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Notes from lecture series in ‘Science Week’ – 16thof November 2011 By Luke O’Neill, Professor from Trinity College Dublin, School of Biochemistry and Immunology. He is an immunologist and has specialisation in Infammation.

  • In 2012, Dublin will become European city of sciences. The current topic will be discussed is ageing.
  • From “What is Life” by Erwin Schröddinger: a gene is aperiodical crystal
  • 2011 Nobel prize in Medicine was given for the invention of Toll-Like Receptors (TLRs) to Jules A. Hoffmann (National Centre of Scientific Research, Strasbourg) and Bruce Beutler (University of Texas Southwestern Medical Center).
  • Inflammation is the heart of disease (quoted from David Baltimore, nobel laurate who discovered reverse transcriptase). The purpose of inflammation is to sense the abnormal condition and try to get rid of it so that it will come back to its stable condition. So, inflammation is a part of our homeostasis mechanism.
  • One of major inflammatory disease is Multiple Sclerosis (MS). Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. (Wikipedia)
  • One of the drugs being used as a treatment for inflammatory disease is anti-TNF (tumour necrosis factor). One of anti-TNF that is produced in Ireland is called Enbrel under Pfizer license. TNF is one of the biochemical contribute to the cascading effect that will lead to inflammation. Therefore, halting the TNF action can lead to stop the domino effect that will lead to inflammation. Other biochemicals contribute in signal cascade of inflammation are Interleukin (IL) and other cytokines. TNF, IL, and other cytokine will give signals for inflammation to occur. Abnormal inflammation will lead to many inflammatory disease such as Rheumatoid Arthritis, Crohn’s Disease, and Lupus.
  • Mechnikov got 1908 Nobel Prize for discovering phagocyte. He discovered macrophage in starfish.
  • At first, vaccine was made from attenuated form of pathogen. Nowadays, vaccine can be made from :

–          Killed pathogen. The pathogen being treated by chemical or heat and leave the dead pathogen only. Several examples are: Polio vaccine, cholera vaccine, bubonic plaque vaccine.

–          Attenuated pathogen. Live viruses that have been cultivated in such condition that they lose their virulence properties.

–          Toxoid. Inactivated toxin compounds of pathogen. Some pathogens cause the disease not because of their selves but due to their toxin, e.g. tetanus and diphtheria.

–          Subunit. Introduce subunit of proteins to increase the safety of the vaccine. But the immune response produced is lesser than the one with whole pathogen. The immune response will only recognize few epitopes.

–          Experimental. There are a lot of other type of experimental vaccines being developed to increase the safety and also the effectiveness of the vaccines.

  • TLRs recognized Pathogen-associated Molecular Patterns (PAMPs). These molecules are ‘additional’ recognizing site that help the epitope binding and boost our immune system.
  • In vaccine, we add some molecule to boost up our immune system which we called as adjuvant. Adjuvants work by stimulating TLRs. The adjuvant usually contains microbial products besides the specific antigen.
  • TLR negative mutant flies we called them as mouldly flies. Due to growth of moulds on the surface of the flies. The moulds grow due to ineffective immune system of the flies.
  • While TLR4 negative mutant which is created by Bruce Beutler express LPS non-resistant mice.
  • Our immune system works by sensing imbalance in our body. It include foreign antigen and also damaged ‘self’ cells.
  • TLR genes are very conservative. Plant also has TLRs which far more diverse than human TLRs (more than hundred).
  • Blocking TLR2 activity prevents cytokine production in Rheumatoid Arthritis (RA) synovial tissue.
  • The signal cascade :

TLRs > MyD88 > IL-1 > NFκB > Inflammatory protein > Inflammation > Arthritis

  • IL-1 is overproduced in inflammation.
  • Another signal pathway :

TLRs > NLRP3 > IL-1 > NFκB and JNK > Insulin ressitance > β cell death > Type 2 Diabetes

  • Muckle-Wells syndrome à flu-like symptoms, cause deafness, due to NLRP3 mutation.
  • Now, the traditional medicines become a trend in finding active molecule that will affect the body metabolism. Feverfew (flower) has an active ingredient called parthenolide. Being use in inflammatory treatment. It also induces apoptosis.
  • Another inflammatory disease is gout which is caused by uric acid deposition.
  • In Diabetes Mellitus Type 2 (DM2), one of the histology marks is the deposition of IAPP fibrils in pancreas (red in histology preparate).  IAPP driving IL-1 to increase in concentration. It is proved by creating mouse model which increased in IAPP gene expression. The mouse then gets DM2.
  • Sequence events in pathogenesis of DM2:

–          Low grade inflammation (due to excess fat & sugar), insulin resistance and hyperglycaemia.

–          Β cells makes more insulin and IAPP

–          IAPP form oligomers

–          Macrophages infiltrate to pancreas, high expression of NLRP3.

–          Macrophages start to destroy β cells.

  • NLRP3 activated by many stimulator molecules besides IAPP such as cholesterol crystal in atherosclerosis and β amyloid in Alzheimer.
  • Future Prospects

–          Treatment of inflammatory disease, new vaccines being produced (TB, Malaria), and cure of cancer.

–          Many new drugs in development.

–          Understanding the underlying cause of many diseases. Whether it comes from environmental influences (infection,diet) or due to specific genetic background  (defective protein: CCR5-CCX4 in AIDS).

  • Statin is also an immunosuppressant. Therefore, exercise will induce muscle to produce IL-6. IL-6 will help pancreas to function properly. Exercise may also lower the obesity probability and lower excess fat deposition in body.
  • Pregnancy will lower the autoimmune disease. After giving birth, usually the autoimmune disease that the mother possesses will be worsened. The decrease in immune response is due to high estrogen concentration in the mother’s body. Estrogen can act as anti-inflammatory molecule.
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