JAK3 inhibitor suppresses multipotent ILC2s and attenuates steroid-resistant asthma.

Steroids are the standard treatment for allergic airway inflammation in asthma, but steroid-refractory asthma poses a challenge. Group 2 innate lymphoid cells (ILC2s), such as T helper 2 (TH2) cells, produce key asthma-related type 2 cytokines. Recent insights from mouse and human studies indicate a potential connection between ILC2s and steroid-resistant asthma. Here, we highlight that lung ILC2s, rather than TH2 cells, can develop steroid resistance, allowing them to persist and maintain their disease-driving activity even during steroid treatment. The emergence of multipotent IL-5+IL-13+IL-17A+ ILC2s is associated with steroid-resistant ILC2s. The Janus kinase 3 (JAK3)/signal transducer and activator of transcription (STAT) 3, 5, and 6 pathways contribute to the acquisition of steroid-resistant ILC2s. The JAK3 inhibitor reduces ILC2 survival, proliferation, and cytokine production in vitro and ameliorates ILC2-driven Alternaria-induced asthma. Furthermore, combining a JAK3 inhibitor with steroids results in the inhibition of steroid-resistant asthma. These findings suggest a potential therapeutic approach for addressing this challenging condition in chronic asthma.

Memory-like innate lymphoid cells in the pathogenesis of asthma.

Innate lymphoid cells (ILCs) are recently discovered innate immune cells that reside and self-renew in mucosal tissues and serve as the first line of defense against various external insults. They include natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells. The development and functions of ILC1-3 reflect those of their adaptive immunity TH1, TH2, and TH17 T-cell counterparts. Asthma is a heterogeneous disease caused by repeated exposure to specific allergens or host/environmental factors (e.g., obesity) that stimulate pathogenic pulmonary immune cells, including ILCs. Memory used to be a hallmark of adaptive immune cells until recent studies of monocytes, macrophages, and NK cells showed that innate immune cells can also exhibit greater responses to re-stimulation and that these more responsive cells can be long-lived. Besides, a series of studies suggest that the tissue-resident innate lymphoid cells have memory-like phenotypes, such as increased cytokine productions or epigenetic modifications following repetitive exposure to allergens. Notably, both clinical and mouse studies of asthma show that various allergens can generate memory-like features in ILC2s. Here, we discuss the biology of ILCs, their roles in asthma pathogenesis, and the evidence supporting ILC memory. We also show evidence suggesting memory ILCs could help drive the phenotypic heterogeneity in asthma. Thus, further research on memory ILCs may be fruitful in terms of developing new therapies for asthma.

Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells.

Although cigarette smoking is known to exacerbate asthma, only a few clinical asthma studies have been conducted involving smokers. Here we show, by comparing paired sputum and blood samples from smoking and non-smoking patients with asthma, that smoking associates with significantly higher frequencies of pro-inflammatory, natural-cytotoxicity-receptor-non-expressing type 3 innate lymphoid cells (ILC3) in the sputum and memory-like, CD45RO-expressing ILC3s in the blood. These ILC3 frequencies positively correlate with circulating neutrophil counts and M1 alveolar macrophage frequencies, which are known to increase in uncontrolled severe asthma, yet do not correlate with circulating eosinophil frequencies that characterize allergic asthma. In vitro exposure of ILCs to cigarette smoke extract induces expression of the memory marker CD45RO in ILC3s. Cigarette smoke extract also impairs the barrier function of airway epithelial cells and increases their production of IL-1ß, which is a known activating factor for ILC3s. Thus, our study suggests that cigarette smoking increases local and circulating frequencies of activated ILC3 cells, plays a role in their activation, thereby aggravating non-allergic inflammation and the severity of asthma.

The Dynamic Contribution of Neutrophils in the Chronic Respiratory Diseases.

Asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis are representative chronic respiratory diseases (CRDs). Although they differ in terms of disease presentation, they are all thought to arise from unresolved inflammation. Neutrophils are not only the first responders to acute inflammation, but they also help resolve the inflammation. Notably, emerging clinical studies show that CRDs are associated with systemic and local elevation of neutrophils. Moreover, murine studies suggest that airway-infiltrating neutrophils not only help initiate airway inflammation but also prolong the inflammation. Given this background, this review describes neutrophil-mediated immune responses in CRDs and summarizes the completed, ongoing, and potential clinical trials that test the therapeutic value of targeting neutrophils in CRDs. The review also clarifies the importance of understanding how neutrophils interact with other immune cells and how these interactions contribute to chronic inflammation in specific CRDs. This information may help identify future therapeutic strategies for CRDs.

Targeting the Epithelium-Derived Innate Cytokines: From Bench to Bedside.

When epithelial cells are exposed to potentially threatening external stimuli such as allergens, bacteria, viruses, and helminths, they instantly produce "alarmin" cytokines, namely, IL-33, IL-25, and TSLP. These alarmins alert the immune system about these threats, thereby mobilizing host immune defense mechanisms. Specifically, the alarmins strongly stimulate type-2 immune cells, including eosinophils, mast cells, dendritic cells, type-2 helper T cells, and type-2 innate lymphoid cells. Given that the alarm-raising role of IL-33, IL-25, and TSLP was first detected in allergic and infectious diseases, most studies on alarmins focus on their role in these diseases. However, recent studies suggest that alarmins also have a broad range of effector functions in other pathological conditions, including psoriasis, multiple sclerosis, and cancer. Therefore, this review provides an update on the epithelium-derived cytokines in both allergic and non-allergic diseases. We also review the progress of clinical trials on biological agents that target the alarmins and discuss the therapeutic potential of these agents in non-allergic diseases.

Interactions between NCR+ILC3s and the Microbiome in the Airways Shape Asthma Severity.

Asthma is a heterogeneous disease whose development is shaped by a variety of environmental and genetic factors. While several recent studies suggest that microbial dysbiosis in the gut may promote asthma, little is known about the relationship between the recently discovered lung microbiome and asthma. Innate lymphoid cells (ILCs) have also been shown recently to participate in asthma. To investigate the relationship between the lung microbiome, ILCs, and asthma, we recruited 23 healthy controls (HC), 42 patients with non-severe asthma, and 32 patients with severe asthma. Flow cytometry analysis showed severe asthma associated with fewer natural cytotoxicity receptor (NCR)+ILC3s in the lung. Similar changes in other ILC subsets, macrophages, and monocytes were not observed. The asthma patients did not differ from the HC in terms of the alpha and beta-diversity of the lung and gut microbiomes. However, lung function correlated positively with both NCR+ILC3 frequencies and microbial diversity in the lung. Sputum NCR+ILC3 frequencies correlated positively with lung microbiome diversity in the HC, but this relationship was inversed in severe asthma. Together, these data suggest that airway NCR+ILC3s may contribute to a healthy commensal diversity and normal lung function.

Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells.

Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma. Here, we examined the effect of human umbilical cord blood-derived MSCs (hUC-MSC) on two mouse models of severe asthma, namely, Alternaria alternata-induced and house dust mite (HDM)/diesel exhaust particle (DEP)-induced asthma. hUC-MSC treatment attenuated lung type 2 (Th2 and type 2 innate lymphoid cell) inflammation in both models. However, these effects were only observed with particular treatment routes and timings. In vitro co-culture showed that hUC-MSC directly downregulated the interleukin (IL)-5 and IL-13 production of differentiated mouse Th2 cells and peripheral blood mononuclear cells from asthma patients. Thus, these results showed that hUC-MSC treatment can ameliorate asthma by suppressing the asthmogenic cytokine production of effector cells. However, the successful clinical application of MSCs in the future is likely to require careful optimization of the route, dosage, and timing.

Analysis of Innate and Adaptive Immunological Characteristics in Patients with IgG4-Related Disease.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immunological disorder characterized by fibro-inflammatory conditions; however, the pathobiology of IgG4-RD has not been fully identified. OBJECTIVE: This study aimed to analyze systemic differences of innate and adaptive immune cells from healthy controls and patients with IgG4-RD. METHODS: Healthy controls (n = 9) and IgG4-RD patients (n = 7) were recruited with informed consent. Peripheral blood was collected from healthy controls and IgG4-RD patients, and three blood samples from IgG4-RD patients were re-collected two months after the last rituximab (RTX) treatment. The various immune cells and cytokine productions were measured by flow cytometry. RESULTS: Blood CD14+ monocytes and steady-state follicular helper T cells were increased in patients with IgG4-RD. However, there were no changes in other immune cell populations, including B cells, CD4 T cells, CD8 T cells, and innate lymphoid cells. Also, the TGF-ß-producing CD14+ monocytes were significantly augmented in patients with IgG4-RD. Two months after RTX treatment, total B cells (CD19+) were depleted; however, the expressions of TGF-ß from CD14+ monocytes remained unchanged. CONCLUSION: These findings showed that IgG4-RD is related to the increment of CD14+ monocytes. Besides, controlling increased TGF-ß-producing CD14+ monocytes with RTX treatment might be a conducive way to regulate IgG4-RD.

Altered T cell and monocyte subsets in prolonged immune reconstitution inflammatory syndrome related with DRESS (drug reaction with eosinophilia and systemic symptoms).

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous adverse reaction involving various internal organs. Flare-ups after recovery from the initial presentation of DRESS are caused by relapse of drug-induced T-cell-mediated reactions. However, the specific underlying mechanism is unclear. Here, we report a case of a 60-year-old man with allopurinol-induced DRESS who suffered recurrent episodes of generalized rash with eosinophilia, which mimicked immune reconstitution inflammatory syndrome. Analysis of immunological profiles revealed that the percentages of T lymphocytes and regulatory T cells in the patient with DRESS were higher than those in healthy controls. In addition, there was a notable change in the subtype of monocytes in the patient with DRESS; the percentage of nonclassical monocytes increased, whereas that of classical monocytes decreased. Upon viral infection, nonclassical monocytes exhibited strong pro-inflammatory properties that skewed the immune response toward a Th2 profile, which was associated with persistent flare-ups of DRESS. Taken together, the results increase our understanding of the pathogenesis of DRESS as they suggest that expansion of nonclassical monocytes and Th2 cells drives disease pathogenesis.