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Tuberculosis (TB) is a leading cause of mortality due to infectious disease, but the factors determining disease progression are unclear. Transcriptional signatures associated with type I IFN signalling and neutrophilic inflammation were shown to correlate with disease severity in mouse models of TB. Here we show that similar transcriptional signatures correlate with increased bacterial loads and exacerbate pathology during Mycobacterium tuberculosis infection upon GM-CSF blockade. Loss of GM-CSF signalling or genetic susceptibility to TB (C3HeB/FeJ mice) result in type I IFN-induced neutrophil extracellular trap (NET) formation that promotes bacterial growth and promotes disease severity. Consistently, NETs are present in necrotic lung lesions of TB patients responding poorly to antibiotic therapy, supporting the role of NETs in a late stage of TB pathogenesis. Our findings reveal an important cytokine-based innate immune effector network with a central role in determining the outcome of M . tuberculosis infection. GM-CSF is involved in control over M. tuberculosis infection. Here the authors show that GM-CSF reduces type 1 interferon driven neutrophil recruitment, NETosis and bacterial growth in the lungs of infected mice, and provide evidence that this NETosis occurs in infected humans who are not responsive to antibiotic therapy.

B lymphocytes are important in secreting antibodies that protect against invading pathogens such as viruses, bacteria, parasites, and also in mediating pathogenesis of allergic diseases and autoimmunity. B lymphocytes develop in the bone marrow and contain heavy and light chains, which upon ligation form an immunoglobulin M (IgM) B cell receptor (BCR) expressed on the surface of naïve immature B cells. Naïve B cells expressing either IgM or IgD isotypes are thought to play interchangeable functions in antibody responses to T cell-dependent and T cell-independent antigens. IgM short-lived plasma cells (SLPCs) and antigen-specific IgM memory B cells (MBCs-M) are critical in the first few days of infection, as well as long-term memory induced by vaccination, respectively. At mucosal surfaces, IgM is thought to play a critical part in promoting mucosal tolerance and shaping microbiota together with IgA. In this review, we explore how IgM structure and BCR signaling shapes B cell development, self and non-self-antigen-specific antibody responses, responses to infectious (such as viruses, parasites, and fungal) and non-communicable diseases (such as autoimmunity and allergic asthma). We also explore how metabolism could influence other B cell functions such as mucosal tolerance and class switching. Finally, we discuss some of the outstanding critical research questions in both experimental and clinical settings targeting IgM.

Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposing factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells is involved is unclear. Targeting interleukin 4 receptor alpha (IL-4Rα), an IL-4/IL-13 signalling axis, with dupilumab shows efficacy in AD. We investigated the importance of IL-4Rα signalling specifically on B and T cells during acute and chronic models of AD. We used House dust mite (HDM) and Ovalbumin (OVA) in chronic models and a low-calcemic analog of vitamin D (MC903) for acute models of AD. We used mb1 cre IL-4Rα −/lox , iLCK cre IL-4Rα −/lox , LCK cre IL-4Rα −/lox , CD4 cre IL-4Rα −/lox , Foxp3 cre IL-4Rα −/lox and IL-4Rα −/lox littermate controls. IL-4Rα-responsive B cells were essential in serum IgE levels, but not in epidermal thickening in both chronic and acute models. IL-4Rα-responsive T cells were essential in epidermal thickening in the pan-T cell, but not CD4 or CD8 T cells suggesting the importance of γδT cells during acute AD. Our results suggest that IL-4Rα responsiveness on innate T cells regulates acute atopic dermatitis, while on B cells it regulates IgE.

Asthma is a chronic debilitating airway disease affecting millions of people worldwide. Although largely thought to be a disease of the first world, it is now clear that it is on the rise in many middle- and lower-income countries. The disease is complex, and its etiology is poorly understood, which explains failure of most treatment strategies. We know that in children, asthma is closely linked to poor lung function in the first 3-years of life, when the lung is still undergoing post-natal alveolarization phase. Epidemiological studies also suggest that environmental factors around that age do play a critical part in the establishment of early wheezing which persists until adulthood. Some of the factors that contribute to early development of asthma in children in Western world are clear, however, in low- to middle-income countries this is likely to differ significantly. The contribution of fungal species in the development of allergic diseases is known in adults and in experimental models. However, it is unclear whether early exposure during perinatal or post-natal lung development influences a protective or promotes allergic asthma. Host immune cells and responses will play a crucial part in early development of allergic asthma. How immune cells and their receptors may recognize fungi and promote allergic asthma or protect by tolerance among other immune mechanisms is not fully understood in this early lung development stage. The aim of this review is to discuss what fungal species are present during early exposure as well as their contribution to the development of allergic responses. We also discuss how the host has evolved to promote tolerance to limit hyper-responsiveness to innocuous fungi, and how host evasion by fungi during early development consequentially results in allergic diseases.

Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR), and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β 2 adrenergic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model. We sensitised wild-type (WT) and IgM-deficient (IgM KO) mice with HDM and measured AHR, and Th2 responses. We performed RNA sequencing on the whole lung of WT and IgM KO mice sensitised to saline or HDM. We validated our AHR data on human ASM by deleting genes using CRISPR and measuring contraction by single-cell force cytometry. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 ( Baiap2l1 ) and other genes. Deletion of BAIAP2L1 led to a differential reduction in human ASM contraction when stimulated with TNF-α and Acetylcholine, but not IL-13. These findings have implications for future treatment of asthma beyond current therapies.

Asthma is a heterogeneous disease that affects approximately 300 million people worldwide, largely in developed countries. The etiology of the disease is poorly understood, but is likely to involve specific innate and adaptive responses to inhaled microbial components that are found in allergens. Fungal-derived allergens represent a major contributing factor in the initiation, persistence, exacerbation, and severity of allergic asthma. C-type lectin like receptors, such as dectin-1, dectin-2, DC-specific intercellular adhesion molecule 3-grabbing nonintegrin, and mannose receptor, recognize many fungal-derived allergens and other structurally similar allergens derived from house dust mites (HDM). In some cases, the fungal derived allergens have been structurally and functionally identified alongside their respective receptors in both humans and mice. In this review, we discuss recent understanding on how selected fungal and HDM derived allergens as well as their known or unknown receptors shape allergic airway diseases.

Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and β-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these microbial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.

Impaired tolerance to innocuous particles during allergic asthma has been linked to increased plasticity of FoxP3 + regulatory T cells (Tregs) reprogramming into pathogenic effector cells, thus exacerbating airway disease. However, failure of tolerance mechanisms is driven by Th2 inflammatory signals. Therefore, the in vivo role of canonical IL-4 receptor α (IL-4Rα) signaling, an essential driver of Th2-type airway responses to allergens, on the regulatory function of FoxP3 + Tregs in allergic asthma was explored. Here, we used transgenic Foxp3 cre IL-4Rα –/lox and littermate control mice to investigate the role of IL-4 and IL-13 signaling via Tregs in house dust mite–induced (HDM-induced) allergic airway disease. We sensitized mice intratracheally on day 0, challenged them on days 6–10, and analyzed airway hyperresponsiveness (AHR), airway inflammation, mucus production, and cellular profile on day 14. In the absence of IL-4Rα responsiveness on FoxP3 + Tregs, exacerbated AHR and airway inflammation were shown in HDM-sensitized mice. Interestingly, reduced induction of FoxP3 + Tregs accompanied increased IL-33 alarmin production and type 2 innate lymphoid cell activation in the lung, exacerbating airway hyperreactivity and lung eosinophilia. Taken together, our findings indicate that IL-4Rα–unresponsive FoxP3 + Tregs result in exaggerated innate Th2-type, IL-33–dependent airway inflammation and a break in tolerance during allergic asthma.

The innate recognition of fungi by leukocytes is mediated by pattern recognition receptors (PRR), such as Dectin-1, and is thought to occur at the cell surface triggering intracellular signalling cascades which lead to the induction of protective host responses. In the lung, this recognition is aided by surfactant which also serves to maintain the balance between inflammation and pulmonary function, although the underlying mechanisms are unknown. Here we have explored pulmonary innate recognition of a variety of fungal particles, including zymosan, Candida albicans and Aspergillus fumigatus, and demonstrate that opsonisation with surfactant components can limit inflammation by reducing host-cell fungal interactions. However, we found that this opsonisation does not contribute directly to innate fungal recognition and that this process is mediated through non-opsonic PRRs, including Dectin-1. Moreover, we found that pulmonary inflammatory responses to resting Aspergillus conidia were initiated by these PRRs in acidified phagolysosomes, following the uptake of fungal particles by leukocytes. Our data therefore provides crucial new insights into the mechanisms by which surfactant can maintain pulmonary function in the face of microbial challenge, and defines the phagolysosome as a novel intracellular compartment involved in the innate sensing of extracellular pathogens in the lung.