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Basic Immunology  as it Relates to Allergy

Basic Immunology  as it Relates to Allergy. David Sloane, MD Allergy and Immunology Brigham and Women’s Hospital NESA 5 April, 2013. Disclosures. (Genentech + Novartis) Unbranded Educational Talks on Asthma Contributor to the Mathematics Consortium Working Group. Objectives.

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Basic Immunology  as it Relates to Allergy

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  1. Basic Immunology as it Relates to Allergy David Sloane, MD Allergy and Immunology Brigham and Women’s Hospital NESA 5 April, 2013

  2. Disclosures • (Genentech + Novartis) Unbranded Educational Talks on Asthma • Contributor to the Mathematics Consortium Working Group

  3. Objectives • 1) To review the biology of cells, antibodies, and mediator molecules in healthy immunity and dys-immunity germane to allergy. • 2) To explore the rationale for therapeutic agents such as omalizumab in the treatment of allergic diseases • 3) Participants will develop the skills needed to educate patients about those aspects of the immune system relevant to the patient's allergic or immunologic disease and its treatment

  4. Teleology • Two theories of the purpose of the immune system: • (1) Defense against microbes (Janeway) • (2) Defense against danger (Matzinger) What do you think the difference is between these two theories?

  5. Immune System as a Matter Processing Network

  6. Reality Check

  7. The Whole Megilah: Allergic Reaction System Slide courtesy of Dr. Tse Wen Chang

  8. Components of the System • Cells: • Dendritic Cells and other “professional APCs” • T cells • B cells • Mast cells (and Basophils?) • Eosinophils • Antibodies: What are they? What are they good for? • IgE • IgG4 • Mediator Molecules: What are they? What are they good for? • Interleukin (IL)-4 • IL-13 • Thymic Stromal Lymphopoetin (TSLP)

  9. Processing Stuff Microbe Antigen Presenting Cell (APC) {DC}

  10. Processing Stuff APC T cell

  11. The Whole Megilah: A closer view IL4, TSLP

  12. Wait a Minute! • Why is this happening? • Do the two theories of the purpose of the immune system help you? • What is the hygiene hypothesis?

  13. Antibodies: The Immune System’s Attacks Dogs From Janeway et al. Immunobiology V. 2001.

  14. Antibodies: The Various Species or Isotypes From Janeway et al. Immunobiology V. 2001.

  15. The Role of IgE in Allergic Inflammation • Necessary but not sufficient factor for *antigenic* stimulation of mast cells and basophils. • Prausnitz (grass) and Küstner (fish) 1920s. • Reagin identified as IgE in mid 1960s.

  16. IgE: Structure • Molecular Weight ≈ 190,000 kD • Monomeric, two identical heavy chains, two identical light chains (k or l)

  17. IgE: Synthesis • B cells that undergo the isotype switch to Ce produce IgE • Help from Th2 cells that express • a) CD40L and • b) IL-4, IL-13, TSLP

  18. IgE: Circulation • IgE circulates in the blood with a t½= 2-4 days (serum!) • Normal serum concentration = 0-0.002mg/mL (the lowest of all five isotypes) • x IU = 2.4x ng/mL (E.g., 125 IU = 300ng/mL)

  19. IgE in Blood and Tissues • In the blood, IgE binds to Basophils through the high affinity receptor for IgE, FceRI. • IgE crosses from blood space into the extracellular space • It binds to Mast Cells through FceRI • FceRI is also expressed by monocytes, eosinophils, dendritic cells in peripheral blood, and Langerhans’ cells in skin.

  20. FceRI and FceRII • FceRI Structure: • One a chain that binds the Fc portion of IgE • One b chain with ITAM • Two g chains, each with ITAM • FceRII • CD23 • Expressed on mature B cells, activated T cells, macrophages, eosinophils, follicular dendritic cells, platelets • C-type lectin • Antigen capture leading to processing and presentation to enhance immune responses.

  21. Mast Cells (and Basophils) FceRI IgE

  22. Mast Cells • Live in • mucosal layers (gut, lung) • submucosal layer • dermis • Mediators • Preformed (histamine, tryptase) • Rapidly synthesized (PGD2, LTC4) • Not so rapidly synthesized (cytokines)

  23. Measurement of Total Serum IgE: Why bother? Burrows B, Martinez FD, Halonen M, Barbee RA, and Cline MG. Association of Asthma with Serum IgE Levels and Skin-Test Reactivity to Allergens. NEJM 1989;320(5):271-277.

  24. Mast Cells and IgE IgE FceRI Allergen Mediator Release Mast cell granules

  25. Wait a Minute! • Where is IgE acting? • Where do we measure IgE?

  26. So What?

  27. How do we treat Allergic Inflammation? • Avoid the allergenic trigger (“I can’t eat that”) • Antagonize the mast cell mediators (“Where’s my antihistamine?” • Throw a monkey wrench into the response system (The story of the yetzer ha’rah) • Try to teach the immune network not to attack (“Stay….staaaaay…. Good dog!”)

  28. The binding specificities of a therapeutic anti-IgE Slide courtesy of Dr. Tse Wen Chang

  29. IgE:anti-IgE complexes 3 IgE:3 anti-IgE the largest Soluble and no immune complex problems T1/2 : anti-IgE ca. 20 days, IgE 1-2 days, IgE:anti-IgE ca. 20 days Immune complexes accumulate rapidly. Could IgE:anti-IgE complexes be beneficial? They may serve as antigen sweepers, blocking antigens to access receptors on inflammatory cells. Slide courtesy of Dr. Tse Wen Chang

  30. Down regulation of FceRI in patients • FceRI density on basophils falls by 97% in 3 months. • FceRI on basophils decreases with a half life of about 3 days. • FceRI on dendritic cells are decreased substantially in two weeks. From MacGlashan DW et al., J. Immunol. 158:1438 (1997) Slide courtesy of Dr. Tse Wen Chang

  31. Down regulation of FceRI in patients (cont.) From MacGlashan DW et al., J. Immunol. 158:1438 (1997)

  32. Allergy Immunotherapy:teaching an old dog a new trick, orteaching it not to do an old trick • Introduce allergen in a non-threatening manner and context • Elicit an IL-10 response from Treg cells instead of an IL-4 and TSLP response from Th2 cells. • Thus, lead B cells to make the isotype switch to IgG4. • IgG4 binds to mast cell inhibitory receptors and blocks activation.

  33. Mast Cells post Immunotherapy IgE FceRI Allergen IgG4 NO Mediator Release FcgRIIb Mast cell granules

  34. Question 1 • Which of the following cells is thought to be the primary effector cell in anaphylaxis? • A. Eosinophils • B. Basophils • C. CD8+ T cells • D. Mast cells • E. Th17 cells

  35. Question 1 • Which of the following cells is thought to be the primary effector cell in anaphylaxis? • A. Eosinophils • B. Basophils • C. CD8+ T cells • D. Mast cells • E. Th17 cells

  36. Question 2 • Which of the following cells promotes B cells to undergo an isotype switch to make IgE? • A. Th1 cells • B. Th2 cells • C. Th17 cells • D. Treg cells • E. NKT cells

  37. Question 2 • Which of the following cells promotes B cells to undergo an isotype switch to make IgE? • A. Th1 cells • B. Th2 cells • C. Th17 cells • D. Treg cells • E. NKT cells

  38. Question 3 • Fill in the blanks to make this statement correct: A major hypothesis on how allergy immunotherapy works is the belief that ____ promotes B cells to make ____. • A. IL-4.... IgE • B. IL-13.... IgA • C. IL-10.... IgG4 • D. IL-18.... IgD • E. Fractalkine.... Thymic Stromal Lymphopoetin (TSLP)

  39. Question 3 • Fill in the blanks to make this statement correct: A major hypothesis on how allergy immunotherapy works is the belief that ____ promotes B cells to make ____. • A. IL-4.... IgE • B. IL-13.... IgA • C. IL-10.... IgG4 • D. IL-18.... IgD • E. Fractalkine.... Thymic Stromal Lymphopoetin (TSLP)

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