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Patient-driven discovery reveals potential target for autoimmune diseases
Context: Researchers at Yale School of Medicine discovered mutations causing a deficiency in phosphatidylinositol 3-kinase-gamma (PI3Kγ), a crucial signalling molecule in immune cells.
Research Findings & Significance:
- Role of PI3Kγ in Immune Response: The team discovered that PI3Kγ is essential for activated B cells to differentiate into antibody-secreting cells.
- Implications for Autoimmune Diseases: Therapeutically blocking PI3Kγ might treat the overproduction of antibodies in autoimmune diseases.
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- Potential for Broader Impact: Beyond the rare cases of PI3Kγ deficiency, these findings could help develop new interventions for autoimmune diseases.
- “These sorts of monogenic, single-gene defect diseases help us learn fundamental biology directly from patients
- Impact of PI3Kγ Deficiency:
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- Focus: The lab studies rare immune disorders caused by single gene mutations to understand human immunology.
- Immune Defects: The mutation led to immune-mediated damage in the patient’s gut and lungs and reduced antibody levels.
What is Genetic Mutations:
- A genetic mutation is a change in a sequence of DNA that can affect cell function and potentially lead to experiencing symptoms of genetic conditions.
- Occurrence: Mutations happen during cell division, which includes:
- Mitosis: Creates new body cells by copying chromosomes, resulting in two identical cells.
- Meiosis: Produces egg and sperm cells with half the number of chromosomes (23), ensuring genetic material is inherited from both parents.
How do B cells become antibody-producing cells?
- Antibodies are key components of the adaptive immune system, targeting foreign invaders such as bacteria or viruses.
- B cells are crucial for antibody production and immune memory.
- B cells activate when an antigen binds to their receptors and form germinal centres. Germinal centres help B cells become optimal antibody producers and decide their fate.
- B cells can become memory cells or antibody-secreting cells (ASCs).
- Memory cells “remember” antigens for rapid immune responses upon re-exposure.
- ASCs release large amounts of antibodies into the blood to target the intruder.
PI3Kγ plays essential role in B cell differentiation:
- 2019 Experiment: Knockout and control lab mice were exposed to pet store mice, revealing that PI3Kγ is critical for antibody production in mice, similar to humans.
- Latest Research: The team created mouse models with PI3Kγ knocked out in specific immune cells (B cells, T cells, macrophages, dendritic cells) to determine which cells require PI3Kγ.
- Findings: Removing PI3Kγ from B cells caused significant reductions in antibody response, indicating its necessity for proper B cell function.
- PI3Kγ was found to be crucial for B cell differentiation into antibody-secreting cells (ASCs), but not for B cell activation or germinal centre formation.
What is Lymphocytes:
- Lymphocytes: A type of white blood cell crucial for the immune system, helping the body combat disease and infection.
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- T Lymphocytes (T Cells): Regulate the immune response and directly attack infected or tumour cells.
- B Lymphocytes (B Cells): Produce antibodies, proteins that target viruses, bacteria, and other foreign invaders.
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- Types of B-cells:
- Plasma Cells: Release antibodies quickly and have a short lifespan.
- Memory Cells: Remember antigens for faster immune responses in the future, aiding in vaccine effectiveness.
PI3K inhibitors could potentially treat autoimmune diseases
- Team identified PI3Kγ as crucial for B cell differentiation and a potential target for treating autoimmune diseases.
- Current autoimmune treatments often wipe out B cells, increasing infection risk, if PI3K inhibitors, used for cancers and rare diseases, could regulate an overactive immune system.
- By using human tonsil organoid models, PI3Kγ-targeting drugs blocked B cells’ ability to differentiate into antibody-secreting cells (ASCs).
- Future studies will test PI3K inhibitors in pre-clinical autoimmunity mouse models.
About Immune System and Autoimmune Diseases:
- The immune system typically protects against diseases and infections by creating specific cells to target foreign pathogens.
- Normally, the immune system distinguishes between foreign cells and your own cells.
- In autoimmune diseases, the immune system mistakenly identifies parts of the body, such as joints or skin, as foreign.
- This leads to the release of autoantibodies that attack healthy cells.
Antigen vs antibody:
- An antigen is a foreign substance that enters your body. This can include bacteria, viruses, fungi, allergens, venom and other various toxins.
- An antibody is a protein produced by your immune system to protect your body against unwanted substances. Antibodies also known as Immunoglobulin.
- Antibodies attach to foreign substances to help remove them from your system.