{"doi":"10.1111/cea.13977","title":"Subclasses of allergen‐specific IgG: Serum IgG2 and IgG3 levels are not predicted by IgG1/IgG4 levels","abstract":"Allergen immunotherapy (AIT) used for patients with allergic rhinitis has been a mainstay of treatment for more than a century.1 The mechanisms underlying the efficacy of AIT, or lack thereof, are only partially understood. For several decades, one hypothesis has been that immunotherapy induces IgG antibody production to suppress the patient's response to allergenic proteins. It is thought that these IgG antibodies bind to epitopes on allergens that in turn block the allergen's access to cell surface IgE on mast cells and basophils.2, 3 This behaviour has led to the term blocking antibodies. However, the ability of an IgG antibody to interfere with allergen binding to cell-bound IgE is only one way that IgG could potentially inhibit cell secretion. IgG-allergen complexes could interact with the inhibitory receptor (CD32b, FcgRIIb) on basophils and mast cells, co-crosslinking with surface IgE and down-regulating the allergen-driven signalling reaction.4, 5 Recently, we examined the question of whether CD32b interacted with the subclasses of IgG differently.6 Early studies working with mouse IgG subclasses had uncovered distinct interactions between the various subclasses and murine CD32b,7 so we examined this behaviour in the context of the inhibition of the human basophil response, a leukocyte that expresses CD32b. Our studies showed that human IgG1 has very little functional interaction with CD32b, IgG4 had none11 In our published study 6, IgG4 concentrations were limited but studies in mice also demonstrate the absence of IgG4 binding to CD32b. and only IgG2 and IgG3 allow CD32b to act as a strong inhibitor of IgE-mediated secretion, with IgG3 being 10-fold more efficacious than IgG2 in blocking the IgE-mediated response. Historically, studies of immunotherapy only measure IgG4 or both IgG1 and IgG4 and rarely examine IgG2 or IgG3 (e.g. see the early studies of 8, 9). The collective decision to focus on IgG1/4 largely took place before there was knowledge of CD32 inhibitory receptors that could modulate the IgE-mediated reaction. There were early studies examining all subclasses, although these assays had limitations. In addition, while there have been a few more recent studies (e.g. see10) examining either IgG2 or IgG3 subclasses in mechanistic studies of allergic subjects or AIT, most studies do not. In light of the functional studies in which IgG2/3 subclasses are most effective in engaging CD32b, this oversight is unfortunate. To study the efficacy of immunotherapy without knowing the changes that occur in the levels of these two subclasses, which are potentially important for suppressing the IgE-mediated response at the cellular level, could be problematic. A critical question is whether the fraction of allergen-specific IgG2 and IgG3 in a subject's serum can be predicted from knowledge of IgG1 and IgG4 subclass fractions. For example, if there were a constant proportion of IgG2 and IgG3 antibodies relative to IgG1 or IgG4, then it would be possible to extrapolate from prior studies as to the potential levels of IgG2 and IgG3. Therefore, a first step is to determine the population variability in the relative proportions of the 4 subclasses of IgG to allergens. Two metrics were of particular interest, the constancy of the ratio of IgG2/3 to IgG1/4 and the absolute concentration of IgG2 and IgG3. These values are relevant because these are the two metrics that most influence the role of CD32b in inhibiting IgE-mediated secretion.6 The following study was not designed to answer questions about the role of IgG2 or IgG3 in AIT but to promote further interest in whether future studies should examine these two subclasses. An ELISA methodology was developed using established WHO-approved anti-subclass antibodies to make measurements of allergen-specific subclasses. Pilot studies described in the online repository (see Supplementary Material) addressed several issues with allergen-specific IgG assays. In particular, subclass tra","journal":"Clinical & Experimental Allergy","year":2021,"id":201372,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":780145,"name":"Santiago Alvarez‐Arango","orcid":"0000-0002-4110-7221","position":1,"is_corresponding":false},{"id":766023,"name":"Jody Tversky","orcid":"0000-0003-3674-4143","position":2,"is_corresponding":false},{"id":495691,"name":"Donald W. MacGlashan","orcid":"0000-0003-4525-0452","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-18T23:50:56.394488Z","pmid":"34192382","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}