# Sex-Based Differences in Bronchial Asthma: What Are the Mechanisms behind Them?
## 3 Endotypes and Phenotypes of Bronchial Asthma  
In accordance with the dominant type of granulocyte inflammation and the contributions of specific subtypes of T-lymphocytes, three main endotypes of asthma may be distinguished: eosinophil, non-eosinophilic, and mixed granulocyte asthma [1]. However, the different asthma endotypes and phenotypes are not fully understood, and additional research is needed to adequately define the different asthma endotypes and phenotypes and describe their characteristics. The eosinophil (or T2-high) endotype of asthma, which is present in about 50% of adult asthma patients, is divided into allergic and non-allergic subendotypes. The allergic subendotype is characterized by sensitization to allergens (pollen, house-dust mites, etc.). Contact between allergens and alarmins--epithelial barrier-derived mediators such as thymic stromal lymphopoietit (TSLP), interleukin (IL)-25, and IL-33--activate dendritic cells and group 2 innate lymphoid cells (ILC2s) and induce the type 2 signaling pathway through the mediation of T-helper (Th)2 lymphocytes. Activated dendritic cells and ILC2s are potent producers of IL-4, IL-5, and IL-13, which recruit eosinophils into the lungs, promote goblet cell overexpression, stimulate the secretion of mucus, increase airway hyperresponsiveness, and increase expression of extracellular matrix proteins (e.g., periostin), contributing to airway fibrotic remodeling [3]. IL-4 drives the switching of the B-cell isotype and synthesis of immunoglobulin (Ig)E, which binds to mast cell high-affinity IgE receptors. Subsequent activation of mast cells leads to allergen-mediated IgE cross-linking [1]. In the non-allergic subendotype of eosinophil asthma, ILC2s produce IL-5 and IL-13 in response to prostaglandin (PG)D2 and the alarmins IL-33, IL-25, and TSLP released from the epithelium due to deterioration resulting from pollutants and microbes [1; 2; 3]. T2-high asthma clinically presents in three phenotypes that have been identified up to now. Atopic asthma, one subtype of early-onset asthma, is corticosteroid-sensitive and typically appears during childhood because of allergic sensitization. Late-onset asthma is a steroid-resistant phenotype of eosinophil asthma that develops in older patients as more severe asthma with fixed airflow obstruction. Aspirin-exacerbated respiratory disease (AERD) is a subset of late-onset asthma that originates due to dysregulated arachidonic acid metabolism [3]. The non-eosinophilic (or non-T2 or T2-low) endotype of asthma is characterized by the absence of eosinophil and the presence of neutroph inflammation with neutrophil sputum levels greater than 40% (i.e., neutrophilic asthma) or may manifest as the paucigranulocytic type of asthma with normal sputum levels of eosinophils and neutrophils [3]. Although the mechanisms of neutroph asthma are not yet fully understood, chronic infection with atypical bacteria, obesity, and smoking likely contribute to the activation of Th1 and/or Th17 lymphocytes or type 3 ILCs [1; 2; 3]. Paucigranulocytic asthma is a special endotype of asthma in which both eosinophils and neutrophils are below the thresholds for the diagnosis of the previously mentioned types of asthma. Paucigranulocytic asthma is poorly understood and, instead of inflammation, airway smooth muscle dysfunction and bronchial hyperresponsiveness appear as the main pathophysiological features [2; 8]. Several T2-low phenotypes have also been identified. Obesity-associated asthma is a non-atopic and corticosteroid-refractory form of asthma occurring in middle-aged women with obesity. Smoking-associated asthma originates due to smoking exposure-induced oxidative stress. Very late-onset asthma develops in older patients because of decreased lung function due to reduced elastic recoil and immunosenescence [3]. However, non-eosinophilic asthma may also present in children and adolescents as one form of early-onset asthma [9].