Asthma is a complex disease with varied clinical manifestations resulting from the interaction between environmental and genetic factors. While chronic airway inflammation and hyperresponsiveness are central features, the etiology of asthma is multifaceted, leading to a diversity of phenotypes and endotypes. Although most research into the genetics of asthma focused on the analysis of single nucleotide polymorphisms (SNPs), studies highlight the importance of structural variations, such as copy number variations (CNVs), in the inheritance of complex characteristics, but their role has not yet been fully elucidated in asthma. In this context, an integrative review was conducted to identify the genes and pathways involved, the location, size, and classes of CNVs, as well as their contribution to asthma risk, severity, control, and response to treatment. As a result of the review, 16 articles were analyzed, from different types of observational studies, such as case-control, cohort studies and genotyped-proband or trios design, that have been carried out in populations from different countries, ethnicities, and ages. Chromosomes 12 and 17 were the most studied in three publications each. CNVs located on 12 chromosomes were associated with asthma, the majority being found on chromosome 6p and 17q, of the deletion type, encompassing 30 different coding-protein genes and one pseudogene region. Six genes with CNVs were identified as significant expression quantitative locus (eQTLs) with mean expression in asthma-related tissues, such as the lung and whole blood. The phenotypic variability of asthma may hinder the clinical application of these findings, but the research shows the importance of investigating these genetic variations as possible biomarkers in asthma patients.

The intestinal microbiota is a complex community of organisms present in the human gastrointestinal tract, some of which can produce short-chain fatty acids (SCFAs) through the fermentation of dietary fiber. SCFAs play a major role in mediating the intestinal microbiota's regulation of host immunity and intestinal homeostasis. Respiratory syncytial virus (RSV) can cause an imbalance between anti-inflammatory and proinflammatory responses in the host. In addition, changes in SCFA levels and the structure of the intestinal microbiota have been observed after RSV infection. Therefore, there may be a link between SCFAs and RSV infection, and SCFAs are expected to be therapeutic targets for RSV infection.

Exosomes, small extracellular vesicles secreted by various cell types, have emerged as key players in the pathophysiology of autoimmune diseases. These vesicles serve as mediators of intercellular communication, facilitating the transfer of bioactive molecules such as proteins, lipids, and nucleotide. In autoimmune diseases, exosomes have been implicated in modulating immune responses, oxidative stress, autophagy, gut microbes, and the cell cycle, contributing to disease initiation, progression, and immune dysregulation. Recent advancements in exosome isolation techniques and their molecular characterization have paved the way for exploring their clinical potential as biomarkers and therapeutic targets. This review focuses on the mechanisms by which exosomes influence autoimmune disease development and their potential clinical applications, particularly in diagnosis. The role of exosomes in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes mellitus (T1DM), inflammatory bowel disease (IBD), and Sjögren's syndrome (SS), is discussed in relation to their involvements in antigen presentation, T-cell activation, and the induction of inflammatory pathways. Additionally, exosome-based biomarkers offer promising non-invasive diagnostic tools for early diagnostic, disease monitoring, and therapeutic response assessment. However, challenges such as standardization of exosome isolation protocols and validation of their clinical significance remain. This review highlights the potential of exosomes as both diagnostic biomarkers and therapeutic targets in autoimmune diseases, emphasizing the need for further research to overcome current limitations and fully harness their clinical value.

In recent years, epigenetic modifications have attracted significant attention due to their unique regulatory mechanisms and profound biological implications. Acting as a bridge between environmental stimuli and changes in gene activity, they reshape gene expression patterns, providing organisms with regulatory mechanisms to respond to environmental changes. A growing body of evidence indicates that epigenetic regulation plays a crucial role in the pathogenesis and progression of psoriasis. A deeper understanding of these epigenetic mechanisms not only helps unveil the molecular mechanisms underlying the initiation and progression of psoriasis but may also provide new insights into diagnostic and therapeutic strategies. Given the unique roles and significant contributions of various cell types involved in the process of psoriasis, a thorough analysis of specific epigenetic patterns in different cell types becomes a key entry point for elucidating the mechanisms of disease development. Although epigenetic modifications encompass multiple complex layers, this review will focus on histone modifications and DNA methylation, describing how they function in different cell types and subsequently impact the pathophysiological processes of psoriasis. Finally, we will summarize the current problems in research concerning histone modifications and DNA methylation in psoriasis and discuss the clinical application prospects and challenges of targeting epigenetic modifications as therapeutic strategies for psoriasis.

Gastrointestinal Defects and Immunodeficiency Syndrome-1 (GIDID-1), caused by abnormalities in TTC7A, is an autosomal recessive disorder characterized by multiple gastrointestinal malformations and immune deficiencies, often accompanied by inflammatory bowel disease (IBD). This condition typically results in poor treatment outcomes and is usually fatal in early infancy. This paper examined the genetic abnormalities and clinical features of GIDID by analyzing data from three children and one fetus with gastrointestinal dysfunction and immune deficiency associated with TTC7A abnormalities at our hospital, and reviewed reported cases worldwide. Genetic analysis of the four patients identified eight novel variants in the TTC7A, five of which were likely pathogenic variants, while three were of uncertain significance. Including the cases reported in this paper and through a literature review, there were 89 known cases globally, involving 79 TTC7A variants. Patients typically presented with multiple gastrointestinal malformations, immune deficiencies, or IBD. Thus, genetic testing is recommended for patients with multiple gastrointestinal malformations and recurrent infections to determine if GIDID is due to TTC7A abnormalities. The syndrome generally has a poor prognosis, and this information is crucial for treatment planning, prenatal screening, and genetic counseling.

Neutrophils have a critical role in inflammation. Recent studies have identified their distinctive presence in certain types of atopic dermatitis (AD), yet their exact function remains unclear. This review aims to compile studies elucidating the role of neutrophils in AD pathophysiology. Proteins released by neutrophils, including myeloperoxidase, elastase, and lipocalin, contribute to pruritus progression in AD. Neutrophilic oxidative stress and the formation of neutrophil extracellular traps may further worsen AD. Elevated neutrophil elastase and high-mobility group box 1 protein expression in AD patients' skin exacerbates epidermal barrier defects. Neutrophil-mast cell interactions in allergic inflammation steer the immunological response toward Th2 imbalance and activate the Th17 pathway, particularly in response to allergens or infections linked to AD. Notably, drugs alleviating pruritic symptoms in AD inhibit neutrophilic inflammation. In conclusion, these findings underscore that neutrophils may be therapeutic targets for AD symptoms, emphasizing their inclusion in AD treatment strategies.

Non-allergic rhinitis (NAR) is a prevalent condition with limited effective treatments. Capsaicin, an agonist of the transient receptor potential vanilloid subfamily 1 (TRPV1) receptor, has emerged as a potential therapeutic option for NAR by targeting heightened nasal reactivity. This systematic review and meta-analysis, conducted in accordance with PRISMA guidelines and registered on PROSPERO, evaluated the efficacy of capsaicin for NAR treatment. Nine studies with placebo-controlled group were included, with primary outcomes assessed as total nasal symptom scores (TNSS), visual analog scale (VAS) scores, and the proportion of therapeutic responders. Meta-analysis revealed significant improvements in TNSS and VAS scores, along with a higher proportion of therapeutic responders in patients receiving capsaicin treatment compared to placebo. While some studies demonstrated reductions in substance P levels and TRPV1 expression after capsaicin treatment, further investigation is warranted. This meta-analysis provides preliminary evidence suggesting that capsaicin treatment holds promise for alleviating symptoms in patients with NAR. However, the limited number of studies and methodological heterogeneity necessitate larger and more rigorously designed clinical trials with standardized methodologies and advanced diagnostic techniques to establish their definitive roles in clinical practice.

The presence of IgG anti-IgA in the serum of primary immunodeficiency (PID) patients has long been considered responsible for hypersensitivity (HS) to immunoglobulin preparations (IgPs), but this link is increasingly being questioned. The aim of this work was to describe the prevalence of IgG anti-IgA and its association with HS, and to explore a new pathophysiological hypothesis involving the complement system. We measured IgG anti-IgA, using a standardised commercial technique, in controls and PID patients, and compared our results to a systematic literature review. We measured complement activation in PID patients before and after IgP infusion, and in vitro after incubation of IgP with serum from controls and PID patients. IgG anti-IgA was detected in 6% (n = 2/32) of PID patients, 30% (n = 3/10) of selective IgA deficiency patients and 2% (n = 1/46) of healthy controls. In the literature and our study, 38 PID patients had IgG anti-IgA and HS to IgPs and 9 had IgG anti-IgA but good tolerance to IgPs. In our patients, we observed a constant complement activation after IgP infusion compared to baseline. In vitro, IgP induced significant complement activation with all sera from tested individuals. IgA immunisation is not rare in PID, higher in selective IgA deficiency, but may also occur in healthy controls. Our results question the clinical relevance and pathophysiological implication of IgG anti-IgA in the context of HS with IgPs. Complement activation-related pseudoallergy could explain the clinical characteristics and natural history of HS symptoms.

Apart from the skin and mucosal immune barrier, the first line of defense of the human immune system includes MDA5 (ifih1 gene) which acts as a cellular sensor protein for certain viruses including SARS-CoV-2. Upon binding with viral RNA, MDA5 activates cell-intrinsic innate immunity, humoral responses, and MAVS (mitochondrial antiviral signaling). MAVS signaling induces type I and III interferon (IFN) expressions that further induce ISGs (interferon stimulatory genes) expressions to initiate human cell-mediated immune responses and attenuate viral replication. SARS-CoV-2 counteracts by producing NSP1, NSP2, NSP3, NSP5, NSP7, NSP12, ORF3A, ORF9, N, and M protein and directs anti-MDA5 antibody production presumably to antagonize IFN signaling. Furthermore, COVID-19 resembles several diseases that carry anti-MDA5 antibodies and the current COVID-19 vaccines induced anti-MDA5 phenotypes in healthy individuals. GWAS (genome-wide association studies) identified several polymorphisms (SNPs) in the ifih1-ifn pathway genes including rs1990760 in ifih1 that are strongly associated with COVID-19, and the associated risk allele is correlated with reduced IFN production. The genetic association of SNPs in ifih1 and ifih1-ifn pathway genes reinforces the molecular findings of the critical roles of MDA5 in sensing SARS-CoV-2 and subsequently the IFN responses to inhibit viral replication and host immune evasion. Thus, MDA5 or its pathway genes could be targeted for therapeutic development of COVID-19.

Long-term prophylaxis (LTP) has been shown to reduce the frequency of hereditary angioedema (HAE) attacks; however, attacks occurring in patients receiving LTP have not been well characterized. The objective of this systematic review was to evaluate the proportion of type I/II HAE (HAE-C1INH) patients who experience attacks while receiving LTP, the characteristics of these attacks, and associated on-demand therapy use. A systematic search was conducted in PubMed to identify studies reporting LTP use with plasma-derived C1 inhibitor (pdC1INH), lanadelumab, berotralstat, androgens, or antifibrinolytics in patients with HAE-C1INH. Forty-five primary studies met the inclusion criteria. In phase 3 trials, attack-free rates were 40% for subcutaneous pdC1INH 60 IU/kg twice weekly at 16 weeks, and 44% for lanadelumab 300 mg every second week at 6 months (77% during steady-state [days 70-182]); there was no difference in attack-free rate for berotralstat 150 mg versus placebo at 24 weeks. Phase 3 studies reported a lower average attack severity with subcutaneous and intravenous pdC1INH versus placebo. With lanadelumab and berotralstat, the prophylactic treatment effect was more pronounced in peripheral attacks than in abdominal and laryngeal attacks. Laryngeal attacks accounted for 2%-7% of all attacks in observational and interventional studies, regardless of the LTP agent received. On-demand therapy was used in 49%-94% of attacks occurring in the presence of LTP. In conclusion, patients receiving LTP experienced attacks in all anatomic locations, including the larynx. Most attacks were treated with on-demand therapy, although outcomes were not reported. Access to on-demand therapy remains essential for all people with HAE-C1INH.

NKp46 is a natural killer cell activating receptor primarily expressed on NK cells and non-NK innate lymphoid cells. In the context of anti-infection, NKp46 activates NK cells by binding to ligands on pathogens or infected cells, enabling NK cells to kill the infected cells. In antitumor activities, NKp46 plays a pivotal role in combating tumor growth through mechanisms such as directly killing tumor cells, inhibiting tumor immune escape, and reducing tumor growth rate through immune editing. The expression levels of NKp46 are closely associated with the progression of immune-related diseases, viral infections, leukemia, tumors, and reproductive failure, affecting diagnosis and prognosis. However, the functionality and mechanistic actions of NKp46, as well as the identification of additional NKp46 ligands, require further investigation. This review provides a comprehensive understanding of NKp46, offering a theoretical foundation for the research and development of diagnostic and therapeutic approaches for related diseases.

The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes (also referred to as BAF complexes) are composed of multiple subunits, which regulate the nucleosome translocation and chromatin accessibility. In recent years, significant advancements have been made in understanding mutated genes encoding subunits of the SWI/SNF complexes in cancer biology. Nevertheless, the role of SWI/SNF complexes in immune response and inflammatory diseases continues to attract significant attention. This review presents a summary of the significant functions of SWI/SNF complexes during the overall process from the development to the activation of innate and adaptive immune cells. In addition, the correlation between various SWI/SNF subunits and diverse inflammatory diseases is explored. Further investigations are warranted in terms of the mechanism of SWI/SNF complexes' preference for binding sites and opposite pro-/anti-inflammatory effects. In conclusion, further efforts are needed to evaluate the druggability of targeting SWI/SNF complexes in inflammatory diseases, and we hope this review will inspire the development of novel immune modulators in clinical practice.

Asthma is a chronic airway inflammatory disease that affects millions globally. Although glucocorticoids are a mainstay of asthma treatment, a subset of patients show resistance to these therapies, resulting in poor disease control and increased morbidity. The complex mechanisms underlying steroid-resistant asthma (SRA) involve Th1 and Th17 lymphocyte activity, neutrophil recruitment, and NLRP3 inflammasome activation. Recent studies provided evidence that innate lymphoid cells type 3 (ILC3s) might be potential therapeutic targets for non-eosinophilic asthma (NEA) and SRA. Like Th17 cells, ILC3s play crucial roles in immune responses, inflammation, and tissue homeostasis, contributing to disease severity and corticosteroid resistance in NEA. Biologics targeting ILC3-related pathways have shown promise in managing Th2-low asthma, suggesting new avenues for SRA treatment. This review aims to explore the risk factors for SRA, discuss the challenges and mechanisms underlying SRA, consolidate current findings on innate lymphoid cells, and elucidate their role in respiratory conditions. We present the latest findings on the involvement of ILC3s in human diseases and explore their potential mechanisms in SRA development. Furthermore, we review emerging therapeutic biologics targeting ILC3-related pathways in managing NEA and SRA. This review highlights current challenges, and emerging therapeutic strategies, and addresses a significant gap in asthma research, with implications for improving the management of steroid-resistant asthma.

Olfactory dysfunction (OD) can have serious consequences as it hinders individuals from detecting important warning signals like smoke, spoiled food, and gas leaks. This can significantly impact their nutritional status, eating satisfaction, and overall quality of life. Allergic rhinitis (AR) is a common disease that greatly affects the quality of life and can lead to a decrease, distortion, or complete loss of olfactory ability. There are various tools available for diagnosing OD, ranging from simple screening tests to more detailed and complex methods such as electrophysiological and imaging procedures not available in everyday practice but reserved for experimental studies. The underlying mechanisms by which AR impacts olfactory ability are still not fully understood and are likely to be multifactorial. Current therapeutic options for OD resulting from AR are limited and only provide partial or temporary relief from olfactory impairment. However, there are promising treatments investigated such as biologics, olfactory training, neural stem cell transplantation, and various novel target therapies that might help improve OD in AR in the future. This review aims to evaluate the epidemiology, mechanisms, and detection of OD in AR, as well as provide an overview of the management strategies for OD secondary to AR.

Allergen-based diagnostics are essential in the management algorithm of allergic diseases. Unlike systemic allergy, where the indications and interpretation of these diagnostic modalities are well established, their utility in ocular allergy is not well-defined. With the rising prevalence of ocular allergies and the need for personalized treatment strategies, there is a growing demand for precision allergen diagnostics. This review describes the commonly used tests with their indications, procedures, and limitations. A review of the literature was carried out on articles on allergen diagnostics in ocular allergy, and after excluding articles that were not relevant, 82 papers were included in the current review. IgE-mediated pathways contribute significantly to seasonal and perennial ocular allergy and partly to vernal keratoconjunctivitis. Most diagnostic techniques aim to detect IgE sensitization. In vivo tests include skin prick (SPT), intradermal, and patch tests. SPT is considered the gold standard and directly evaluates the presence of allergen-specific IgE in the skin. In vitro tests measure total and specific IgE from either tears or sera. Tear IgE measurement is relatively specific for allergic conjunctivitis and can provide insight into the potential allergens responsible for local sensitization. The conjunctival provocation test can help establish true allergy, especially in patients with polysensitization. This review also provides an overview of evidence in literature segregated based on the test employed. This includes 17 studies on only SPT; 42 studies on IgE measured in serum, tears, or both; and 20 studies which have evaluated both SPT and IgE. The pattern of allergen sensitization can guide recommendations for avoidance measures and immunotherapy. Thus, this could create a corticosteroid-sparing therapy avenue in these patients, reducing disease severity and resulting visual morbidity.

Regulatory T (Treg) cells are crucial for maintaining immune tolerance by suppressing response to self-antigens and harmless antigens to prevent autoimmune diseases and uncontrolled immune responses. Therefore, using Treg cells is considered a therapeutic strategy treating inflammatory diseases. Based on their origin, Treg cells are classified into thymus-derived, peripherally induced, and in vitro induced Treg cells. Our group discovered a novel Treg cell subset, namely, Treg-of-B (Treg/B) cells, generated by culturing CD4CD25 T cells with B cells, including Peyer's patch B cells, splenic B cells and peritoneal B1a cells, for 3 days. Treg/B cells express CD44, OX40 (CD134), cytotoxic T-lymphocyte-associated antigen-4 (CD152), glucocorticoid-induced tumor necrosis factor receptor family-related protein (CD357), interleukin-10 receptor, lymphocyte activation gene-3 (CD223), inducible co-stimulator (CD278), programmed-death 1 (CD279), tumor necrosis factor receptor II, and high levels of IL-10, but not forkhead box protein P3, similar to type 1 Treg (Tr1) cells. However, unlike Tr1 cells, Treg/B cells do not express CD103, CD226, and latency-associated peptide. Treg/B cells have been applied for the treatment of some murine models of inflammatory diseases, including allergic asthma, inflammatory bowel disease, collagen-induced arthritis, gout, psoriasis and primary biliary cholangitis. This review summarizes the current knowledge of Treg/B cells.

Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, modulate immune cell functions, particularly macrophages. This review explores the potential therapeutic applications of SCFAs in pulmonary fungal infections, a critical concern due to their high mortality rates and antifungal resistance. SCFAs enhance macrophage functions by promoting phagosome-lysosome fusion, increasing reactive oxygen species production, and balancing cytokine responses. Pulmonary fungal infections, caused by pathogens like Aspergillus fumigatus, are prevalent in immunocompromised patients, including those with diabetes, chronic obstructive pulmonary disease, and those on high-dose corticosteroids. SCFAs have shown promise in improving macrophage function in these contexts. However, the application of SCFAs must be balanced against potential side effects, including gut microbiota disruption and metabolic disorders. Further research is needed to optimize SCFA therapy for managing pulmonary fungal infections.

NKT cells, unique lymphocytes bridging innate and adaptive immunity, offer significant potential for managing inflammatory disorders like asthma. Activating iNKT induces increasing IFN-γ, TGF-β, IL-2, and IL-10 potentially suppressing allergic asthma. However, their immunomodulatory effects, including granzyme-perforin-mediated cytotoxicity, and expression of TIM-3 and TRAIL warrant careful consideration and targeted approaches. Although CAR-T cell therapy has achieved remarkable success in treating certain cancers, its limitations necessitate exploring alternative approaches. In this context, CAR-NKT cells emerge as a promising approach for overcoming these challenges, potentially achieving safer and more effective immunotherapies. Strategies involve targeting distinct IgE-receptors and their interactions with CAR-NKT cells, potentially disrupting allergen-mast cell/basophil interactions and preventing inflammatory cytokine release. Additionally, targeting immune checkpoints like PDL-2, inducible ICOS, FASL, CTLA-4, and CD137 or dectin-1 for fungal asthma could further modulate immune responses. Furthermore, artificial intelligence and machine learning hold immense promise for revolutionizing NKT cell-based asthma therapy. AI can optimize CAR-NKT cell functionalities, design personalized treatment strategies, and unlock a future of precise and effective care. This review discusses various approaches to enhancing CAR-NKT cell efficacy and longevity, along with the challenges and opportunities they present in the treatment of allergic asthma.

Autoimmune diseases (AIDs) are complex in etiology and diverse in classification but clinically show similar symptoms such as joint pain and skin problems. As a result, the diagnosis is challenging, and usually, only broad treatments can be available. Consequently, the clinical responses in patients with different types of AIDs are unsatisfactory. Therefore, it is necessary to conduct more research to figure out the pathogenesis and therapeutic targets of AIDs. This requires research technologies with strong extraction and prediction capabilities. Single-cell sequencing technology analyses the genomic, epigenomic, or transcriptomic information at the single-cell level. It can define different cell types and states in greater detail, further revealing the molecular mechanisms that drive disease progression. These advantages enable cell biology research to achieve an unprecedented resolution and scale, bringing a whole new vision to life science research. In recent years, single-cell technology especially single-cell RNA sequencing (scRNA-seq) has been widely used in various disease research. In this paper, we present the innovations and applications of single-cell sequencing in the medical field and focus on the application contributing to the differential diagnosis and precise treatment of AIDs. Despite some limitations, single-cell sequencing has a wide range of applications in AIDs. We finally present a prospect for the development of single-cell sequencing. These ideas may provide some inspiration for subsequent research.

Head and neck dermatitis (HND) is a form of atopic dermatitis (AD) that affects the seborrheic areas of the body and causes greater quality of life detriments than other types of AD. HND can be challenging to treat since first-line topical therapies may be ineffective or intolerable for long-term use on areas affected by HND while dupilumab may cause dupilumab-associated HND (DAHND). Current evidence implicates fungi, particularly Malassezia spp., in the pathogenesis of HND. Penetration of fungal antigens through the defective AD skin barrier activates the innate and adaptive immune systems to cause cutaneous inflammation via the T helper (Th)17 and/or Th2 axes. Malassezia sensitization may distinguish HND from other forms of AD. Multiple double-blind, placebo-controlled trials have shown antifungals to benefit HND, yet the persistence of symptom relief with sustained use remains unclear. Oral antifungals appear more effective than topical antifungals but may be harmful with long-term use. DAHND may also be fungal-mediated given improvement with antifungals and evidence of an overactive immune response against Malassezia in these patients. Janus kinase inhibitors are effective for HND, including DAHND, but may cause significant side effects when administered systemically. OX40/OX40L inhibitors and tralokinumab may be promising options for HND on the horizon. Demographic and environmental factors influence the host mycobiome and should be considered in future precision-medicine approaches as microbiome composition and diversity are linked to severity of HND.

The role of abnormal epigenetic modifications, particularly DNA methylation, in the pathogenesis of autoimmune rheumatic diseases (ARDs) has garnered increasing attention. Lymphocyte dysfunction is a significant contributor to the pathogenesis of ARDs. Methylation is crucial for maintaining normal immune system function, and aberrant methylation can hinder lymphocyte differentiation, resulting in functional abnormalities that disrupt immune tolerance, leading to the excessive expression of inflammatory cytokines, thereby exacerbating the onset and progression of ARDs. Recent studies suggest that methylation-related factors have the potential to serve as biomarkers for monitoring the activity of ARDs. This review summarizes the current state of research on the impact of DNA and RNA methylation on the development, differentiation, and function of T and B cells and examines the progress of these epigenetic modifications in studies of six specific ARDs: systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, juvenile idiopathic arthritis, and ankylosing spondylitis. Additionally, we propose that exploring the interplay between RNA methylation and DNA methylation may represent a novel direction for understanding the pathogenesis of ARDs and developing novel treatment strategies.