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.

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.

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.

Tryptophan, an essential amino acid, is primarily metabolized through four key pathways: the kynurenine pathway, serotonin pathways, indole pathways and interleukin 4-induced gene 1 (IL-4I1) pathways. Dysregulation of tryptophan metabolism is implicated in various non-communicable diseases including psychiatric disorders, inflammatory and autoimmune diseases, as well as metabolic diseases. The dogma in the field is that tryptophan is metabolized via the kynurenine pathway in the liver mainly by indoleamine 2,3-dioxygenase 1/2 (IDO 1/2) and Tryptophan dioxygenase 2 (TDO2) enzymes. However, there is growing evidence demonstrating that IL-4I1 and tryptophanase are also crucial tryptophan catabolizing enzymes resulting in metabolites that activate aryl hydrocarbon receptor (AhR) and modulate immune responses. Tryptophan metabolism is crucial in cellular, tissue and organismal function and its disruption is linked to conditions such as inflammatory bowel disease (IBD), multiple sclerosis (MS), and psychiatric disorders like depression, anxiety and metabolic diseases such as obesity and Type 2 diabetes. It is unclear though whether only specific tryptophan pathways are associated with disease or there is a level of redundancy. Some key metabolites from tryptophan catabolism can come from multiple pathways, with opposing or converging effects on cellular functions. This review will explore the critical role of tryptophan metabolism in health and diseases, focusing on its implications in non-communicable diseases. Importantly, this review will focus on recent developments in tryptophan metabolism and strengthen the argument for a revised schematic tryptophan catabolic pathway.

Asthma is a chronic respiratory condition characterised by episodes of shortness of breath due to reduced airway flow. The disease is triggered by a hyperreactive immune response to innocuous allergens, leading to hyper inflammation, mucus production, changes in structural cells lining the airways, and airway hyperresponsiveness. Asthma, although present in adults, is considered as a childhood condition, with a total of about 6.2 million children aged 18 and below affected globally. There has been progress in understanding asthma heterogeneity in adults, which has led to better patient stratification and characterisation of multiple asthma endotypes with distinct, but overlapping inflammatory features. The asthma inflammatory profile in children is not well-defined and heterogeneity of the disease is less described. Although many factors such as genetics, food allergies, antibiotic usage, type of birth, and cigarette smoke exposure can influence asthma development particularly in children, respiratory infections are thought to be the major contributing factor in poor lung function and onset of the disease. In this review, we focus on viral and bacterial respiratory infections in the first 10 years of life that could influence development of asthma in children. We also review literature on inflammatory immune heterogeneity in asthmatic children and how this overlaps with early lung development, poor lung function and respiratory infections. Finally, we review animal studies that model early development of asthma and how these studies could inform future therapies and better understanding of this complex disease.

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.