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Immunologic mechanisms of anaphylaxis

Immunologic mechanisms of anaphylaxis

Presented by Natthiya Pholmoo, MD.

January 15, 2021

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Immunologic mechanisms of anaphylaxis

  1. 1. Immunologic mechanisms of Anaphylaxis Natthiya Pholmoo, M.D.
  2. 2. DEFINITION Cardona et al. World Allergy Organization Journal (2020) 13:100472
  3. 3. Common Triggers ◦ Environmental allergen ◦ Food : peanut, milk, eggs, and nuts ◦ Antibiotics : beta lactams ◦ Chemotherapy agents : platins and taxanes ◦ mAbs ◦ General anesthetics ◦ Immunotherapy allergens ◦ Hymenoptera venoms Mariana Castell. J Allergy Clin Immunol 2017
  4. 4. Classical clinical manifestations ◦ Flushing ◦ Pruritus ◦ Hives, Angioedema ◦ Shortness of breath, Wheezing ◦ Nausea, Vomiting, Diarrhea ◦ Hypotension ◦ Oxygen desaturation ◦ Cardiovascular collapse Mariana Castell. J Allergy Clin Immunol 2017
  5. 5. Atypical symptoms ◦ Chills and fever during reactions to chemotherapy agents, such as Oxaliplatin. ◦ Pain during Taxane and mAb reactions. ◦ These symptoms can also occur during reactions to chemotherapy and mAbs in which no evidence for IgE can be demonstrated. Mariana Castell. J Allergy Clin Immunol 2017
  6. 6. Cytokine storm–like reactions ◦ Caused by release of proinflammatory mediators, such as TNF-a, IL-1B, and IL-6. ◦ Target cells include monocytes, macrophages, mast cells, and other immune cells with FcγR. ◦ Triggers for these reactions include chimeric, humanized, and human mAbs and chemotherapy, including oxaliplatin. ◦ Reactions are characterized by chills, fever, generalized malaise followed by hypotension, desaturation, and cardiovascular collapse. Mariana Castell. J Allergy Clin Immunol 2017
  7. 7. Mixed reactions ◦ Mixed reactions with features of type I and cytokine storm–like reactions can be seen with chemotherapy and mAbs. ◦ Pruritus, hives, and swelling are associated with chills, fever, hypotension, and desaturation. Mariana Castell. J Allergy Clin Immunol 2017
  8. 8. Clinical criteria for diagnosis EAACI anaphylaxis guidelines 2014
  9. 9. Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis
  10. 10. Cardona et al. World Allergy Organization Journal (2020) 13:100472
  11. 11. Risk of severe anaphylaxis Denise Anne Moneret-Vautrin. Pathophysiology : IgE-mediated & non-IgE-mediated anaphylaxis 2014
  12. 12. 15/01/64Cardona et al. World Allergy Organization Journal (2020) 13:100472
  13. 13. PATHOGENESIS OF ANAPHYLAXIS ◦ Immunologic mechanisms ◦ IgE-dependent anaphylaxis ◦ IgE-independent anaphylaxis ◦ IgG-mediated reactions ◦ Complement Activation ◦ Non-Immunologic mechanism : Direct mast cell activation ◦ Idiopathic Mariana Castell. J Allergy Clin Immunol 2017
  14. 14. 15/01/64 FINKELMAN, KHODOUN, AND STRAIT. J ALLERGY CLIN IMMUNOL 2016.
  15. 15. POTENTIAL EFFECTOR CELLS ◦ Mast cells ◦ Basophils ◦ Monocytes/macrophages ◦ Neutrophils ◦ Platelets ◦ PAF
  16. 16. IgE- dependent anaphylaxis http://sciencemission.com
  17. 17. IgE-dependent anaphylaxis ◦ IgE is the isotype found at by far the lowest concentrations in the circulation (50-200 ng/mL total circulating IgE in healthy subjects vs approximately 10 mg/mL for IgG) ◦ IgE can be found at much higher levels in patients with allergic diseases. REBER, HERNANDEZ, AND GALL. J Allergy Clin Immunol 2017
  18. 18. IgE-dependent anaphylaxis ◦ IgE binds to the high-affinity receptor FcεRI on the surfaces of basophils, mast cells, neutrophils, eosinophils, monocytes and dendritic cells, and platelets. ◦ Cross-linking of FcεRI-bound IgE induces activation of mast cells and basophils and the immediate release of preformed mediators. REBER, HERNANDEZ, AND GALL. J Allergy Clin Immunol 2017
  19. 19. IgE-dependent anaphylaxis ◦ The mechanism classically associated with human anaphylaxis is initiated by an allergen interacting with allergen-specifc IgE bound to the FcεRI receptor on mast cells, basophils, or both. ◦ These allergens interact with IgE molecules on 2 or more receptors of the cell surface to cause cross-linking, which leads to receptor aggregation and initiates intracellular signaling. ◦ If signaling is suffciently robust, mast cell/basophil activation and degranulation develop. ◦ The release of preformed mediators, enzymes, and cytokines, such as histamine, tryptase, and tumor necrosis factor. Muñoz-Cano. J Investig Allergol Clin Immunol 2016 http://sciencemission.com
  20. 20. ◦ IgE levels alone do not explain a subject’s susceptibility to anaphylaxis. ◦ Some patients can experience near-fatal anaphylaxis despite having low or undetectable levels of circulating allergen-specific IgE. ◦ Conversely, allergen-specific IgE can be detected in the plasma of many subjects who do not have clinical symptoms when exposed to that allergen. ◦ This is particularly true for Hymenoptera venom, with the vast majority (approximately 80%) of patients with IgE antibodies specific for Hymenoptera venoms having no history of systemic reactions to such venoms.
  21. 21. http://sciencemission.com IgE- in dependent anaphylaxis
  22. 22. IgG-Mediated Reactions ◦ IgG can bind to 6 different Fc gamma receptors (FcγR) ◦ FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB ◦ All 6 induce activation, except FcγRIIB, which mediates an inhibitory signal. ◦ FcγRI is considered to be the high-affinity receptor. ◦ The role of IgG in anaphylactic reactions has been demonstrated in mouse models. Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  23. 23. IgG-Mediated Reactions ◦ In a passive systemic anaphylaxis model, the allergen interacts with the specific IgG bound to FcγRIII on macrophages and basophils. ◦ Macrophage activation results mainly in the release of platelet- activating factor (PAF), rather than histamine. ◦ The IgG-mediated pathway requires more antibody and antigen than the IgE-mediated pathway. Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  24. 24. IgG-Mediated Reactions ◦ IgG blocks IgE-dependent anaphylaxis when the individual is exposed to low doses of allergen. ◦ IgG either intercepts the antigen before it can cross-link mast cells/basophil–associated IgE or activates FcγRIIB, an inhibitory receptor. ◦ Low doses of IgG are insuffcient to induce IgG-mediated anaphylaxis, presumably because FcγRs have a much lower affnity than FcεRI (high-affnity IgE receptor). Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  25. 25. IgG-Mediated Reactions ◦ A previous study showed that the activation of FcγRIV receptors by IgG2 antibodies in neutrophils played a major role in mouse models of anaphylaxis. ◦ Neutrophils have been reported to be major PAF producers, and PAF secretion has been observed in mice undergoing neutrophil- dependent anaphylaxis. ◦ PAF, rather than histamine, was the most important mediator in this type of anaphylaxis. Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  26. 26. IgG-Mediated Reactions ◦ Release of PAF is not exclusively observed in IgG-mediated anaphylaxis, and some animal models have also demonstrated its presence in IgE- mediated reactions. ◦ Circulating PAF levels are increased and PAF acetylhydrolase (PAF-AH) activity is decreased in proportion to the severity of anaphylaxis. ◦ The biological half-life of PAF, which ranges from 3 to 13 minutes. Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  27. 27. IgG-Mediated Reactions ◦ Patients with the lowest levels of PAF-AH activity are 27 times more at risk of severe or fatal anaphylaxis than patients with normal levels of PAF-AH activity. ◦ These and other studies suggest that PAF-AH defciency predisposes to severe anaphylaxis. Muñoz-Cano. J Investig Allergol Clin Immunol 2016 Vadas et al N Engl J Med. 2008 https://www.scielo.br
  28. 28. IgG-Mediated Reactions ◦ The results of a recent study suggest that both IgG and neutrophils may be involved in human anaphylaxis. ◦ In a group of patients with food anaphylaxis induced by lipid transfer proteins (LTP) ◦ increased presence of specific anti-LTP IgG1 and IgG3 ◦ increased expression of the activating receptor FcγRI (CD64). Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  29. 29. IgG-Mediated Reactions ◦ LTP allergic patients presented both specifc IgG and anti-LTP IgE, suggesting that the activation of both IgG and IgE pathways may contribute substantially to the anaphylactic response. ◦ LTP may be eliciting the allergic response via IgE, IgG, or both, activating not only mast cells and basophils, but also neutrophils. ◦ Patients allergic to galactose-alpha-1,3-alphagalactose (α-gal), an allergen involved in allergy to red meat and cetuximab, demonstrated the existence of both specific IgE and IgG anti–α-gal; these antibodies were IgG1. Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  30. 30. Complement Activation ◦ C3a, C4a, and C5a also named anaphylatoxins ◦ Potent inflammatory mediators. ◦ Depletion of complement levels and production of C3a and C5a is observed in human anaphylaxis. REBER, HERNANDEZ, AND GALL. J Allergy Clin Immunol 2017
  31. 31. Complement Activation ◦ Immune complexes also activate the complement system, generating anaphylatoxins. ◦ C3a has a direct effect on mast cell activation in rat and in the human mast cell line HMC-1. ◦ Although FcγRI receptors are normally occupied by serum monomeric IgG, this does not prevent their activation by IgG immune complexes. ◦ C3a also demonstrated a synergistic effect with FcγRI activation. ◦ The combined effect of IgG and C3a results in greater mast cell activation Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  32. 32. Complement Activation ◦ In a mouse model demonstrated that peanut induces severe allergic reactions by Ig-independent activation of the complement system with production of large amounts of the anaphylatoxin C3a. ◦ Peanut induces dose-dependent shock ◦ Peanut-induced shock depends more on macrophages and basophils than on mast cells ◦ Peanut and IgE-mediated mast cell degranulation synergistically induce shock ◦ Tree nuts have similar effects to peanut ◦ Milk and egg white do not. Khodoun et al. J Allergy Clin Immunol. 2009
  33. 33. Complement Activation ◦ Cremophor EL was the diluent of the older preparations of propofol and paclitaxel; it formed large micelles with serum lipids and cholesterol that could stimulate complement activation under physiological conditions. ◦ Complement activation leads to the release of C3a, C5a, and C5b-9, which trigger activation of mast cells, basophils, and other cells via their specific receptors. ◦ These reactions mostly arise upon first treatment. ◦ Cannot be differentiated from IgE-mediated reactions. ◦ The reactions respond to the infusion rate and premedication with corticosteroids and antihistamines. Muñoz-Cano. J Investig Allergol Clin Immunol 2016
  34. 34. ◦ Complement activation ◦ Chondroitin sulfate glycosaminoglycans ◦ contrast media ◦ Generation of the anaphylatoxins C3a and C5a, which can bind to complement receptors. ◦ The resulting release of histamine, leukotrienes, and prostaglandins can induce flushing, hives, hypoxia, vasodilation, and hypotension. Mariana Castell. J Allergy Clin Immunol 2017
  35. 35. MRGPRX2 ◦ The new Gcoupled receptor MRGPRX2 ◦ Expressed on mast cells and other cells. ◦ Its participation in human hypersensitivity reactions and anaphylaxis is being investigated and does not involve IgE. ◦ Activated by ◦ quinolone antibiotics such as ciprofloxacin and levofloxacin ◦ general anesthetics such as atracuronium and rocuronium ◦ Icatibant ◦ other drugs with Tetrahydroisoquinoline (THIQ) motifs. Mariana Castell. J Allergy Clin Immunol 2017
  36. 36. MRGPRX2 ◦ Patients presenting with anaphylaxis during anesthesia or after quinolone use for whom an IgE mechanism cannot be demonstrated by skin testing may have either increased protein levels or functional MRGPRX2 receptors. Mariana Castell. J Allergy Clin Immunol 2017
  37. 37. Mariana Castell. J Allergy Clin Immunol 2017
  38. 38. ◦ Anaphylaxis phenotypes are defined by clinical presentation into - type I–like reactions - cytokine storm–like reactions - mixed reactions. ◦ The endotypes underlying these phenotypes include ◦ IgE and non-IgE-mediated mechanisms ◦ cytokine release ◦ mixed reactions ◦ direct activation of immune cells Mariana Castell. J Allergy Clin Immunol 2017
  39. 39. Mediators Mariana Castell. J Allergy Clin Immunol 2017
  40. 40. Denise Anne Moneret-Vautrin. Pathophysiology : IgE-mediated & non-IgE-mediated anaphylaxis 2014
  41. 41. Progestogen hypersensitivity ◦ Presenting with anaphylaxis before and during the menstrual period. ◦ Diagnosis of catamenial anaphylaxis ◦ Patients can present with dermatitis simulating fixed drug eruptions. ◦ Endogenous and exogenous sources of progesterone can be the allergenic triggers. ◦ Desensitization to progesterone has reversed infertility. Mariana Castell. J Allergy Clin Immunol 2017
  42. 42. Anaphylaxis and the heart Kounis syndrome ◦ an acute coronary syndrome with chest pain manifested as unstable angina ◦ increased troponin levels ◦ occur during anaphylaxis ◦ caused by inflammatory mediators of mast cells and other immune cells ◦ symptoms reverse without sequelae within a few hours of initial anaphylactic symptoms. ◦ Rarely, coronary damage can occur in severe episodes. Mariana Castell. J Allergy Clin Immunol 2017
  43. 43. Anaphylaxis and the heart Apical ballooning syndrome or Takotsubo syndrome ◦ Stress miocardiopathy during anaphylaxis ◦ Associated with intravenous epinephrine administration in middle- aged women. ◦ This can lead to fatal cardiac arrhythmias with cardiac failure. Mariana Castell. J Allergy Clin Immunol 2017
  44. 44. ◦ Thank you 15/01/64

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