Even though drug reactions are frequently associated with the human leukocyte antigen (HLA), the exact way it contributes to causing skin symptoms remains unclear. In a recent study, scientists utilized genetically modified mice to illustrate how HLA plays a role in triggering internal reactions in keratinocytes, which can lead to drug eruptions in the skin. Their discoveries may lead to improved methods for preventing and treating drug eruptions.
Drug eruptions are a common occurrence, often causing symptoms such as redness, blisters, and itching on the skin. In severe cases, these eruptions can be life-threatening and have lasting effects. This has led to a focus on researching how and why these eruptions happen in the field of medical science.
Previous research has pinpointed certain gene variants as potential causes of drug eruptions. Specifically, scientists have identified variants of genes encoding the human leukocyte antigen (HLA), a protein found on the surface of leucocytes that plays a crucial role in the body’s immune response. This discovery has shed light on the mechanisms behind drug eruptions.The immune system plays a role in the development of drug eruptions, but it is not fully understood why HLA-related drug eruptions tend to affect the skin rather than multiple organs in the body. To address this gap in knowledge, a team of researchers from Chiba University conducted a detailed study on the connection between HLA and drug eruptions. Their findings were published in PNAS Nexus on April 2, 2024. The researchers conducted experiments on keratinocytes from mice to investigate this link.The study focused on keratinocytes, the main type of cells found in the skin. These cells were genetically modified to express a specific variant of the HLA gene called HLA-B57:01, which is known to bind to the antiviral drug abacavir. The researchers then tested these modified cells in mice that also expressed HLA-B57:01 and were exposed to abacavir.
The results showed that the HLA-B57:01 expressing keratinocytes exposed to abacavir exhibited stress responses in the endoplasmic reticulum (ER), including immediate release of calcium into the cytosol and increased expression of heat shock protein 70 (HSP70). Additionally, there was a higher production ofCytokines and the migration of immune cells were impacted by the exposure to Abacavir, which caused HLA misfolding in the endoplasmic reticulum (ER) and resulted in ER stress. The researchers discovered that the use of 4-phenylbutyrate (4-PB) could decrease this stress and effectively reduce the symptoms of severe drug eruptions. This new understanding has the potential to lead to innovative treatment options for managing drug eruption symptoms. The researchers also found that HLA molecules play a crucial role in presenting foreign antigens to white blood cells in the immune system. This new information contrasts with what was previously known about the function of HLA.Identify whether these antigens are self or non-self. HLAs generally play a secondary role,” says Dr. Aoki. “However, our research shows a new function of the HLA molecule in skin cells. We found that a specific HLA genotype in keratinocytes can identify certain drugs as foreign, which triggers a stress response in the endoplasmic reticulum.”
Overall, this study reveals a new role of HLA proteins in detecting and responding to potential threats in skin cells. This suggests that their functions may go beyond just presenting antigens for the immune system. Furthermore, since the variant of HLAAn individual’s genetic makeup can be identified through genetic testing, and this research could aid in creating preventive measures and tools for severe adverse drug reactions. Dr. Aoki states that this aligns with current research in medical science and predicts that personalized medicine based on individual genomes will become the norm within the next decade. He believes that understanding the mechanism behind HLA-dependent adverse drug reactions will lead to safe medical treatments.
Dr. Shigeki Aoki, a lecturer at the Graduate School of Pharmaceutical Sciences at Chiba University in Japan, specializes in cancer metabolism and drug toxicity research. He has published numerous papers in reputable journals and is a member of various professional organizations in Japan. Dr. Aoki has been recognized with several awards for his research contributions.
In a recent study, Dr. Aoki and his team found that a specific enzyme plays a crucial role in drug eruptions, which are adverse reactions to medications. By identifying this enzyme, they hope to develop new strategies to minimize drug eruptions and prevent potentially fatal adverse drug reactions, ultimately improving patient care and quality of life. Their findings may help patients avoid unnecessary suffering from medication side effects. This research has the potential to make a significant impact on the field of drug toxicity and patient safety.
The Pharmaceutical Society of Japan has honored Akira Kazaoka, Sota Fujimori, Yushiro Yamada, Tomohiro Shirayanagi, Yuying Gao, Saki Kuwahara, Naoki Sakamoto, Takeshi Susukida, Shigeki Aoki, and Kousei Ito with the Award for Young Scientists.
