Immunological Reviews最新文献

W. L. Kan, C. M. Weekley, T. L. Nero, et al. “The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities,” Immunological Reviews 329 (2025): e13430, https://doi.org/10.1111/imr.13430.

In the article, there was an error in the funding grant in the Acknowledgment.

The second sentence reads:

Hercus and A.F. Lopez (APP1148221) and Leukemia & Lymphoma Society Chronic Myelomonocytic Leukemia Special Initiative to R. Majeti, D. Thomas, and A.F. Lopez (LLS 8042-24).

The sentence should read:

Hercus and A.F. Lopez (APP1148221) and the Leukemia & Lymphoma Society with support from the Mike & Sofia Segal Foundation to R. Majeti, D. Thomas, and A.F. Lopez (LLS 8042-24).

We apologize for this error.

It has long been appreciated that farm exposure early in life protects individuals from allergic asthma. Understanding what component(s) of this exposure is responsible for this protection is crucial to understanding allergic asthma pathogenesis and developing strategies to prevent or treat allergic asthma. In this review, we introduce the concept of Farm-Friends, or specific microbes associated with both a farm environment and protection from allergic asthma. We review the mechanism(s) by which these Farm-Friends suppress allergic inflammation, with a focus on the molecule(s) produced by these Farm-Friends. Finally, we discuss the relevance of Farm-Friend administration (oral vs. inhaled) for preventing the development and severity of allergic asthma throughout childhood and adulthood. By developing a fuller understanding of which Farm-Friends modulate host immunity, a greater wealth of prophylactic and therapeutic options becomes available to counter the current allergy epidemic.

Asthma is a common chronic inflammatory disease of the airways. A substantial number of patients present with severe and therapy-resistant asthma, for which the underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation is characterized by chronic activation of type 2 immunity. CD4⁺ T helper 2 (Th2) cells are the canonical producers of the cytokines that fuel type 2 inflammation: interleukin (IL)-4, IL-5, IL-9, and IL-13. However, more recent findings have shown that other lymphocyte subsets, in particular group 2 innate lymphoid cells (ILC2s) and type 2 CD8⁺ cytotoxic T (Tc2) cells, can also produce large amounts of type 2 cytokines. Importantly, a substantial number of severe therapy-resistant asthma patients present with chronic type 2 inflammation, despite the high sensitivity of Th2 cells for suppression by corticosteroids—the mainstay drugs for asthma. Emerging evidence indicates that ILC2s and Tc2 cells are more abundant in severe asthma patients and can adopt corticosteroid-resistance states. Moreover, many severe asthma patients do not present with overt type 2 airway inflammation, implicating non-type 2 immunity as a driver of disease. In this review, we will discuss asthma pathophysiology and focus on the roles played by ILC2s, Tc2 cells, and non-type 2 lymphocytes, placing special emphasis on severe disease forms.

Chronic lung diseases including asthma are characterized by an abnormal immune response and active tissue remodeling. These changes in the architecture of the tissue are a fundamental part of the pathology across the life course of patients suffering from asthma. Current treatments aim at dampening the immune system hyperactivation, but effective drugs targeting stromal or acellular structures are still lacking. This is mainly due to the lack of a detailed understanding of the composition of the large airways and the cellular interactions taking place in this niche. We and others have revealed multiple aspects of the spatial architecture of the airway wall in response to airborne insults. In this review, we discuss four elements that we believe should be the focus of future asthma research across the life course, to increase understanding and improve therapies: (i) specialized lung niches, (ii) the 3D architecture of the epithelium, (iii) the extracellular matrix, and (iv) the vasculature. These components comprise the main stromal structures at the airway wall, each playing a key role in the development of asthma and directing the immune response. We summarize promising future directions that will enhance lung research, ultimately benefiting patients with asthma.

Asthma has become more appreciated for its heterogeneity with studies identifying type 2 and non-type 2 phenotypes/endotypes that ultimately lead to airflow obstruction, airway hyperresponsiveness, and remodeling. The pro-inflammatory environment in asthma influences airway smooth muscle (ASM) structure and function. ASM has a vast repertoire of inflammatory receptors that, upon activation, contribute to prominent features in asthma, notably immune cell recruitment and activation, hypercontractility, proliferation, migration, and extracellular matrix protein deposition. These pro-inflammatory responses in ASM can be mediated by both type 2 (e.g., IL-4, IL-13, and TSLP) and non-type 2 (e.g., TNFα, IFNγ, IL-17A, and TGFβ) cytokines, highlighting roles for ASM in type 2 and non-type 2 asthma phenotypes/endotypes. In recent years, there has been considerable advances in understanding how pro-inflammatory cytokines promote ASM dysfunction and impair responsiveness to asthma therapy, corticosteroids and long-acting β2-adrenergic receptor agonists (LABAs). Transcriptomic analyses on human ASM cells and tissues have expanded our knowledge in this area but have also raised new questions regarding ASM and its role in asthma. In this review, we discuss how pro-inflammatory cytokines, corticosteroids, and LABAs affect ASM structure and function, with particular focus on changes in gene expression and transcriptional programs in type 2 and non-type 2 asthma.

Asthma is orchestrated by an aberrant immune response involving a complex interplay between multiple inflammatory cell types. An increase in Th2 cells in the asthmatic airway is a hallmark of asthma, and biologics blocking their effector functions have been life-changing for many severe asthma patients who poorly respond to immunosuppression by corticosteroids. However, studies in the past decade have highlighted not only other cell types that also produce Th2 cytokines boosting the Type 2/T2 phenotype but also a heightened IFN-γ response, primarily from T cells, referred to as a Type 1/T1 immune response. Data derived from studies of immune cells in the airways and mouse models of severe asthma suggest a role of IFN-γ in corticosteroid resistance, airway hyperreactivity, and also airway remodeling via effects on other cell types including mast cells, eosinophils, airway epithelial cells, and airway smooth muscle cells. The simultaneous presence of T1 and T2 immune responses is detectable in the sickest of asthma patients in whom corticosteroids suppress the T2 but not the T1 response. This article has reviewed our current understanding of the complex T1–T2 interplay in severe asthma highlighting mediators that impact both arms which may be targeted alone or in combination for disease alleviation.

Cystic fibrosis (CF) is a common autosomal recessive disease resulting from mutations of the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). Although severe pulmonary neutrophilic inflammation is a primary pathologic feature of CF, more recent studies reveal a role for type 2 inflammation that is characterized by eosinophilia directed by both the innate and adaptive immune systems through ILC2 and CD4⁺ Th2 cells, respectively. We have published that a clear type endotype exists within CF subjects stratified by Th2 inflammation, defined by increased obstructive pulmonary disease and a distinct phenotypic signature of increased allergic disease, infections, and burden of CF complications. Further, we showed an increased risk of death among CF subjects with type 2 inflammatory signatures compared to CF subjects lacking significant type 2 inflammation. The mechanisms of this heightened type 2 inflammatory signature in CF are still being defined, but it is clear that airway epithelial cells from CFTR-deficient mice have increased expression and release of IL-33, a key activator of ILC2 and Th2 cells, compared to persons with normal CFTR function. Further, there is strong evidence that CF regulates CD4⁺ Th2 function in a cell-intrinsic fashion. These concepts are explored in this review article.