Studying the mechanism of drug-induced skin rashes

Although medications often help patients recover or improve their condition, millions of people around the world suffer from unpredictable toxic reactions to medications every year. In particular, drug rashes, which present with symptoms such as redness, blistering and itching of the skin, are quite common.

Severe drug rashes can become life-threatening and have long-lasting effects. Therefore, understanding how and why drug rashes occur is an important area of research in medical science.

To this end, previous studies have identified specific variants in certain genes as potential causative agents of drug eruptions. Scientists believe that genes encoding human leukocyte antigen (HLA), a protein expressed on the surface of white blood cells that plays an important role in the immune system, are involved in drug rashes. However, current theories cannot explain why HLA-associated drug eruptions typically appear on the skin rather than in multiple organs throughout the body.

To address this knowledge gap, a research team including faculty members Shigeki Aoki, Kousei Ito, and Akira Kazaoka from Chiba University's Graduate School of Medical and Pharmaceutical Sciences conducted an in-depth study of the relationship between HLA and drug eruptions. Their results were published in PNAS Nexus.

The researchers first conducted a series of experiments on mouse keratinocytes, which are the main type of cells found in the skin. These keratinocytes have been modified to express a specific variant of the HLA gene called HLA- B57:01, which specifically binds to the antiviral drug abacavir. They then confirmed these results in genetically engineered mice expressing HLA- B57:01 that were exposed to abacavir.

Researchers found that keratinocytes expressing HLA-B*57:01 and exposed to abacavir exhibited endoplasmic reticulum (ER) stress responses, such as immediate release of calcium into the cytosol and increased expression of heat shock protein 70 (HSP70). They also observed increased cytokine production and migration of immune cells. Exposure to abacavir caused HLA misfolding in the ER, leading to ER stress.

Furthermore, researchers have found that ER stress can be reduced by using 4-phenylbutyrate (4-PB). By eliminating this stress, they were able to suppress the onset of severe drug rash symptoms. This new knowledge could provide the basis for innovative treatment options for drug rashes.

But how does this new information contrast with what was already known about HLA?

"HLA molecules are an integral component of our immune system, typically presenting foreign antigens to white blood cells, which evaluate these antigens as self or non-self. In this established role, HLAs usually play a minor role," explains Dr. Aoki.

"However, our study highlights a new function of the HLA molecule in skin cells. We found that a specific HLA genotype in keratinocytes can recognize certain drugs as foreign, causing an endoplasmic reticulum stress response."

Taken together, the results of this study reveal a new role for HLA proteins in detecting and responding to potential threats in skin cells. Thus, their functions may extend far beyond the simple presentation of antigens to the immune system. Moreover, given that an individual's HLA variant can be determined through genetic testing, this research may help develop preventive measures and diagnostic methods against severe adverse drug reactions.

According to Dr. Aoki, this is in line with current directions and trends in medical science. "In 10 years, we expect to enter the era of the 'whole genome', when personalized medicine based on individual genomes will become standard practice," he comments.

"Based on the results of this study, we believe that a comprehensive understanding of the mechanism underlying HLA-dependent adverse drug reactions will enable safe health care while allowing patients to avoid unnecessary suffering due to side effects."

Overall, future research in this area may minimize the occurrence of drug rashes and save people from potentially fatal adverse drug reactions.