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Investigation of the mechanism of drug rashes on the skin

 
, medical expert
Last reviewed: 02.07.2025
 
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15 May 2024, 18:28

Although medications often help patients to cure or relieve their condition, millions of people worldwide suffer from unpredictable toxic reactions to medications each year. In particular, drug rashes, which include symptoms such as redness, blisters, and itching of the skin, are quite common.

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

To this end, previous studies have identified specific variants of certain genes as potential causative agents of drug rashes. 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 the development of drug rashes. However, current theories cannot explain why HLA-related drug rashes typically occur 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 the Chiba University Graduate School of Medical and Pharmaceutical Sciences conducted an in-depth study of the relationship between HLA and drug rashes. Their findings were published in PNAS Nexus.

The researchers first conducted a series of experiments on mouse keratinocytes, which are the main type of cell found in the skin. These keratinocytes were 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 modified mice expressing HLA-B 57:01 that were exposed to abacavir.

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

Furthermore, the researchers found that ER stress can be reduced using 4-phenylbutyrate (4-PB). By eliminating this stress, they were able to suppress the occurrence of severe drug rash symptoms. This new knowledge may 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 those antigens as self or non-self. In this established role, HLA usually plays a secondary 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, triggering 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. Their functions may thus extend far beyond simply presenting antigens to the immune system. Moreover, given that an individual’s HLA variant can be determined through genetic testing, this study may help develop preventive measures and diagnostic methods against severe adverse drug reactions.

According to Dr. Aoki, this is in line with current trends and directions in medical science. "In 10 years, we expect to enter the era of the 'comprehensive genome', where 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 medical care, 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.

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