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The role of the thymus in T cell differentiation

The role of the thymus in T cell differentiation. TCR interrogates MHC1 peptide binding site looking for 8-10 aa peptide placed there via endogenous pathway. TCR interrogates MHCII peptide binding site looking for 18-34 aa peptide placed there via exogenous pathway.

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The role of the thymus in T cell differentiation

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  1. The role of the thymus in T cell differentiation

  2. TCR interrogates MHC1 peptide binding site looking for 8-10 aa peptide placed there via endogenous pathway TCR interrogates MHCII peptide binding site looking for 18-34 aa peptide placed there via exogenous pathway

  3. T cells are MHC restricted. They only help or kill cells with whom they share MHC. Zinkernagel 1994.

  4. This work indicated that T cells recognize both MHC and specific antigen fragments. Does one receptor recognize the MHC and another receptor recognize the antigen fragment embedded in the binding site on the MHC ? Or is there one receptor with specificity for MHC in combination with a specific antigen fragment ?

  5. Dual Receptor Theory

  6. Experiment demonstrating the thymus selects this MHC specificity.

  7. T cell differentiation in the thymus

  8. T cell differentiation :How to explain MHC restriction and double the number of T helper cells compared to cytotoxic cells.

  9. T lymphocytes spend three weeks in the thymus. • T cells leaving the thymus circulate in blood and lymphatics and enter secondary immune tissues. • The thymus involutes following puberty and shrinks. In a human infant the thymus weighs 70 gms by age 40-50 it is only 3 gms.

  10. In cortex, thymic epithelial cells presents 2X the amount of MHC2 molecules as MHC1 molecules.They present all the alleles in the persons genome: 6 MHC class 1 molecules and 12 different MHC class 2 molecules. This determines the ratio of Th to Tc as 2:1. This determines that only T cells with a TCR receptor that recognizes the persons own MHC survives the cortex.

  11. Now those T cells that survive the cortex move to the medulla,they upregulate the number and affinity of their TCRs and become committed as either CD4 or CD8 positive.

  12. Present day Present day Present day Present day Present day

  13. Emerging Pathogens

  14. Emerging areas of concern : • New virulent organisms that develop spontaneously • Antibiotic resistant strains of bacteria • Epidemic spread in a global economy • New virulent organisms engineered for Bioterrorism

  15. Hypersensitivity Reactions

  16. antibody mediated antibody mediated antibody mediated cell mediated Ig E Ig M or IgG Ig M or IgG T lymphocyte Immediate Immediate Immediate Delayed Fastest (sec) 4-6 hrs w/i 4-6 hrs 48-72 hrs.

  17. Type 1 hypersensitivity • All hypersensitivity reactions require a first asymptomatic exposure to antigen • Second exposure manifests a exaggerated and extensive reaction • In type one reactions, these are very fast within secs and usually but not always can resolve not causing permanent damage. They can during the reactive phase however cause death.

  18. Type 1 hypersensitivity • A. Systemic anaphylaxis • B. Local Anaphylaxis-atopic allergies • 1. Allergic rhinitis 20% of the population • 2. Asthma • 3. Food allergies • 4. Atopic dermatitis

  19. First exposure All type 1 Rxs. Second exposure

  20. HS1 A. Systemic anaphylaxis • Portier and Richet Nobel 1913 • Dogs with jelly fish toxins • Guinea pigs with penicillin

  21. Systemic Analyphaxis-Shock • Within secs of second exposure to drugs, venoms or specific foods (peanuts). • Mast cells degranulate. • GI tract –increased fluid (edema), increased peristalsis = severe diarrhea and vomiting. • Lungs- this is life threatening . Every time the person exhales, SMC constrict causing further decreased diameter of bronchi, increased mucous secretion and swelling of connective tissue closes airways completely. Within minutes they cant take a breathe in = asphyxiation.

  22. Severe Upper and lower respiratory Tract, GI tract, skin reaction. At multiple sites simultaneously- GI tract, upper and lower respiratory tract, skin constriction Severe permeability Severe secretion Severe Histamine release

  23. 1. Processing of antigen 2. T help that produces a Ig E response 3. 2- 10 X more mast cells 4. Mast cells with 10 x higher affinity receptors What is different about an allergic individual and a non-allergic individual.

  24. 5. Mast cells with 10-100 x more histamine per cell 6. More and higher histamine receptors on SMC 7. Mast cells with 10 x higher affinity receptors

  25. If you suspect that you or someone you are with is having an anaphylactic reaction, inject epinephrine immediately. The shot is given into the outer thigh and can be administered through light fabric. Rub the site to improve absorption of the drug. An Epi Pen kit is shown. Epinephrine antagonist of histamine and causes EC tight junction to re-formation and SMC relaxation.

  26. Type 1 hypersensitivity • Systemic anaphylaxis-severe. • Local Anaphylaxis-mild-severe • Allergic rhinitis 20% of the population. hay fever, animal dander. • Asthma (Extrinsic not Intrinsic)-pollen, dust mites, fumes, insect products. • Food allergies-hives, anaphylaxis. • Atopic dermatitis-fabric softeners, wool.

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