Medicine Nobel for scientists who demystified the immune system

Why in the News?

• The 2025 Nobel Prize in Physiology or Medicine has been awarded jointly to Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi.
• They were recognised for their fundamental discoveries relating to peripheral immune tolerance, which explains how the body’s immune system avoids attacking its own cells.
  

Background

• The human immune system comprises diverse cells — B cells, T cells, neutrophils, and macrophages — that defend the body against infections and disease-causing agents.
  
• However, sometimes this defence system malfunctions, resulting in autoimmune diseases such as Type-1 diabetes, multiple sclerosis, and lupus, where immune cells attack healthy tissues.
  
• Traditionally, it was believed that immune tolerance was maintained only by eliminating self-reactive immune cells during their development in the thymus, a process known as central tolerance.

Features

• Sakaguchi’s Discovery (1995):
  Identified a previously unknown subset of T cells that suppress immune responses, termed regulatory T cells (Tregs).
• This revealed that the immune system has an additional, peripheral mechanism to maintain self-tolerance beyond central tolerance.

Brunkow and Ramsdell’s Contribution (2001):

• Discovered that mutations in the Foxp3 gene lead to the breakdown of immune tolerance.
• Mice with the Foxp3 mutation suffered from severe autoimmune diseases.
• Similar mutations in humans were found to cause IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome.

Connecting the Dots (2003):

• Sakaguchi later established that Foxp3 regulates the development and function of regulatory T cells.
• Thus, the Foxp3-Treg axis became the cornerstone of peripheral immune tolerance research.

Medical Implications:

• Opened pathways for developing therapies targeting autoimmune diseases, cancer immunotherapy, and organ transplantation.
• Currently, Treg-based treatments are under clinical trials for diseases like Type-1 diabetes and multiple sclerosis.

Challenges

• Therapeutic Precision: Balancing suppression and activation of the immune system without triggering new complications remains difficult.
• Complex Interactions: The immune system’s network of genes and cells makes it challenging to design targeted interventions.
• Clinical Translation: Despite promising lab results, translating Treg-based therapies into safe and effective clinical treatments remains slow.
• Autoimmune Diversity: Different autoimmune diseases may involve distinct immune pathways, complicating one-size-fits-all therapies.

Way Forward

• Personalised Immunotherapy: Designing gene- and cell-based therapies tailored to individual immune profiles.
• Advanced Genetic Tools: Using CRISPR and single-cell sequencing to refine understanding of Treg cell development and function.
• Integrative Research: Bridging immunology, genomics, and bioinformatics for faster translation into clinical treatments.
• Global Collaboration: Encouraging international research partnerships and funding to accelerate immune regulation studies.

Conclusion

The discoveries by Sakaguchi, Brunkow, and Ramsdell have revolutionised our understanding of immune regulation. Their work on peripheral immune tolerance has not only deepened the biological understanding of autoimmunity but also opened transformative avenues for treating cancer, autoimmune disorders, and improving organ transplantation outcomes. This Nobel recognition celebrates how fundamental research can pave the way for life-saving medical innovation.