B cell memory in STAT3 Hyper-IgE Syndrome: Cytokine integration, IgE regulation, and the architecture of human memory B cell subsets

Deleterious allergen-specific IgE responses cause lifelong and life-threatening allergic disease. However, the cellular reservoir of IgE memory in humans is incompletely characterised and prior studies have been unable to reproducibly detect human IgE+ memory B cells (MBCs). Individuals with Inborn Errors of Immunity (IEI) shed light on the molecular and cellular requirements for immune responses in diverse clinical contexts. Patients with heterozygous pathogenic dominant negative (DN) variants in STAT3 present with a Hyper-IgE Syndrome (HIES) which is characterised by clinical features of extremely high serum IgE levels, atopic disease, and susceptibility to diverse infections. The studies described in this thesis evaluate the B cell compartment of patients with STAT3 HIES alongside that of healthy donors (HD), individuals with polygenic atopy (AD) and other IEI. Aim 1 (Chapter 3) outlines detailed in vitro studies of naïve and memory B cells to clarify the interaction of the cytokines IL-4 and IL-21 in the regulation of IgE class-switch recombination (CSR). We furthermore show that naïve B cells from most IEI, including STAT3 HIES, do not exhibit an intrinsic propensity for IgE CSR in vitro. Aim 2 (Chapter 4) addressed whether IgE+ B cells exist in humans, and found they were rare but significantly enriched in STAT3 HIES. Single-cell RNA and BCR sequencing demonstrated that the transcriptional signature and somatic hypermutation profile of IgE+ B cells resembled that of a recently described allergy-associated subset of human IgG1+ B cells (termed type 2 memory B cells; MBC2s). Furthermore, our analyses revealed that BCR signalling is differentially regulated in MBC2s, providing a mechanism by which IgE+ MBCs might escape fate constraints described in prior murine studies. To reconcile the relative abundance of allergic memory in STAT3 HIES with clinical evidence of impaired humoral responses to infections, we quantified antigen-specific B cell and IgG responses induced by SARS-CoV-2 vaccination (Aim 3, Chapter 5). The SARS-CoV-2 specific B cell response in STAT3 HIES was quantitatively similar but phenotypically skewed compared to HD. Furthermore, the SARS-CoV2 IgG response in STAT3 HIES was significantly delayed and required ongoing boosting to achieve levels observed in HD. Overall, this thesis clarifies the regulation of IgE CSR and B cell memory in humans, highlighting how relevant regulatory axes are conserved and perturbed in STAT3 HIES.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2026

Author dc:creator

• Pathmanandavel, Karrnan

• B cell
• Humoral Immunity
• STAT3 Hyper IgE Syndrome
• IgE
• anzsrc-for: 320405 Humoural immunology and immunochemistry

Statement dc:rights

• embargoed access
• CC BY 4.0

Licence

• http://purl.org/coar/access_right/c_f1cf
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/32521

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/108277