Immunologic mechanisms of anaphylaxis

Immunologic
mechanisms of
Anaphylaxis
Natthiya Pholmoo, M.D.

DEFINITION
Cardona et al. World Allergy Organization Journal (2020) 13:100472

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

Classical clinical manifestations
◦ Flushing
◦ Pruritus
◦ Hives, Angioedema
◦ Shortness of breath, Wheezing
◦ Nausea, Vomiting, Diarrhea
◦ Hypotension
◦ Oxygen desaturation
◦ Cardiovascular collapse

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.

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.

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.

Clinical criteria for diagnosis
EAACI anaphylaxis guidelines 2014

Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations,
Assessment, Development and Evaluation (GRADE) analysis

Cardona et al. World Allergy Organization Journal (2020) 13:100472

Risk of severe anaphylaxis
Denise Anne Moneret-Vautrin. Pathophysiology : IgE-mediated & non-IgE-mediated anaphylaxis 2014

15/01/64Cardona et al. World Allergy Organization Journal (2020) 13:100472

PATHOGENESIS OF ANAPHYLAXIS
◦ Immunologic mechanisms
◦ IgE-dependent anaphylaxis
◦ IgE-independent anaphylaxis
◦ IgG-mediated reactions
◦ Complement Activation
◦ Non-Immunologic mechanism : Direct mast cell activation
◦ Idiopathic

15/01/64
FINKELMAN, KHODOUN, AND STRAIT. J ALLERGY CLIN IMMUNOL 2016.

POTENTIAL EFFECTOR CELLS
◦ Mast cells
◦ Basophils
◦ Monocytes/macrophages
◦ Neutrophils
◦ Platelets
◦ PAF

IgE-
dependent
anaphylaxis
http://sciencemission.com

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

◦ 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.

◦ 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

◦ 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.

IgE-
in dependent
anaphylaxis

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.

◦ 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.

◦ 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).

◦ 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.

◦ 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.

◦ 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.
Vadas et al N Engl J Med. 2008
https://www.scielo.br

◦ 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).

◦ 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.

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.

◦ 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

◦ 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

◦ 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.

◦ 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.

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.

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.

◦ 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

Mediators

Denise Anne Moneret-Vautrin. Pathophysiology : IgE-mediated & non-IgE-mediated anaphylaxis 2014

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.

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.

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.

Immunologic mechanisms of anaphylaxis

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