrent infections, a marked deficiency of IgG2 and IgG4, and an inability to respond to polysaccharide antigens. This child was also found to have isolated growth hormone (GH) deficiency. Laboratory results included a positive anti-smooth muscle antibody, a positive Raji-cell assay for immune complexes, and normal levels of IgG, IgM, and IgA. IgG subclasses revealed an IgG1 of 1225 (normal for age, 280–1120 mg/dl), IgG2 of <10 (30–630 mg/dl), IgG3 of 36 (40–250 mg/dl), and IgG4 of <4 (11–620 mg/dl). No increase in antibody titer was noted to either Pneumovax or unconjugatedHaemophilus influenzae vaccine. Numbers of circulating B cells (CD19) were markedly diminished (<0.5%). Liver biopsies have shown chronic active hepatitis. Somatomedin C was 0.28 U/ml (normal for age, 0.5–2.06 U/ml). Challenge with eitherl-dopa or clonidine produced a peak GH response of 2.3 ng/ml (normals = >7 ng/ml). Children with autoimmune disorders should be evaluated for IgG subclass deficiencies and ability to make antibody in response to antigen challenge regardless of the serum immunoglobulin levels. Growth failure in immune-deficient children should not be assumed to be due to chronic illness or recurrent infections. Other etiologies for growth failure should be sought.     

The inductive effect of interleukin-4 on IgG4 and IgE synthesis in human peripheral blood lymphocytes

Using murine monoclonal antibodies against human IgG subclasses, specific and sensitive ELISAs assay to quantify the four human IgG subclasses in cell culture supernatants were established. The effect of human recombinant interleukin-4 (IL-4) on the regulation of IgG subclasses by normal peripheral blood lymphocytes was investigated. In addition to the enhancement of IgE synthesis, IL-4 preferentially induced IgG4 synthesis in vitro, whereas IL-4 had no effect on IgG1, IgG2, and IgG3 synthesis. IL-4-induced IgG4 production was blocked in a dose-dependent manner by recombinant interferon-gamma and anti-human IL-4 monoclonal antibody. Collectively, this data indicates that IL-4 plays an important regulatory role in both IgG subclass and IgE synthesis.     

Relationship of in vitro phagocytosis of serotype 14 Streptococcus pneumoniae to specific class and IgG subclass antibody levels in healthy adults

The role of specific IgG2 antibody in the protection against serious infection with Streptococcus pneumoniae is unclear. We therefore decided to investigate the relationship between serum antibody levels and opsonization and phagocytosis of this microorganism. We have measured serum IgM, IgA and IgG subclass antibody specific for pneumococcal capsular polysaccharide and in vitro phagocytosis of serotype 14 pneumococcus by polymorphs, in healthy adults before and after immunization with Pneumovax II. IgM and IgG2 were the predominant anti-pneumococcal antibodies seen, IgA and IgGl being present at low titre. No significant relationship of phagocytosis with specific IgM and IgA antibodies was found. However, both specific IgG 1 and IgG2 antibodies in post-immunization sera correlated significantly with phagocytosis of the pneumococcus in the presence of complement (r= 0.57, P= 0.029 and r= 0.59, P= 0.022 respectively). After heat-inactivation, the remaining opsonic activity of sera correlated only with levels of specific IgG2 antibody (r= 0.61, P = 0.0006). Whereas phagocytosis supported by specific IgG 1 and IgG2 antibody to serotype 14 pneumococcus after immunization is mediated by complement activation, IgG2-specific antibody in high titre may also be able to function by complement-independent interaction with Fcγ receptors on polymorphs.