Deepening Understanding of Immune Disorders

Deepening Understanding of Immune Disorders
An interdisciplinary team seeks to advance knowledge of rare, genetic immune diseases.

Historically, it has been a challenge to identify genes that cause immune disorders. However, the field of inborn errors of immunity has progressed over the last decade thanks to advancements in genome sequencing. To further propel an understanding of genetic drivers of these rare immune disorders, a team of researchers and clinicians from Vanderbilt University Medical Center have joined efforts through the Human Immunology Discovery Initiative (HIDI) to phenotype and study immune diseases in pediatric and adult patients.

Jeffrey Rathmell, Ph.D., Cornelius Vanderbilt Professor of Immunobiology and principal investigator for the HIDI project, said the initiative was established in 2019 after ongoing discussions with Jim Connelly, M.D., who leads the Comprehensive Hematology, Immunology and Infectious Disease Program (CHIIP) at Monroe Carell Jr. Children’s Hospital at Vanderbilt. The CHIIP clinic evaluates and cares for a range of poorly understood immune disorders in pediatric patients, and collaboration with Vanderbilt scientists provided an opportunity to investigate and discover new genes involved in human immunology.

“These children arrive with a wide variety of genetic disorders. We want to organize expertise across the medical center and Vanderbilt broadly to help these patients clinically and to take advantage of the really amazing opportunity to understand how the human immune system works,” Rathmell said.

Benefiting from Collaboration 

Led by the Vanderbilt Center for Immunobiology and supported by a five-year Trans-Institutional Program grant, HIDI is a collaborative, multidisciplinary project that integrates investigators with clinical and basic science expertise from across Vanderbilt to perform cellular, genetic and biochemical analyses of immune disorders.

The HIDI team spent 2019 establishing its research platforms and last year began working with pediatric patients in the CHIIP clinic who have known and unknown immune disorders. Patients receive a coordinated evaluation by specialists in hematology/oncology, immunology, infectious diseases and where applicable, genetics.

“We want to organize expertise across the medical center and Vanderbilt broadly to take advantage of the really amazing opportunity to understand how the human immune system works.”

Collaborating with researchers in Vanderbilt’s Department of Pathology, Microbiology and Immunology, the HIDI team has been able to sequence DNA from patients with unknown disorders and identify new genes that regulate the human immune system. HIDI also uses advanced techniques to further its research, including mass cytometry, biomarker discovery and phenotype-based single-cell drug screens to complement molecular discoveries made by deep genetic sequencing. The team can then compare these patterns to those of known disorders and potentially identify important mutations — essentially using what it learns about these rare disorders to deliver a diagnosis and gain insight into broader immune function.

Rathmell said HIDI’s work is critical because most of the medical community’s understanding of genetic immune disorders comes from mouse studies.

“We don’t actually have near the level of understanding as we should about how immune disorders work in humans, so this is an opportunity – through these genetic diseases – to better understand human immunology in general,” he said.

Linking Genetics and Immune Diseases

HIDI currently has recruited 82 patients and conducted immunophenotyping of 35 patients with known disorders and 10 patients with unknown disorders. Rathmell says the team is studying a range of immune disorders, including patients with deficiencies leading to severe infections and immune dysfunction resulting in autoimmune and autoinflammatory disorders. However, as each inborn error of immunity disorder is rare, the researchers often see a specific mutation or genetic polymorphism that is only carried by a single patient, emphasizing the importance of building a clinical and research program to evaluate these unique patients.

“It’s very timely for us to have this interdisciplinary model and take advantage of new technologies that enable us to do so much more now than we could even five years ago.”

HIDI’s goal is to collect clinical data and biosamples from 40 patients a year. The program has also created an immunology biobank and an anonymized patient registry for clinical annotation of biobank samples. Along with its core research focus, the team is currently conducting research on the body’s immune response to the COVID-19 vaccine.

Although much of the work has been conducted on patients with immune deficiencies to date, the long-term goals of HIDI are to interrogate their platform to study the role of immunology in many human diseases, including hematopoietic defects and cancer.

Paving the Way for Medical Advancements

While the HIDI team’s work will go a long way toward accelerating human immunology education and research, it also may have positive implications for clinical care and future drug development. Rathmell hopes the team’s research will help discover new biomarkers, drug treatments for immune disorders and personalized immune therapies.

“It’s very timely for us to have this interdisciplinary model and to dive deep and take advantage of new technologies that enable us to do so much more now than we could even five years ago,” Rathmell said.