WFDC2, also known as HE4 (Human epididymis protein-4), is a protein-coding gene. The encoded protein contains two WAP four-disulfide core domains and is involved in multiple biological processes. It may play a role in innate immune defenses in the oral and respiratory cavities, and is associated with pathways related to tumorigenesis, immunity, and epithelial cell function.

Recessively inherited deficiency of secreted WFDC2 causes nasal polyposis and bronchiectasis. Biallelic pathogenic variants in WFDC2 were identified in individuals from different regions. WFDC2 is predominantly expressed in secretory cells of the control airway epithelium and submucosal glands, and its deficiency leads to undetectable levels in serum and other secretions. A disease-causing founder variant structurally hampers glycosylation and secretion of mature WFDC2. In colonic epithelial cells, WFDC2, an antiprotease molecule expressed by goblet cells, inhibits bacterial growth. In vivo, it preserves the integrity of tight junctions between epithelial cells, preventing bacterial invasion and mucosal inflammation, and is downregulated in IBD.

In summary, WFDC2 is crucial for maintaining the normal function of the respiratory and digestive tracts, especially in innate immunity and epithelial barrier integrity. The discovery of its role in causing nasal polyposis, bronchiectasis, and its changes in IBD through genetic studies enriches our understanding of these disease mechanisms, providing potential diagnostic and therapeutic targets.

References:

1. Dougherty, Gerard W, Ostrowski, Lawrence E, Nöthe-Menchen, Tabea, Zariwala, Maimoona A, Omran, Heymut. . Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis. In American journal of respiratory and critical care medicine, 210, 63-76. doi:10.1164/rccm.202308-1370OC. https://pubmed.ncbi.nlm.nih.gov/38626355/

2. Parikh, Kaushal, Antanaviciute, Agne, Fawkner-Corbett, David, Koohy, Hashem, Simmons, Alison. 2019. Colonic epithelial cell diversity in health and inflammatory bowel disease. In Nature, 567, 49-55. doi:10.1038/s41586-019-0992-y. https://pubmed.ncbi.nlm.nih.gov/30814735/

3. Bingle, Lynne, Cross, Simon S, High, Alec S, Campos, Michael A, Bingle, Colin D. 2006. WFDC2 (HE4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. In Respiratory research, 7, 61. doi:. https://pubmed.ncbi.nlm.nih.gov/16600032/