Anaphylaxis beyond IgE

Anaphylaxis
Beyond IgE
Thitima Kantachatvanich, M.D.
Division of Allergy and Clinical Immunology
Faculty Medicine, Chulalongkorn University

Anaphylaxis
• A serious, generalized or systemic, allergic or
hypersensitivity reaction that can be life-
threatening or fatal.
Simons et al. International Consensus on Anaphylaxis,WAO Journal 2014

Anaphylactic Phenotypes
• Type I like hypersensitivity
– Mast cell/Basophil degranulation
– IgE/non IgE/direct activation/MRGPRX2
receptor/complement mediated
• Cytokine storm reaction
– TNF-α, IL-1β, and IL-6 from monocytes, macrophages,
mast cells, and other immune cells with FcγR
– Atypical symptoms : fever, chill, malaise, hypotension
– mAbs, oxaliplatin
– Premedication with COX1 inhibitor , steroid
• Mixed reaction
J ALLERGY CLIN IMMUNOL 2017 :The pathophysiology of anaphylaxis

Anaphylaxis Pathways
• IgE dependent
– Ag crosslinking of Ag specific IgE that has bound to
the high-affinity IgE receptor (FcεRI) on mast cells
and basophils.
• Preformed mediators : histamine, various proteases
• De novo mediators : LTs, PG, cytokines
– FcεRI is on mast cell, basophil, neutrophil,
eosinophil, monocyte, dendritic cell, platelet

Anaphylaxis Pathways
• Others
– IgG dependent
– Complement activation
– Antibody and complement independent : direct
mast cell activation, MRGPRX2 receptor
– Cytokine release from effector cells
– Contact system activation

Non-IgE dependent Anaphylaxis
• ↑Use of chemotherapies and targeted
therapies, including mAbs
↑Drug hypersensitivity and anaphylaxis
dramatically worldwide
Undetectable levels of antidrug IgE

• Mouse model
– Anaphylaxis can occur in the absence of the
classical IgE/FcεRI/mast cell pathway
(but not in mice that lacked all stimulatory FcRs (ie,
FcRγ deficient mice)
– Anaphylaxis can occur even if mice were first
treated with an anti-IgE mAb but was suppressed
with rat IgGmAb
J ALLERGY CLIN IMMUNOL 2016 : Human IgE-independent systemic anaphylaxis

• Human clinical observations
– Anaphylaxis in patients treated with a biologic
therapeutic and had IgG but not detectable IgE
– Anaphylaxis in IgA-deficient subjects (had IgG anti-
IgA Ab after IVIG infusion

IgG dependent Anaphylaxis
• FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB
on effector cells*
– FcγRIIB : inhibitory signal
• IgG or immune complex on Fc receptor on
effector cell
• IgG : depending on Ab and Ag concentrations
– Activate anaphylaxis
– blocker of IgE-mediated anaphylaxis
J Investig Allergol Clin Immunol 2016 : Mechanisms of Anaphylaxis Beyond IgE

• Mouse model
– Allergen vs FcγRIII on macrophages and basophils
 release platelet-activating factor (PAF), rather
than histamine

• Mouse model
– IgG2 vs FcγRIV on neutrophil : major role of IgG
mediated anaphylaxis
– Neutrophil : PAF producers
– The most important mediator : PAF
• PAF is not exclusively observed in IgG-mediated
anaphylaxis, also in IgE-mediated
• PAF : mast cell, basophil, neutrophil

PAF : Platelet Activating Factor
• In most models combined inhibition of
histamine and PAF almost entirely blocked
anaphylaxis,
– suggesting additive or synergistic effects of
histamine and PAF
• The main cellular source of PAF : likely
depends on the exact model used
– PAF receptor antagonist CV-6209 can reduce
anaphylaxis in wild-type mice but has no effect in
monocyte/macrophage-depleted mice

• Severe reaction
– Circulating PAF levels are increased
– PAF acetylhydrolase (PAF-AH) activity is decreased
N ENGL J MED 358;1 www.nejm.org january 3, 2008

Neutrophil : Another Effector Cell
• FcγRs, FcεRI
• Major enzyme stored in neutrophils
: myeloperoxidase (MPO)
• ↓Expression of the activating FcγRIII and
FcγRIV on mouse neutrophils after IgG-
• ↑Circulating MPO levels in patients with
anaphylaxis compared with healthy

Neutrophils in local and systemic antibody-dependent inflammatory and anaphylactic reactions ,JLB 2013

Mouse model
• This IgG2b-PSA can be abrogated following the
depletion of neutrophils
• The deletion of monocytes/macrophages had
no effect on severity in this model
– suggest that neutrophils are activated directly by
immune complex forming in circulation
Neutrophils in local and systemic antibody-dependent inflammatory and anaphylactic reactions ,JLB 2013

• LTP-dependent anaphylaxis
– ↑markers of neutrophil activation and trafficking
– ↑levels of reactive oxygen species/reactive
nitrogen species
– Via IgE, IgG, or both
– Activate mast cells and basophils, but also
neutrophils

LTP : Lipid Transfer Protein
Int Arch Allergy Immunol 2000 :Lipid Transfer Protein: A Pan-Allergen
in Plant-Derived Foods That Is Highly Resistant to Pepsin Digestion

Platelet : Another Effector Cell
• Anaphylaxis in human subjects is associated
with platelet activation
• Activated platelet releases platelet facter 4,
serotonin
• Platelet :High affinity FcεRI, Low affinity FcεRII, FcγRIIA
J Investig Allergol Clin Immunol 2006 : Platelet function in anaphylaxis

IgE vs IgG mediated Anaphylaxis
• 100- to 1000 fold less TNP-conjugated protein
was required to induce shock in IgE- than in
IgG-sensitized mice
– Higher affinity of FcεRI than FcgRIII
– Higher ratio of cell-bound to serum IgE than IgG
– Better crosslinking of an antigen-specific mAb by
an antigen

IgE vs IgG mediated Anaphylaxis
• IgG blocks IgE-dependent anaphylaxis when
exposed to low doses of allergen
– IgG intercepts Ag before cross-linking mast
cells/basophil–associated IgE
– Activates FcγRIIB
– Low doses of IgG are insufficient to induce IgG-
 FcγRs : lower affinity than FcεRI (high-affinity IgE
receptor)

Parenteral administration of a large quantity of an antigen

IgG4 mediated Anaphylaxis
• 20-year-old female with allergic rhinitis
• Generalized urticaria and dyspnea with
wheezing, and hoarseness within 1 hour after
first oral ingestion of ofloxacin 100 mg
• History of acute, generalized urticaria and
drug allergy to NSAIDs
• FH : her mother had asthma
Korean J Crit Care Med 2017 August 32(3):302-305

• Total IgE level was 42 kU/L
• Allergy skin prick tests
– Positive to Dermatophagoides farinae and D.
pteronyssinus
– Negative to ofloxacin at concentrations of 0.1−10
mg/ml
– Positive control : wheal size of 4 mm to histamine

This case
High serum specific IgG4
Undetectable serum specific IgE antibody
Previous study
reported IgE-mediated
mechanism detected by
serum specific IgE 30-80%

BAT result

Allergy Asthma Immunol Res. 2015 May : Immunologic Evaluation of Patients
with Cefotetan-Induced Anaphylaxis

Case 1
• 70-year-old asthmatic woman
• Anaphylactic shock(wheezing, urticaria,
hypotension) after infusing cefotetan a few
minutes
• Positive IDT to cefotetan 10mg/ml
• High serum-specific IgE to cefotetan-human
serum albumin conjugate
Allergy Asthma Immunol Res. 2015 May : Immunologic Evaluation of Patients
with Cefotetan-Induced Anaphylaxis

Case 2
• 63-year-old reactive airway dysfunction
syndrome, due to 2,2-dichlorovinyl dimethyl
phosphate 11 years ago
• Anaphylactic shock (dyspnea, hypotension and
loss of consciousness)
• High serum-specific IgG1, IgG4 with no serum
specific IgE

Complement mediated
• C3a, C4a, C5a : anaphylatoxins
• Allergen or immune complex  activate
complement cascade
• Activate mast cell, basophil,
monocyte/macrophage, other myeloid cell,
vascular endothelial cell

Blood level of anaphylatoxin
correlated with
the severity of anaphylaxis
J Allergy Clin Immunol 2013 : Anaphylaxis: Clinical patterns, mediator
release, and severity

Complement mediated
• Mouse model
– Injected soluble peanut extract  components of
activated complement through both the classical and
the lectin pathways

Complement mediated
• Synergize other pathways with anaphylatoxin
effects
– Synergistic effect with FcγRI activation, mast cell
activation or activation
– Peanut activation of complement may synergize with
the IgE  severe reactions
• Insufficient to independently induce murine
systemic anaphylaxis
– No anaphylaxis after relevant antigen challenge
with antigen-specific mouse IgG3(able to activates
complement but not bind to FcgRs)

Complement Activation vs
Intrinsic Characteristics of the Allergen
• Milk and egg white  little ability to activate
complement in human plasma
• Peanut activation of complement may synergize with
the IgE  severe reactions
• Activation of complement (without immune
complex formation) : drugs solubilized in
liposomes and lipid based excipients
– New dialysis membrane
– Protamine neutralization of heparin

Liposomes and Lipid Based Excipients
• hydrophilic blocks (continuous adhesive layer
on the surface of the oil phase) : bind plasma
proteins and activate complement
Complement Activation by Cremophor EL as a Possible Contributor to Hypersensitivity to
Paclitaxel: an In Vitro Study , Journal of the National Cancer Institute, 1998

Complement activation-related pseudoallergy: a stress reaction in
blood triggered by nanomedicines andbiologicals. Mol Immunol 2014

MRGPRX2 receptor mediated
• ↑level or function of MRGPRX2 receptor
during anaphylaxis from some medication
• THIQ motifs(tetrahydroisoquinoline )
– General anesthetics atracuronium and rocuronium
– Quinolones ;ciprofloxacin, levofloxacin
– Icatibant
• Activate mast cells without IgE,
• Not been confirmed in human subjects
J Allergy Clin Immunol 2017 : Diagnosis and management of anaphylaxis in precision medicine

Drugs Containing a THIQ
Nature. 2015 : Identification of a mast cell specific receptor crucial for pseudo-allergic drug reactions

MRGPRX2 receptor mediated

IgE-mediated inflammation
does not differ between
wild type and MrgprB2MUT
mice

no significant difference between
WT and MrgprB2MUT cells was
found at any dose of anti-IgE Ab
WT (red diamonds) and
MrgprB2MUT (black squares)

n engl j med 355;10 www.nejm.org september 7, 2006

Cytokine storm reaction
• Chimeric, humanized, and human mAbs and
chemotherapy, including oxaliplatin
• mAb vs Fc receptors on T cells, monocytes,
macrophages, mast cells, and other immune
cells with FcgR.
• Proinflammatory mediators e.g.TNF-a, IL-1B,
and IL-6,

Contact System Activation
• Depletion of high-molecular-weight kininogen,
factor V, VIII observed in patients with
anaphylaxis
• Bradykinin induce hypotension via Bradykinin
receptor type 2
• In extreme cases experience disseminated
intravascular coagulation
• Direct or indirect activation of the intrinsic blood
coagulation pathway in IgE-mediated reactions

Chemotherapy & Targeted Therapy
• Engineered Chimeric mAb different
glycosylation patterns  allergenic
determinants
• Even with fully human mAbs, such as
adalimumab and ofatumumab, anaphylaxis
has been reported

Chemotherapy & Targeted Therapy
• Type I like reactions
– Platins : IgE-mediated mechanism
– Taxanes : IgE- and non–IgE-mediated mechanisms
• Cytokine storm–like reactions
– Rituximab
– anti-CD28 mAb (TGN1412)

Food Induced Anaphylaxis
• Not always IgE mediated
• Lipid transfer proteins (LTP) anaphylactic
patient  ↑anti-LTP IgE, IgG1, IgG3 and ↑3
genes coding for FcγRI (CD64) expression
– IgG1, IgG3 vs FcγRI on macrophage, mast cell,
neutrophil
• Galactose-alpha-1,3-alphagalactose (α-gal)
: specific IgE and IgG anti–α-gal(IgG1)

Genetic Diversity in Anaphylaxis
• PAF-AH activity levels inversely correlated with
severity of anaphylaxis
• Variants in angiotensinogen (ie, the MM genotype
associated with ↓angiotensinogen) : ↑rates of
Hymenoptera venom allergy and more reactions during
venom immunotherapy
• Activating mutation in c-KIT D816V
– Clonal mast cell disorder
– Recurrent anaphylaxis (not meet the criteria for
mastocytosis)
• BRCA1 and BRCA2 mutations in ovarian cancer female
carboplatin allergy occurs early and with fewer exposures

Clinical Implication & Application
• Skin test use : Type I phenotype, mixed reaction
• Skin test of mAb : variation, unknown NPV
• Level of proinflammatory cytokines (unknown
sensitivity, specificity) : insight into phenotype and
mechanism, desensitization and premedication
usefulness
• Biomarkers beyond tryptase
• Level and function of MRGPRX2 receptor : THIQ motifs
medication allergy
• Ketotifen in THIQ motifs medication allergy
• Selective Bradykinin B2 Receptor Antagonists in
anaphylaxis treatment

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