The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their work on how immune systems work in determining what should be attacked or protected. 

About the Immune System

• The immune system is a complex network of cells, tissues, and organs that defends the body against disease-causing organisms such as bacteria, viruses, fungi, and parasites.
• Functions: The immune system protects the body from infections and tumors.
  • It must distinguish self-cells (the body’s own tissues) from non-self (pathogens).
  • Mistakes can lead to autoimmune diseases, where the body attacks itself.
• T Cells (Key Players in Immunity): A type of white blood cell essential for immune defense.
  • Helper T cells: Helper T cells constantly patrol the body. If they discover an invading microbe, they alert other immune cells, which then mount an attack.
  • Killer T cells: These eradicate cells which have been infected by a virus or other pathogens. They can also attack tumour cells.
    • T cells have T-cell receptors to recognize invaders.
• Negative Selection: By the 1990s, scientists knew that T cells are trained in the thymus organ to distinguish between the body’s cells and enemy cells. 
  • During this training, any “self-reactive” or “rogue” T cells that would potentially harm the body are identified and destroyed. 

Key Points of the Discoveries

Shimon Sakaguchi and Regulatory T Cells (Tregs)

• Evidence for Peripheral Regulation:
  • Even after thymic negative selection, some rogue T cells persist in healthy individuals without causing harm.
  • This suggested an additional regulatory mechanism outside the thymus.
• The Experiment (1995):
  • Sakaguchi removed CD4+ T cells from mice.
  • Result: Mice developed severe autoimmune diseases (liver, kidney, skin) and died.
  • Recovery: Reintroduction of CD4+ T cells restored health.
• Conclusion:
  • CD4+ T cells function as Regulatory T cells (Tregs).
  • Tregs act as immune checkpoints, monitoring other T cells and preventing excessive attacks on the body.

Mary Brinko and Fred Ramsell and the FOX P3 Gene

• Observation: Studied “scurfy mice” that died shortly after birth from autoimmune attacks.
• Genetic Discovery:
  • Identified a mutation in a previously unknown gene on the X chromosome, later named FOX P3.
  • Male mice (XY) were affected, highlighting the lack of a second X chromosome as a backup.
• Significance:
  • FOX P3 is the master switch for Tregs.
  • Without FOX P3, Tregs do not form, allowing rogue T cells to attack the body, causing autoimmune disease.
• Human Connection:
  • Linked to IPEX syndrome in boys with FOX P3 mutations.

Implications of the Discovery

• Conceptual Shift: The discoveries showed that the immune system is not a simple “on/off” switch but rather a dynamic system maintaining a constant balance between activation and restraint.
• Real-World Benefits:
  • Autoimmune Disease Treatment: Scientists are exploring ways to increase Treg numbers in the body to treat and prevent autoimmune diseases.
    
  • Organ Transplantation: Engineered Tregs are being used to help the recipient’s body accept transplanted organs.
  • Cancer Therapy: Treg research provides new strategies for fighting cancer by modulating the immune system to target tumors effectively.

Conclusion

The discovery underscores that scientific progress is gradual, often requiring extensive research, and highlights the crucial role of private-sector contributions in advancing fundamental science.

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