Pathogenesis of allergic diseases and implications for therapeutic interventions

Abstract

Allergic diseases such as allergic rhinitis (AR), allergic asthma (AAS), atopic dermatitis (AD), food allergy (FA), and eczema are systemic diseases caused by an impaired immune system. Accompanied by high recurrence rates, the steadily rising incidence rates of these diseases are attracting increasing attention. The pathogenesis of allergic diseases is complex and involves many factors, including maternal-fetal environment, living environment, genetics, epigenetics, and the body's immune status. The pathogenesis of allergic diseases exhibits a marked heterogeneity, with phenotype and endotype defining visible features and associated molecular mechanisms, respectively. With the rapid development of immunology, molecular biology, and biotechnology, many new biological drugs have been designed for the treatment of allergic diseases, including anti-immunoglobulin E (IgE), anti-interleukin (IL)-5, and anti-thymic stromal lymphopoietin (TSLP)/IL-4, to control symptoms. For doctors and scientists, it is becoming more and more important to understand the influencing factors, pathogenesis, and treatment progress of allergic diseases. This review aimed to assess the epidemiology, pathogenesis, and therapeutic interventions of allergic diseases, including AR, AAS, AD, and FA. We hope to help doctors and scientists understand allergic diseases systematically.

Fig. 1

Timeline of major findings related to allergic diseases. Allergic reactions in Western countries were first recorded in 2641 BCE, when the Egyptian Pharaoh Menes died after being bitten by a bumblebee. In 1911, Leonard Noon published an article in The Lancet, reporting a clinical paper treating pollinosis by subcutaneous injection of grass pollen extract, which marked the beginning of modern immunotherapy. In 1966, the Japanese scientist Ishizaka and his wife discovered IgE, which led to a leap in the understanding of immediate allergy. Following their discovery, IgE became a new indicator for the diagnosis of allergy

Fig. 2

Allergic diseases are caused by a variety of factors. External factors include changes in gut microbiota and metabolites, drugs, and air pollution. Internal influencing factors include genetic and epigenetic changes

Fig. 3

Immune imbalance caused by dysbiosis under the combined effect of gene environment in IgE-related FA. During childhood, the human microbiota is influenced by a combination of the maternal microbiome, mode of delivery, genetics, epigenetics, environment, etc. Dysbiosis resulting from aberrant damage to the gut microbiota early in life impairs Treg differentiation. This results in imbalance of Treg and Th2 cells. Food allergens and the microbiota promote T follicular helper (Tfh) responses to induce B cells, which produce large amounts of IgE through IL-4, IL-13 cytokines, causing allergic reactions

Fig. 4

Graphical summary of NF-κB pathway’s role in allergic diseases. The NF-κB pathway is highly involved in the occurrence and development of allergic diseases by acting on different cells and releasing inflammatory factors

Fig. 5

The roles of the hippo and Notch pathways in AAS. Under stimulation by allergens, epithelial cells synthesize large amounts of proinflammatory cytokines (IL-25, IL-33, TSLP, etc.), thereby acting on innate lymphocytes (ILC2 cells) and DCs. Jag1 on DCs interacts with Notch receptors on T cells for Notch pathway induction. Notch transforms induced Tregs into Th2 and Th17 cells. Naive CD4 + cells affect Tfh cell class switch recombination by secreting IL-5, thus acting on B cells to induce plasma cells, which produce IgE. At the same time, Th2 cells secrete IL-4 and others to activate B cells to synthesize IgE, which interacts with IgE receptors on mast cells. In case the allergen invades the body again, it directly cross-links with IgE on the cell surface and releases a variety of active mediators, which trigger the clinical symptoms of asthma. Th17 cells are activated through the Hippo pathway; Th2 cells are activated through the Wnt pathway, and GDF-15 molecules are stimulated to act on ILC2 cells to enhance the expression of IL-13, although this remains controversial. Notch converts induced Tregs into Th2 and Th17 cells via hippo pathway-dependent mechanisms. IL interleukin, TSLP thymic stromal lymphopoietin, ILC2 group 2 innate lymphoid cell, DC dendritic cell, Jag1 jagged1

Fig. 6

Application of biologics in allergic diseases. Multiple cell interactions trigger allergic reactions. Therefore, treatment with biologics aims to target the cytokines produced by various cells, with a potential impact on the interaction between cells. Some biologics exert their effects by targeting IgE, IL-5, IL-4, IL-13, IL-31, IL-9, IL-33, and TSLP, among others