Immunoglobulin G4 (IgG4), a unique subclass of IgG antibodies, plays diverse roles in human health and disease. Its distinct features, such as Fab-arm exchange and specific mutations, confer reduced effector functions compared to other IgG subclasses. In health, IgG4 responses contribute to immune tolerance, particularly in the context of allergen-specific immunotherapy (AIT), where they can mediate tolerance to environmental antigens, inhibit IgE-dependent mast cell degranulation, and compete with IgE for allergen binding. This helps in attenuating allergic symptoms and is associated with increased levels of allergen-specific IgG4. However, in disease scenarios, the role of IgG4 is complex. IgG4 lacks complement fixation and, thus, shows a reduced ability to activate immune effector pathways, it was initially thought to be protective against autoimmune diseases. However, emerging evidence suggests that it can contribute to pathology. For instance, IgG4 autoantibodies against specific antigens can aggravate conditions in certain autoimmune disorders. In some cancers, it may play a role in immune evasion, with higher levels correlating with poor patient survival, albeit in others, its exact function remains elusive. Overall, understanding the precise role of IgG4 in various physiological and pathological conditions is crucial for developing targeted therapeutic strategies and improving patient outcomes.

Background: Peanut oral immunotherapy (OIT) is an effective way to treat peanut allergy. Patients undergoing OIT show high rates of desensitization to the triggering food items after a completed therapy. Long‐term tolerance is often achieved, but the mechanism of tolerance after OIT is not well understood. In this study, we aimed to characterize the changes in allergen‐specific B cell gene expression caused by peanut OIT and the effects of extended allergen avoidance after OIT. Methods: We analyzed the gene expression of Ara h 2‐specific B cells from 34 peanut allergic children from the peanut OIT IMPACT trial. We labeled PBMCs using biotinylated allergen to sort and pool allergen‐specific B cells for sequencing. We compared the OIT and placebo arm after 30 months of active treatment and additionally after an avoidance phase of 6 months with no allergen exposure. Results: After OIT, there was significantly altered gene expression in allergen‐specific B cells. In tolerant participants, they exhibited gene expression related to regulatory B cells, suppressed B cell activation, immune regulation, increased cell–cell communication, and antigen presentation. These tolerance‐induced changes in gene expression are different from remission as the 6‐month avoidance period caused some participants to lose clinical tolerance. The difference between tolerance and desensitization appeared in increased antiviral response in desensitized individuals, whereas IL‐10 and TGFβ‐related signaling increased in the tolerant group. Conclusion: Allergen‐specific B cells from OIT participants display a transcriptional profile associated with clinical remission, characterized by the expression of genes previously linked to regulatory B cell function.