FIGURE 2 Illustration of inflammation-related mechanisms in severe patients with Class II mutation. TNFSF10-TNFRSF11A/1A cytokine-cytokine receptor interaction causes activation of NF kappa B signaling pathways and release of proinflammatory genes such as CXCL1/2/8 and IL1B. On the other hand, G85E and F508del-CFTR undergo endoplasmic reticulum-associated degradation (ERAD) which is a protein quality control system. The accumulation of misfolded proteins in the ER, causes ER stress. Downregulation of CFTR activates CFTR interaction protein STX1A and STX1A binding partner SNAP23. Also, CFTR negative regulator subunits SLC9A3R2 and SCNN1G are upregulated. All the mentioned pathways above causes airway inflammation in Class II group severe patients (Significant differentially expressed genes are shown in bold and asterisk).