Type 2 Immunity Mechanisms in Allergic Inflammation

Type 2 immunity underlies the pathogenesis of allergic inflammation through a complex network of cellular and molecular interactions. Central to this response are T helper 2 (Th2) lymphocytes, group 2 innate lymphoid cells (ILC2s), mast cells, eosinophils and basophils, all of which secrete interleukins IL-4, IL-5 and IL-13. These cytokines drive IgE class switching in B cells, enhance eosinophil recruitment and activation, and promote mucus production and airway hyper-responsiveness. Alarmin cytokines released by epithelial cells—namely IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)—initiate and amplify type 2 responses by acting on both innate and adaptive effectors. Cross-talk between basophils and dendritic cells shapes Th2 polarisation, while emerging insights reveal interconnections with other immunity programmes, including IL-6-mediated modulation of Th17 differentiation. Tissue residency and migratory behaviour of effector cells are finely tuned by sequential engagement of adhesion molecules and cytokine receptors, determining the magnitude and localisation of degranulation events. This dynamic interplay between barrier epithelial signals and specialised granulocytes not only orchestrates protective responses against helminths and toxins but also underpins chronic allergic disorders such as asthma, atopic dermatitis and food allergy. Growing understanding of these pathways has informed the development of biologics targeting IL-4Rα, IL-5, IL-13 and TSLP, offering precision treatments for severe allergic disease and highlighting the global imperative to translate mechanistic insights into effective interventions.

Research from Nature Portfolio

Single‐cell transcriptomic analysis has delineated a previously unrecognised pre-basophil population that bridges early myeloid progenitors and mature basophils. These pre-basophils expand in peripheral sites during helminth infection, are highly proliferative and display a distinct pattern of cytokine responsiveness, suggesting novel checkpoints in basophil ontogeny and tissue mobilisation. Complementing this, work on basophil‐derived mediators has revealed that, in addition to IL-4, basophils secrete IL-6 and tumour necrosis factor-α upon IgE crosslinking. Basophil‐derived IL-6 cooperates with dendritic cells to drive Th17 differentiation, indicating that basophils contribute to the interplay between type 2 and type 17 programmes and may influence inflammatory outcomes beyond classical allergy settings.

Type 2 Immunity Mechanisms in Allergic Inflammation publication trend

The graph below shows the total number of articles in type 2 immunity mechanisms in allergic inflammation across all publications each year (not limited to Nature Index journals).

Technical terms

Alarmin cytokines: Epithelial‐derived IL-25, IL-33 and TSLP that initiate type 2 responses.

Piecemeal degranulation: Gradual release of granule contents by vesicular transport in basophils.

Anaphylactic degranulation: Rapid, global fusion of granules leading to massive mediator release.

Group 2 innate lymphoid cells (ILC2s): Innate lymphocytes that produce IL-5 and IL-13 in response to alarmins.

IgE class switching: Process by which B cells change antibody production to IgE under IL-4 influence.

References

1. Single cell transcriptomics clarifies the basophil differentiation trajectory and identifies pre-basophils upstream of mature basophils. Nature Communications (2023).
2. Basophils beyond allergic and parasitic diseases. Frontiers in Immunology (2023).
3. Sequential engagement of adhesion molecules and cytokine receptors impacts both piecemeal and anaphylactic degranulation of human basophils. Immunology (2024).
4. Basophil-derived IL-6 regulates TH17 cell differentiation and CD4 T cell immunity. Scientific Reports (2017).