Hypersensitivity Hypersensitivity refers to diseases caused by an immune response:  regardless whether the response is aga...
Four types of immune-mediated hypersensitivity reactions causing tissue damage
A 65 y/o collapsed 20 minutes after a penicillin injection.  PI: One day prior to admission ~ sore throat and fever. On th...
(1) Was penicillin appropriate? (2) Immunological events leading to this reaction? Why no reaction to initial penicillin? ...
IgE production arm mast cells trigger mediator release clinical effects Development of Immediate Hypersensitivity Anaphyla...
Response to an Allergen Challenge skin lung Histamine Heparin Tryptase LTC 4  & PGD 2 MC Cytokines Basophils Eosinophils T...
IgE-Mediated Allergic Reactions Syndrome Common Allergens Route of Entry Response Systemic Anaphylaxis Drugs Venoms Foods ...
Features of inhaled allergens that may promote the priming of T H 2 cells that drive IgE responses Protein (rarely carbohy...
2008 Mar 13;358(11):1109-17
DerP2 allergenicity results from functional mimicry of a Toll-like receptor 4 complex protein Divanovic et al.  Nature  45...
Pollens
Dust Mite
Proteolytic Allergens Permeabilize Epithelial Tight Junctions
IgE production is amplified following ligation by antigen of IgE bound to mast cells IgE secreted by plasma cells binds to...
Th2 Development is Stat6-dependent
 
Gene Nature of Polymorphism Possible mechanism of association IL-4 promoter variant variation in IL-4 expression IL-4R  ...
Genes & Environment ~ Atopy
The Hygiene Hypothesis Allergies Still Th2 Only child Few infections No allergies Th1 Older sibs Many infections (Th1 stim...
IgE:Fc ε RI β α γ 2 IgE Fc ε RI Fc ε RI Tetramer (trimer) 10 10 M K d   α :IgE β  amplifies γ  transduces IgE 4 Constant d...
IgG-mediated Hypersensitivity Immediate Hypersensitivity Cell-mediated Hypersensitivity Immunity Bacteria Parasites Viruse...
MC T  & MC TC  Cells ~ Developmentally & Functionally Distinct Types of Mast Cells <ul><li>MC T </li></ul><ul><ul><li>T ry...
Anti-Tryptase Immunocytochemistry & Immunogold Electron Microscopy anti-tryptase ~ 5 nm gold anti-chymase  ~ 15 nm gold MC...
Resting Mast Cell    Activated Mast Cell
± Fc  RI-Mediated Activation of Mast Cells Y Y Y Y Y Anti-IgE (Fc  ) Y Anti-Fc  RI Multivalent Antigen C3a C5a CD88 MC ...
Mediators Cell Activation/Proliferation epithelial cells smooth muscle endothelial cells fibroblasts endothelial cells His...
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Hypersensitivity refers to diseases caused

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  • Der p 2-mediated facilitation of TLR4 signalling under conditions of very low ambient LPS exposure, those associated with increasing rates of atopy and aeroallergy, may thus shift the LPS-response curve into the T H 2-inducing range. Similarly, Der p 2 probably promotes LPS-driven exacerbation of established asthma by facilitating TLR4 signalling by airway cells. Here, the ability of Der p 2 to reconstitute TLR4 signalling in the absence of MD-2 may well be of special importance as airway epithelial cells express TLR4, but little or no MD-2 (ref. 28 ). Although the interaction of Der p 2 with vertebrate TLR4–MD-2 is unlikely to be of biological importance to the mite, it is tempting to speculate that Der p 2 has a physiological role in the innate immune system of the dust mite gut. The pathophysiological interactions of Der p 2 with the vertebrate immune system may be more than a unique oddity. Other MD-2-related lipid-recognition domain family members are aeroallergens 13 . More generally, more than 50% of defined major allergens are lipid-binding proteins 5 . Intrinsic adjuvant activity provided by associated lipids may well underlie the allergenicity of such proteins.
  • IgE enhanced production/Th2-Th1 Enhanced antigen recognition/presentation Tissue specific/Therapeutic response
  • Univalent drugs; competitive and non-competitive anti-FcERI
  • Mast cells and their weapons of mass destruction?
  • Hypersensitivity refers to diseases caused

    1. 1. Hypersensitivity Hypersensitivity refers to diseases caused by an immune response: regardless whether the response is against a pathogen, non-pathogen or self; regardless whether the response is directed by antibodies, lymphocytes or innate pathways.
    2. 2. Four types of immune-mediated hypersensitivity reactions causing tissue damage
    3. 3. A 65 y/o collapsed 20 minutes after a penicillin injection. PI: One day prior to admission ~ sore throat and fever. On the morning of admission ~ MD prescribed penicillin injection. 10-15 min after injection weak and diaphoretic, dyspnea, chest pain and slid to the ground. PMH: coronary artery disease. No allergic rhinitis, asthma or dermatitis. Received penicillin 4x in the past for respiratory infections without adverse reaction until the last time -> urticaria that resolved spontaneously. ER: ashen in appearance; cold, clammy skin; tachycardia (160); hypotensive (systolic BP 50); labored respiration with wheezing. Rx: epinephrine SQ, IV fluids and diphenhydramine. Within 20 minutes BP, P & R improved. Additional Rx: diphenhydramine; oral prednisone. ECG (electrocardiogram) ~ new T-wave inversions ~ small MI. Uncomplicated post-MI course. 5 days later: negative allergy skin tests to penicillin. CASE 15
    4. 4. (1) Was penicillin appropriate? (2) Immunological events leading to this reaction? Why no reaction to initial penicillin? (3) Which therapeutic agent (Benadryl, prednisone, epinephrine, fluids) was critical in saving her life? Should prednisone have been given earlier? (4) Were any other allergic reactions apt to occur after the first day? (5) Why were skin tests negative? (6) If the patient later needed penicillin, could she receive it? (7) What is urticaria and how did it develop? Case 15 Questions
    5. 5. IgE production arm mast cells trigger mediator release clinical effects Development of Immediate Hypersensitivity Anaphylaxis Hives/Dermatitis Asthma/Rhinitis Conjunctivitis processing presentation help IL-4 IL-4/13 IL-13/CD40L Nat.Immunol 9:310-318, 2008. antigen antigen T H 0 ->2 B  /  ->  APC DC v Bas v NKT antigen
    6. 6. Response to an Allergen Challenge skin lung Histamine Heparin Tryptase LTC 4 & PGD 2 MC Cytokines Basophils Eosinophils TH2 Lymphocytes
    7. 7. IgE-Mediated Allergic Reactions Syndrome Common Allergens Route of Entry Response Systemic Anaphylaxis Drugs Venoms Foods Parenteral or Oral Edema Vasopermeability Laryngeal edema Shock Death Acute Urticaria (wheal & flare) Insect stings Allergy testing Subcutaneous Local increased vasopermeability & blood flow Allergic Rhinits (hay fever) Pollens, animal dust mites, mold, cockroach Inhaled Nasal congestion, rhinorrhea, itch & sneeze Asthma Inhaled Pollens, animal dust mites, mold, cockroach Bronchospasm, mucus, inflammation & remodeling Food Allergy Oral Shellfish, tree nuts, Peanuts, Milk, Eggs, Fish, Wheat Nausea, vomiting, diarrhea, cramps, urticaria, asthma & anaphylaxis
    8. 8. Features of inhaled allergens that may promote the priming of T H 2 cells that drive IgE responses Protein (rarely carbohydrate) Proteins induce T-cell response Enzyme Some are proteases Low dose Favors activation of IL-4-producing T cells Low mw proteins, High solubility Diffuses off particle, into mucus Stable Survival after dessication Peptides bind MHCII Needed for T cell priming
    9. 9. 2008 Mar 13;358(11):1109-17
    10. 10. DerP2 allergenicity results from functional mimicry of a Toll-like receptor 4 complex protein Divanovic et al. Nature 457:585-588, 2009 LPS: MD2 :CD14 TLR4 -> LPS: DerP2 :CD14 ← TLR4 ( TLR4-dependent, MD2-independent ) Allergic Lung Inflammation TLR4 + TLR4 -
    11. 11. Pollens
    12. 12. Dust Mite
    13. 13. Proteolytic Allergens Permeabilize Epithelial Tight Junctions
    14. 14. IgE production is amplified following ligation by antigen of IgE bound to mast cells IgE secreted by plasma cells binds to a high-affinity Fc receptor on mast cells & basophils Activated mast cells provide contact and secreted signals to B cells to stimulate IgE production ↑ IgE -> ↑Fc ε RI -> ↑ activation, survival, proliferation Positive Feedback Loop
    15. 15. Th2 Development is Stat6-dependent
    16. 17. Gene Nature of Polymorphism Possible mechanism of association IL-4 promoter variant variation in IL-4 expression IL-4R  structural variant increase signaling to IL-4 MHC II structural variant enhanced allergen peptide presentation TCR  microsatellite markers enhanced T cell response to allergens TIM Genes promotor/structural T H 1/T H 2 balance Fc ε RI β structural variant variation in signaling via IgE 5-lipoxygenase promoter variants enhanced leukotriene production  2-AR structural variants β 2 bronchodilator intolerance Filaggrin skin barrier deficiency, atopic dermatitis Susceptibility Genes for Asthma & Atopy
    17. 18. Genes & Environment ~ Atopy
    18. 19. The Hygiene Hypothesis Allergies Still Th2 Only child Few infections No allergies Th1 Older sibs Many infections (Th1 stimuli)
    19. 20. IgE:Fc ε RI β α γ 2 IgE Fc ε RI Fc ε RI Tetramer (trimer) 10 10 M K d α :IgE β amplifies γ transduces IgE 4 Constant domains (175 kDa) <250 ng/ml (16x10 10 M) (vs IgG 10 mg/ml) Circulation t½ ~ 2 days Heat-labile Fc ε
    20. 21. IgG-mediated Hypersensitivity Immediate Hypersensitivity Cell-mediated Hypersensitivity Immunity Bacteria Parasites Viruses Transplant Tolerance Venom Detoxification Biologic Fibrosis/Fibrolysis Vasopermeability Smooth muscle contractility Angiogenesis Anti-coagulation/ thrombosis
    21. 22. MC T & MC TC Cells ~ Developmentally & Functionally Distinct Types of Mast Cells <ul><li>MC T </li></ul><ul><ul><li>T ryptase </li></ul></ul><ul><li>MC TC </li></ul><ul><ul><li>T ryptase </li></ul></ul><ul><ul><li>C hymase </li></ul></ul><ul><ul><li>Carboxypeptidase </li></ul></ul><ul><ul><li>Cathepsin G </li></ul></ul><ul><ul><li>CD88 </li></ul></ul>Progenitor SCF+ ? SCF Mast Cell (committed) progenitor <ul><li>Basophil </li></ul>IL-3 Bone Marrow Circulation Tissue <ul><li>Eosinophil </li></ul>IL-5 MC
    22. 23. Anti-Tryptase Immunocytochemistry & Immunogold Electron Microscopy anti-tryptase ~ 5 nm gold anti-chymase ~ 15 nm gold MC T MC TC Tryptase+/Chymase- MC T Tryptase+/Chymase+ MC TC
    23. 24. Resting Mast Cell Activated Mast Cell
    24. 25. ± Fc  RI-Mediated Activation of Mast Cells Y Y Y Y Y Anti-IgE (Fc  ) Y Anti-Fc  RI Multivalent Antigen C3a C5a CD88 MC T/TC MC TC Substance P Neurokinin A CGRP Morphine/Codeine Vancomycin Major Basic Protein Anti-Fc  blocking Ab Y Y Y Univalent Ag IgE
    25. 26. Mediators Cell Activation/Proliferation epithelial cells smooth muscle endothelial cells fibroblasts endothelial cells Histamine PGD 2 LTC 4 Tryptase/Chymase Cytokines TNF α IL-13 IL-4 IL-5, 6 Chemokines IL-8 MIP-1, MCP-1 Growth factors bFGF, VEGF, TGF β amphiregulin Heparin Bronchospasm hyperreactive IgE Edema Inflammation Neurogenic Tissue Remodeling Mucus Anticoagulation/ Antithrombotic
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