The image shows the FOXP3 protein (in yellow) in the nucleus of an activated human T lymphocyte  cell from peripheral blood. Technique used: Confocal microscopy-flow cytometer

Not the sun, but a microscopic look at a specific gene in a specific cell that has led to a major advance in our understanding and treatment of auto-immune diseases.
Photo Credit: Ciriaco Piccirillo, Research Institute of the McGill University Health Centre

A few drops of blood lead to a breakthrough in immunology

It was one of those tragic cases in medicine.

A newly born child, just weeks old, had a severe auto-immune condition that could not be treated and which led irrevocably to his death.

With just a few drops of the child’s blood, researchers led by a team in McGill University and the Research Institute-McGill University Health Centre (RI-MUHC) in Montreal, have painstakingly discovered the cause in a subset of so-called T-cells, and have created a solution that has major disease treatment implications.

Dr. Ciriaco Piccirillo led an international research team with input from the USA and Japan. He is an immunologist and senior scientist with the “Infectious Diseases and Immunity in Global Health Program” at the Research Institute-McGill University Health Centre (RI-MUHC), and a Professor of Immunology and Medicine at McGill University. He is also the Director of the newly created Centre of Excellence in Translational Immunology (CETI) at the RI-MUHC.

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Dr.Ciriaco Piccirillo (PhD), McGill University immunology professor and senior scientist at the RI-MUHC
Dr.Ciriaco Piccirillo (PhD), McGill University immunology professor and senior scientist at the RI-MUHC © supplied

The baby boy died in 2009 of a rare and often fatal inherited genetic immune disorder called IPEX. The case involved the child’s T-cells, and specifically the Treg cell, the immunosuppressive cells of the immune system.

These latter are a special kind of white blood cells or lymphocytes that regulate the body’s auto-immune response. They prevent other immune cells from attacking the body’s own tissues, as well as controlling immune responses against microbes and other non-pathogenic agents, such as pollen, dust or benign food groups. This is an important “self-check” built into the immune system to prevent excessive reaction.

When the immune response is not controlled it can cause damage to the body in diseases such as rheumatoid arthritis, Lupus, and Crohn’s disease as well as broader conditions such as asthma, allergies and cancer.

The image shows a lymph node in which we see normal T cells (in red) and Treg cells regulated by the FOXP3 gene (in green). Lymph nodes are small glands that are part of the lymph system which is important for body’s defense system against diseases. Technique used: Confocal microscopy
The image shows a lymph node in which we see normal T cells (in red) and Treg cells regulated by the FOXP3 gene (in green). Lymph nodes are small glands that are part of the lymph system which is important for body’s defense system against diseases. Technique used: Confocal microscopy © Ciriaco Piccirillo, Research Institute of the McGill University Health Centre

Through meticulous molecular research and availability of new highly sophisticated technology at the RI-MUHC, the team was able to determine a defect in a particular gene in the Treg cell which prevented it from properly acting in its regulatory role in dampening the immune system response.

Certain genes, but especially the FOXP3 gene are responsible for “programming” so-to-speak a T-cell to become a Treg cell.

The image shows the FOXP3 protein (in yellow) in the nucleus of an activated human T lymphocyte cell from peripheral blood. Technique used: Confocal microscopy-flow cytometer
The image shows the FOXP3 protein (in yellow) in the nucleus of an activated human T lymphocyte cell from peripheral blood. Technique used: Confocal microscopy-flow cytometer ©  Ciriaco Piccirillo, Research Institute of the McGill University Health Centre

What the team found from the baby’s blood was a rare mutation of the FOXP3 gene which negatively impacted its capacity to promote Treg cell development and function in humans.

After the intense research to detect the genetic defect in the specific FOXP3 gene, they developed a drug which appears able to correct the genetic defect resulting in an almost completely normally functioning Treg cell.

The team’s research was published in the online journal “Science-Immunology” under the title “Suppression by human FOXP3+ regulatory T cells requires FOXP3-TIP60 interactions”  (abstract HERE)

The McGill University Health Centre, with its Research Institute and several research bodies, has become world renonwed in medical research
The McGill University Health Centre, with its Research Institute and several research bodies, has become world renonwed in medical research © MUHC

Further, while this should work in those rare patients with IPEX, professor Piccirillo says the team in now working on improving the drug to bolster its effects on the FOXP3 gene and developing Treg cells in other inflammatory and autoimmune diseases.

He says this likely will have far greater treatment possibilities in relation to a number of auto-immune diseases which are typically very difficult to treat.

The study was funded by the Canadian Institutes of Health Research, Canada Research Chair Program, National Institutes of Health and the Abramson Family Cancer Research Institute.

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