Autoimmune Liver Diseases Causing Chronic Fatigue: Genetic Causes Identified

Correlation Between Caspase-10 Gene Mutation and Primary Biliary Cholangitis Onset

Professor Kim Rak-gyun, Department of Biomedical Sciences, Yonsei University College of Medicine (left), Professor Lee Kyung-ah, Department of Laboratory Medicine, Gangnam Severance Hospital.

[Asia Economy Reporter Lee Gwan-ju] A research result identifying the genetic factors of primary biliary cholangitis, an autoimmune liver disease, has been announced.

Professor Lee Kyung-ah of the Department of Laboratory Medicine at Gangnam Severance Hospital, Professors Kim Rak-gyun and Do So-hee of the Department of Biomedical Sciences at Yonsei University College of Medicine, Professor Shin Sae-am of the Department of Laboratory Medicine at Yonsei University College of Medicine, and Professor Park Sang-hoon of Gangnam Severance Hospital, Hallym University, revealed on the 16th the results of a study clarifying the relationship between primary biliary cholangitis and 'caspase-10.'

Autoimmune liver disease is a condition in which the immune system malfunctions and mistakenly identifies the body's own liver cells as pathogens, causing inflammation by itself. It accounts for about 5% of all liver diseases. Primary biliary cholangitis (PBC) is a disease in which inflammation within the portal vein and damage to the intrahepatic bile ducts progress chronically, leading to bile stasis, destruction of liver cells, fibrosis, and eventually cirrhosis. Although the exact pathogenesis of PBC has not been fully elucidated, environmental factors such as infections and chemicals, as well as genetic factors, are known to influence its development.

The research team analyzed the genome of a case in which all four sisters within the same family were diagnosed with PBC to identify genetic factors associated with PBC onset. As a result, they confirmed mutations in the 'caspase-10' gene in the sisters. Additionally, sequencing analysis of 62 other PBC patients showed that mutations in caspase-10 were observed at a frequency ten times higher (P=0.002) in PBC patients compared to the general population.

An inverse correlation was observed between serum caspase-10 activity and inflammatory cytokines. This suggests that the decreased caspase-10 activity in PBC patients may be attributed to the upregulation of inflammatory cytokines.

Caspases are proteases involved in cell death, inflammation, and autoimmunity, playing important roles in tumor development and autoimmune diseases. However, the function of caspase-10 in the human body is largely unknown. To clarify the role of caspase-10 in PBC development, the research team used the gene-editing technology CRISPR/Cas9 to create cell lines with caspase-8, which is structurally similar and functionally well-known, knocked out, and cell lines with caspase-10 gene knocked out, then compared the differences between them.

The study found that unlike caspase-8, caspase-10 does not play a significant role during the differentiation process into macrophages but strongly regulates inflammatory cell death processes after differentiation. Furthermore, macrophages lacking the caspase-10 gene showed potential for promoting liver fibrosis, and administration of ursodeoxycholic acid and obeticholic acid, which are currently approved drugs for PBC treatment, was confirmed to inhibit this progression. Professor Kim Rak-gyun stated, "This study is the first to identify that defects in caspase-10 function in macrophages influence the development of PBC," adding, "We expect this research to provide new directions for PBC patients who do not respond to existing treatments."

This study was published in the international journal 'Journal of Autoimmunity.'

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