Immune responses and exacerbations in severe asthma

Abstract

Asthma as a clinical entity manifests with a broad spectrum of disease severity. Unlike milder asthma, severe disease is poorly controlled by inhaled corticosteroids, the current standard of care. Transcriptomic data, along with patient characteristics and response to biologics show that though Type 2 (T2) immune response remains an integral feature of asthma, additional molecular and immunologic factors may play important roles in pathogenesis. Mechanisms of T2 development, cellular sources of T2 cytokines and their relationship to additional immune pathways concurrently activated may distinguish several different subphenotypes, and perhaps endotypes of asthma, with differential response to non-specific and targeted anti-inflammatory therapies. Recent data have also associated non-T2 cytokines derived from T cells, particularly IFN-γ, and epithelial mediators with severe asthma. These topics and their relationships to acute asthma exacerbations are discussed in this review.

Figure 1.. Immune responses in severe asthma.

Proteases present in complex allergens and pathogens cause epithelial injury triggering secretion of the alarmins TSLP, IL-33 and IL-25. The alarmins activate ILC2s and other cell types that secrete T2 cytokines. IL-5 plays a central role in increased eosinophil differentiation in the bone marrow in turn causing eosinophilia in the periphery and in the airways. IL-5 may also induce local eosinophilopoiesis. TSLP and IL-33 have been also implicated in in situ hematopoiesis from hematopoietic stem progenitor cells (HSPC), either present in the mucosa or recruited from the circulation contributing to increased T2 response. Antigens in allergens or pathogens at the epithelial barrier can also induce an adaptive immune response with generation of effector (TE) and memory (TEM, TCM and TRM) T cells. TRM (CD4 or CD8) cells thus generated reside in the tissue. Second antigen encounter leads to TRM and TCM reactivation. Activated TRM cells undergo rapid proliferation and secretion of pro-inflammatory cytokines that have the ability to promote recruitment of other immune cells to the site of encounter. Some secondary TRM cells can shed tissue residency and migrate to secondary lymphoid organs and the periphery. These TRM cells can also differentiate into TE cells and mount a robust immune response in collaboration with newly generated effector cells. The colored arrows represent the following: green: cell migration, blue: cytokine secretion, red: cytokine milieu or cytokine effect and black: cell differentiation.