Abstract
BACKGROUND: Chronic rhinosinusitis (CRS) affects up to 11% of the population in Europe and the USA, making it one of the most common chronic diseases. The classification of immunological endotypes, particularly the T2 endotype, is gaining increasing importance. This classification is based on the Coombs and Gell hypersensitivity model, which categorizes cell-mediated type IV reactions into T1, T2, and T3 endotypes. In chronic rhinosinusitis with nasal polyps (CRSwNP), genetic and epigenetic alterations in the mucosal immune system play a key role. Identifying specific endotypes helps to better understand the heterogeneity of the disease and develop tailored treatment approaches. This paper aims to systematize the underlying immunological mechanisms and highlight their relevance for diagnosis and therapy. METHODS: The European Academy of Allergy and Clinical Immunology (EAACI) recently published an updated nomenclature for immunological hypersensitivity reactions. The original Coombs and Gell classification of antibody-mediated reactions (type I-III) has been expanded. Cell-mediated reactions now include: type IVa (T1) → Th1-dominated reactions; type IVb (T2) → Th2-dominated reactions; type IVc (T3) → Th17-dominated reactions. These new insights into T1, T2, and T3 signaling pathways form the basis of this study. Additional mechanisms such as epithelial barrier defects (type V), chemical reactions (type VI), and metabolism-related immune dysregulations (type VII) are addressed separately. RESULTS: Endotyping reveals distinct regional differences: The T2 (Th2-high) endotype, predominant in Europe, North and South America, and Australia, is characterized by elevated Th2 cytokines (IL‑4, IL‑5, IL-13) and eosinophilic inflammation. The T1 (Th1-high) endotype shows dominant interferon-gamma activity and non-eosinophilic, mainly neutrophilic inflammation. The T3 (Th17-high) endotype is defined by increased IL-17 presence and can occur in both eosinophilic and non-eosinophilic CRSwNP. CONCLUSION: In CRSwNP patients, all three hyperreactivity endotypes (T1, T2, T3) can occur individually or in combination. The T2 endotype is the most common in Europe. Targeted endotyping enables differentiated treatment approaches and novel therapeutic options.