Asthma biological therapies and autoimmune disease

BACKGROUND: The management of uncontrolled severe asthma has greatly improved since the advent of novel biologic therapies. Up to August 2022, five biologics have been approved for the type 2 asthma phenotype: anti-IgE (omalizumab), anti-IL5 (mepolizumab, reslizumab, benralizumab), and anti-IL4 (dupilumab) monoclonal antibodies. These drugs are usually well tolerated, although long-term safety information is limited, and some adverse events have not yet been fully characterized. Spontaneous reporting systems represent the cornerstone for the detection of potential signals and evaluation of the real-world safety of all marketed drugs...

Toll-like receptors (TLRs) are components of innate immunity that play a crucial role in several diseases, including chronic inflammatory and infectious diseases, autoimmune diseases, and cancer. In particular, TLR7 has been identified as a key player in the innate immune response against viral infections and small-molecule TLR7 agonists have shown potential for vaccine therapy, for treatment of asthma and allergies, and as anticancer drugs. Inspired by our previous discovery of selective TLR7 agonists, our goal was to develop and introduce a new chemotype of TLR7 agonists by replacing the quinazoline ring with a new heterocycle isoxazolo[5,4 -d ]pyrimidine...

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab...

BACKGROUND: Anaphylaxis is an acute, potentially life-threatening allergic reaction that typically occurs after exposure to a trigger, while idiopathic anaphylaxis (IA) occurs in the absence of a trigger. Acute management of both triggered anaphylaxis and IA relies on the use of epinephrine. In some patients with recurrent IA, glucocorticoid prophylaxis with prednisone can be effective. While there is currently no high quality evidence for the use of other prophylactic options to prevent recurrent IA, evolving data exists to support the consideration of biologics that target IgE or the Th2 pathway...

Short-chain fatty acids (SCFAs) derived from the fermentation of carbohydrates by gut microbiota play a crucial role in regulating host physiology. Among them, acetate, propionate, and butyrate are key players in various biological processes. Recent research has revealed their significant functions in immune and inflammatory responses. For instance, butyrate reduces the development of interferon-gamma (IFN-γ) generating cells while promoting the development of regulatory T (Treg) cells. Propionate inhibits the initiation of a Th2 immune response by dendritic cells (DCs)...

Shikonin, the primary active compound found in the rhizome of the traditional Chinese medicinal herb known as "ZiCao", exhibits a diverse range of pharmacological effects. This drug has a wide range of uses, including as an anti-inflammatory, antioxidant, and anti-cancer agent. It is also effective in promoting wound healing and treating autoimmune diseases such as multiple sclerosis, diabetes, asthma, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Although shikonin has a wide range of applications, its mechanisms are still not fully understood...

Oral immunotherapy (OIT) has been recommended to reduce parental burden related to strict allergen avoidance as well as to induce desensitization and immune tolerance for patients with long-lasting allergies to hen's eggs (HE) or cow's milk (CM). OIT should be monitored by pediatric allergists specializing in OIT and oral food challenge tests to cope with allergic reactions. Although a previous history of anaphylaxis or multiple food allergy is not a contraindication to OIT, it is absolutely contraindicated if the patient has uncontrolled asthma, malignancy, active systemic autoimmune disorders, or diseases requiring treatment with beta-blockers...

PURPOSE OF REVIEW: Type-2 (T2)-high asthma represents a well defined group of severe eosinophilic asthma for which there are now effective biologic therapies targetting the interleukins (ILs) 4, 5 and 13, and Immunoglobulin E. T2-low asthma detected in the clinic by a low blood eosinophil count remains ill-defined and is the focus of this review. RECENT FINDINGS: By analysing transcriptomic and proteomic expression in sputum samples in U-BIOPRED cohort, both T2-high and -low molecular phenotypes have been described...

Modulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune-related disorders and cancer. This highlights a critical need for the identification of proteins that regulate T cell function. The kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is emerging as a potent regulator of the immune system, spurring interest in its use as a therapeutic target. In murine models of immune-related diseases including asthma and rheumatoid arthritis, treatment with small-molecule DNA-PKcs inhibitors decreased the disease severity...

Bullous pemphigoid (BP) is an autoimmune disease characterized by itchy erythema and tense blisters on the whole body. Recent reports have unveiled the pathogenic roles of eosinophils in BP (e.g., dermal-epidermal separation, generation of pruritus). Thus, eosinophils are considered a therapeutic target. Benralizumab is an anti-IL-5 receptor alpha (IL-5Rα) monoclonal antibody (mAb) that is widely used to treat severe eosinophilic asthma. By affecting IL-5Rα, benralizumab depletes eosinophils and basophils due to apoptosis through antibody-dependent cell-mediated cytotoxicity...

In the last few decades, there has been a growing interest in Bruton's tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and differentiation. Evidence demonstrating the expression of BTK on the majority of hematological cells has led to the hypothesis that BTK inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias and lymphomas. However, a growing body of experimental and clinical data has demonstrated the significance of BTK, not just in B-cell malignancies, but also in solid tumors, such as breast, ovarian, colorectal, and prostate cancers...

Pemphigus is a rare autoimmune disease and has the potential to be fatal without treatment. Pemphigus erythematosus (PE) is a benign type of pemphigus foliaceus. Glucocorticoids and immunosuppressive agents are primary therapeutic modalities in pemphigus erythematosus, which may lead to considerable side effects. There is a growing need for new pemphigus therapies with fewer adverse effects. Dupilumab is a humanized monoclonal IgG4 antibody that inhibits the signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13) and has been applied for atopic dermatitis and asthma...

INTRODUCTION: The relationship between atopic dermatitis and atopic diseases such as food allergies, asthma, and allergic rhinitis in terms of co-occurrence, underlying mechanisms, and therapy is well documented. There is increasing evidence that atopic dermatitis is associated with non-atopic comorbidities such as cardiac, autoimmune, and neuropsychological comorbidities, as well as cutaneous and extracutaneous infections, establishing atopic dermatitis as a systemic disease. AREAS COVERED: The authors reviewed evidence on atopic and non-atopic comorbidities of atopic dermatitis...

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of cancer and inflammatory diseases. MIF is constitutively present in several cell types and non-lymphoid tissues and is secreted after acute stress or inflammation. MIF triggers the release of proinflammatory cytokines, overrides the anti-inflammatory effects of glucocorticoids, and exerts chemokine function, resulting in increased migration and recruitment of leukocytes into inflamed tissue...

Biologic therapies in asthma are indicated in severe disease, and they are directed against specific inflammatory modulators that contribute to pathogenesis and severity. Currently approved biologics target T2 cytokines (IgE, IL-5, IL-4/IL-13, and TLSP) and have demonstrated efficacy in clinical outcomes such as exacerbation rate and oral corticosteroid dose reductions, blood and airway eosinophil depletion, and lung function improvement. However, a proportion of these patients may show inadequate responses to biologics, with either initial lack of improvement or clinical and functional worsening after an optimal initial response...

Childhood obesity accounts for several psychosocial and clinical consequences. Psychosocial consequences include lower self-esteem, social isolation, poor academic achievement, peer problems, and depression, whereas clinical consequences are cardiovascular diseases, type 2 diabetes, dyslipidemia, cancer, autoimmune diseases, girls early polycystic ovarian syndrome (PCOS), asthma, bone deformities, etc. A growing number of studies have uncovered the association of childhood obesity and its consequences with vitamin-D (vit-D) deficiency and vitamin-D receptor (VDR) gene polymorphisms such as single nucleotide polymorphisms (SNPs), e...

The p38 MAPK is a signaling pathway important for cells to respond to environmental and intracellular stress. Upon activation, the p38 kinase phosphorylates downstream effectors, which control the inflammatory response and coordinate fundamental cellular processes such as proliferation, apoptosis, and differentiation. Dysregulation of this signaling pathway has been linked to inflammatory diseases and cancer. Secretion of glucocorticoids (GCs) is a classical endocrine response to stress. The glucocorticoid receptor (GR) is the primary effector of GCs and plays an important role in the regulation of cell metabolism and immune response by influencing gene expression in response to hormone-dependent activation...

In recent years, probiotics have attracted public attention and transformed the social perception of microorganisms, convening a beneficial role/state on human health. With aging, the immune system, body physiology, and intestinal microbiota tend to change unfavorably, resulting in many chronic conditions. The immune-mediated disorders can be linked to intestinal dysbiosis, consequently leading to immune dysfunctions and a cluster of conditions such as asthma, autoimmune diseases, eczema, and various allergies...

In the last decade, innate lymphoid cells (ILCs) have become established as important players in different areas such as tissue homeostasis, integrity of mucosal barriers and regulation of inflammation. While most of the early work on ILCs was based on murine studies, our knowledge on human ILCs is rapidly accumulating, opening novel perspectives towards the translation of ILC biology into the clinic. In this State-of-the-Art Review, we focus on the current knowledge of these most recently discovered members of the lymphocyte family and highlight their role in three major burdens of humanity: infectious diseases, cancer, and allergy and/or autoimmunity...

OBJECTIVE: Treatments with Food and Drug Administration-approved blocking antibodies targeting inhibitory cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) receptor, or programmed cell death ligand 1 (PD-L1), collectively named checkpoint inhibitors (CPIs), have been successful in producing long-lasting remissions, even in patients with advanced-stage cancers. However, these treatments are often accompanied by undesirable autoimmune and inflammatory side effects, sometimes bringing severe consequences for the patient...