Elucidating Immunogenetic Mysteries: Q&A With Dimitrios Monos, PhD

By Jillian Rose Lim

Dimitrios Monos, PhD, is the director of the Immunogenetics Laboratory at Children’s Hospital of Philadelphia Research Institute. For many years, he has been studying the major histocompatibility complex (MHC), which is one of the most fascinating regions of the human genome. This region spans a swath of about 4 million bases in our genome and plays a key role in immune system responses. Dr. Monos has elucidated many of its mysteries, including characterizing the structure and function of molecules known as human leukocyte antigens (HLA) encoded by genes within the human MHC, pioneering DNA-based methodologies for the accurate and thorough characterization of the HLA genes, and identifying the association of specific structural features of HLAs with many diseases. He has also explored the biological role of micro-RNAs encoded by the MHC and most recently investigated through 3D genomics the interactive relationships of genomic elements, such as enhancers and promoters for the regulation of expression of genes within the MHC.

The American Society for Histocompatibility and Immunogenetics (ASHI) awarded Dr. Monos the 2022 Rose Payne Award for his work with applications in transplantation, autoimmunity, and assessing broadly antigen-specific immune responses. The award, established in 1985, is named in honor of Rose Payne, an immunogenetics scientist, to recognize outstanding contributions in the field. We had the opportunity to sit down with Dr. Monos and learn more about his lifelong dedication to studying the MHC, his thoughts on receiving the award, and his vision for the future of immunogenetics research.

What does the Rose Payne Award mean to you?

It is a high honor to be the recipient of this prestigious award, which is bestowed upon one individual annually at an international level. Recipients in the past 37 years have been renowned for their contributions in the field of Immunogenetics. This recognition of our work is a source of immense gratification for me and my team. It encourages us to continue our research with a renewed enthusiasm and focus.

Would you describe your research?

My lab focuses on the characterization of the human genome region, known as the MHC, at different levels. This genomic fragment of about 4 million base pairs of DNA is associated with more than 120 diseases. This is about 7 times higher than any other number of diseases associated with another genomic region of equivalent size. Accurate and thorough genomic characterization of the MHC is fundamental for the understanding of how different variations contribute to different diseases. Any functional or structural aspect of this region is within our interests. More specifically, a subset of 11 genes of about 80 thousand base pairs cumulatively, within the 4 million base pairs region are what we call human leukocyte antigen (HLA) genes and are relevant and pertinent to any antigen-specific immune responses. As such, our responses to viruses, bacteria, vaccines, or any kind of external agent depends on HLA genes. While some people with different HLA types can respond and survive, others may eventually succumb to a particular infection because they don’t have the appropriate HLA. From that point of view, this region is important to our practice of transplantation--by characterizing these genes properly, we have improved our means of assessing compatibility in transplantation. These HLA genes are also relevant to autoimmunity and cancer.

What led you to specialize in this field?

My interest in the immune system was sparked as a graduate student, specifically in the biochemical mechanisms of the immune response. During my first postdoc at the National Institutes of Health, I was introduced to the HLA genes and later developed an interest in the clinical applications of HLA molecules.

At the time, researchers were utilizing a technique called two-dimensional electrophoresis to biochemically characterize HLA proteins based on size and charge differences. During this time, we discovered that although people were identical in their HLA genes by serological means, they were, in fact, different when characterized biochemically using electrophoresis. These differences were much more significant than initially thought, and we began to investigate the HLA genes and the MHC to understand the importance of these polymorphisms in the immune response

My fascination with the complexity of HLA genes has continued throughout my career. With more than 36 thousand alleles, I am intrigued by the natural adaptations and mechanisms that arise to handle different issues such as the continuous evolution of microbes and the constant need to deal with our environment. I am particularly interested in how this mechanism, which humans developed as a protective measure, can sometimes lead to autoimmunity. The role of HLA genes in transplantation is an exciting and critical health application that affects our patients and their families. My curiosity and interest in this field continue to drive my work.

What excites you right now in the field of immunogenetics?

Technology has been a major driving force for research and discovery in this field. Utilizing new and emerging technologies to answer both old and new questions propels our understanding of this region and fuels our enthusiasm. The MHC has been poorly characterized in human genome sequencing projects, which has limited our ability to fully understand how this region interacts and influences many physiological processes. One recent breakthrough in our laboratory has been the thorough characterization of the whole MHC using technologies that can sequence long fragments of DNA. To build on this exciting discovery, we have combined the comprehensive characterization of the MHC with Hi-C, a technology that allows us to study how different enhancers and promoters interact to modulate the transcription of different genes. This knowledge has provided insights into how different elements interact, under what circumstances and, when we observe the manifestation of different diseases, what can go wrong. The complexity of this region, particularly with regard to the regulation of gene expression within the MHC, is a fascinating and complex phenomenon. While it may not be possible to fully explore all aspects of this topic within one's lifetime, our work serves as a foundation for others to continue and improve our understanding.

Is there anything else you would like to share about this award or your work?

I want to highlight the tremendous support that our lab has received from the Department of Pathology and Laboratory Medicine and CHOP as an institution. Thanks to an endowed chair and an institutional development fund, we have been able to make significant progress in our research. However, none of this would be possible without the incredible team that I work with. Their hard work and expertise are the foundation of all our accomplishments. I'm grateful for the opportunities we've had and am proud of what we've achieved together.