Elucidating the relationship between HLA genes and drug eruptions

Although drugs often help patients cure or put their illnesses to rest, millions of people around the world suffer from unpredictable drug toxicity each year. Drug eruptions, in which symptoms such as redness, blisters, and itching appear on the skin, are particularly common. Severe drug eruptions can be life-threatening and can have long-term effects. Therefore, understanding how and why drug eruptions occur is an important area of ​​research in medicine.

To this end, previous studies have identified specific variants of specific genes as potential causative agents of drug eruptions. Scientists believe that the gene encoding human leukocyte antigen (HLA), a protein expressed on the surface of white blood cells known to play an important role in the immune system, may be involved in the development of drug eruptions. I am. However, current theories do not explain why HLA-related drug eruptions typically appear on the skin rather than in multiple organs throughout the body.

To address this knowledge gap, a research team led by Lecturer Shigeki Aoki, Lecturer Kousei Ito, and Lecturer Akira Kazaoka from Chiba University Graduate School of Pharmaceutical and Pharmaceutical Sciences conducted a detailed study on the relationship between HLA and drug eruptions. did. Their discovery is PNAS Nexus April 2, 2024.

The researchers first performed a series of experiments on mouse keratinocytes, the main type of cell found in the skin. These keratinocytes were engineered to express a specific variant of the HLA gene called HLA-B*57:01, which specifically binds to the antiviral drug abacavir. They then validated these findings in genetically modified mice expressing HLA-B*57:01 that were exposed to abacavir.

The researchers found that keratinocytes expressing HLA-B*57:01 exposed to abacavir exhibited endoplasmic reticulum (ER) stress, including immediate release of calcium into the cytosol and increased expression of heat shock protein 70 (HSP70). It was discovered that there was a reaction. They also observed increased cytokine production and immune cell migration. Exposure to abacavir caused HLA misfolding in the ER, leading to ER stress. Additionally, researchers observed that using 4-phenylbutyric acid (4-PB) could reduce ER stress. By reducing this stress, we succeeded in suppressing the onset of severe drug eruption symptoms. This newly discovered knowledge may form the basis of innovative treatment options for the management of drug eruptions.

But how does this new information contrast with what we already know about HLA? “HLA molecules are an essential part of our immune system and normally allow foreign substances to be present. antigen White blood cells determine whether these antigens are self or non-self. In this well-established role, HLA usually plays a secondary role. ” explains Dr. Aoki. “However, our study revealed a new function of HLA molecules within skin cells: specific HLA genotypes of keratinocytes may recognize certain drugs as foreign and trigger an endoplasmic reticulum stress response. I made it clear.”

Taken together, the results of this study reveal a novel role for HLA proteins in sensing and responding to potential threats in skin cells. Their function may therefore extend far beyond mere antigen presentation to the immune system. Additionally, given that an individual's HLA mutations can be determined through genetic testing, this study could help develop preventive measures and diagnostics for serious side effects. According to Dr. Aoki, this is consistent with current research directions and medical trends. “In 10 years, it is predicted that we will enter the 'whole-genome era,' where personalized medicine based on each individual's genome will become standard practice.” he is commenting. He further added: “Based on the results of this study, a comprehensive understanding of the mechanisms underlying HLA-dependent side effects will enable safe healthcare delivery and help patients avoid unnecessary suffering due to side effects. I believe it will be.”

Overall, future work in this area of ​​research may minimize the occurrence of drug eruptions and save people from potentially fatal side effects.