Cita Rosita Sigit Prakoeswa

Medical Faculty Airlangga University

Dr Soetomo Teaching General Hospital
Surabaya
 Etiology of urticaria

Etiology of angioedema

Pathogenesis urticaria & angioedema

 • Vascular reaction of the skin
– Wheals
– Erythematous
– Severe pruritus.
• Eruption
– Rarely >2 days
– May be recurrent.
• Chronic
– Recurrent episodes
– > 6 weeks.
• Cause of acute urticaria
– frequently established (eg, acute infection,
allergen ingestion).
• Children with chronic urticaria
– + 50-80% of have angioedema.
ZuberbierT, AbererW, AseroR, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management
of urticaria. The 2013 revision and update. Allergy2014;69:868–87
 • Subcutaneous extension of
urticaria

• Deep swelling within subcutaneous

sites.

• Can occur with generalized

urticaria

• Urticaria extends to the face,

hands, feet, and genitalia the
clinical manifestation may be called
angioedema(+ 50% of children)
ZuberbierT, AbererW, AseroR, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management
of urticaria. The 2013 revision and update. Allergy2014;69:868–87
 New
0 13
2

Spontaneous Chronic spontaneous Inducible

urticaria (CSU) urticaria
appearance
of wheals, Known causes of CSU: Physical urticarias
angioedema 45% autoimmunity • Symptomatic
dermographism
or both ≥6 weeks • Cold urticaria
Others:
due to known Chronic infection (viral, • Delayed pressure urticaria
• Solar urticaria
or unknown bacterial, parasitic)
• Heat urticaria
Chronic, non-infectious,
causes. inflammatory processes • Vibratory angioedema
(gastritis, lupus and certain
cancers) & food components. Cholinergic urticaria
Contact urticaria
Aquagenic urticaria
1. ZuberbierT, AbererW, AseroR, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of
urticaria. The 2013 revision and update. ALLERGY 2014
2. Kaplan AP.Therapyof chronic urticaria: a simple, modern approach Annals of Allergy, Asthma & Immunology.2014;112(5):419–425
3. Powell RJ, et al. ClinExperAllergy 2007;37:631−50;
4. KozelMA, SabroeRA. Drugs 2004;64:2525−36
 Key symptoms
of urticaria

Hives Pathogenesis
Itch
The etiopathogenesis urticaria
Reflex is thought to be mediated by
erythema aberrant release of histamine
and other inflammatory
Angioedema mediators from mast cells and
basophils

1.ZuberbierT, et al. Allergy2009;64:1417–26

2.Schocket AL. AllergyAsthma Proc. 2006; 27:90–95.
 Food : suspect 65% (+) 1 / 109
baby < 6 months: cow milk: 10 / 12
children 6 mo-16 yo: 15%
adult (-)
 Drug : Ig E mediated (penicillin)
Pseudoallergic (acetyl salycilic acid)
 Infection: viral upper respiratory infection 28-62%

Zuberbier T. Acute urticaria. In: Zuberbier T, Grattan C, Maurer M, editors.

Urticaria and angioedema. Heidelberg: Springer; 2010. p. 37-44.
Maurer M. Chronic urticaria. In: Zuberbier T, Grattan C, Maurer M, editors.
Urticaria and angioedema. Heidelberg: Springer; 2010. p. 45-56.
Grattan CEH. Aetiopeathogenesis of urticarial. In: Zuberbier T, Grattan C, Maurer
M, editors. Urticaria and angioedema. Heidelberg: Springer; 2010. p. 9-24.
1- Mast cell stimulation
2- Infiltration of varying types of
inflammatory cells
3- Release of mediators
4- Stimulation of local sensory nerves

Grattan CEH. Aetiopeathogenesis of urticarial. In: Zuberbier T, Grattan C, Maurer M,

editors. Urticaria and angioedema. Heidelberg: Springer; 2010. p. 9-24.
Pathophysiology of Angioedema
• Chemical mediators producing
endothelial contraction include:
histamine, leukotrienes, bradykinin,
platelet activating factor, and the C3a
and C5a components from complement
activation.

• Mediators of this process over a longer

term include tumor necrosis factor and
interleukin-1.

• Chemical mediators that promote

vasodilation include: histamine,
prostaglandins, and nitric oxide.
Etiological cause of angioedema
• Hereditary Angioedema (HE)
• Autosomal dominant
• Risk factors include trauma (surgery,
dental manipulation, accidents)
• Result of unopposed complement
activation + kinin generation system
activation due to C1INH deficiency
• In HE3, fluctuation of sex hormone
precipitate attacks
• Acquired form Angioedema (AA)
• Commonly associated with
lymphoproliferative disorder or
malignancy
• Uncommon in pediatric patient
 Mast cell activation in CSU may either be via
autoimmune, allergic or idiopathic mechanisms

1. Greaves M. J Allergy ClinImmunol2000;105:664−72;

2. Kaplan AP, Greaves M. ClinExpAllergy 2009;39:777–87;
3. Metz M, Maurer M. CurrOpinAllergy ClinImmunol2012;12:406–11.
• Two types of mast cell:
1. skin & intestinal submucosa: secrete tryptase,
chymase, carboxypeptidase and protease
2. intestinal mucosa & lung: secrete tryptase
• Mast cells could be stimulated by:
1. Exogenous factors e.g.antigen & opiates.
2. Endogenous agents as cytokines, histamine
releasing factors, neuropeptides and
autoantibodies
Immune-mediated urticaria can be caused by 3
of 4 types of immune mechanisms:
1. Type I allergic IgE response: initiated by antigen-
mediated IgE immune complexes that bind and
cross-link Fc epsilon RI receptors on the surface
of mast cells and basophils
2. Type II responses:mediated by cytotoxic T cells,
activates by products that cause urticarial
vasculitis or bullous pemphigoid
3. Type III immune-complex: associated with SLE
and other connective tissue disorders that
activate urticaria
Mast cells can also degranulate by other non-
immunological stimuli:
– Certain drugs: opiates, polymyxin B & radio contrast
media can cause direct release of histamine by
altering the membrane properties.
– Other drugs: salicylates & NSAIDs block the
prostaglandin pathway from arachidonic acid
through its action on the COX pathway with
accumulation of leukotriens
– Food additives: tartrazine, azodyes, benzoates &
sulphites can provoke urticaria through asimilar
mechanism
Grattan CEH. Aetiopeathogenesis of urticarial. In: Zuberbier T, Grattan C, Maurer
M, editors. Urticaria and angioedema. Heidelberg: Springer; 2010. p. 9-24.
2. Infiltration of varying types of inflammatory cells

1. Elias J, et al. J Allergy ClinImmunol1986;78:914–8;

2. NatbonyS, et al. J Allergy ClinImmunol1983;71:177–83;
3. SabroeRA, et al. J Allergy ClinImmunol1999;103:484–93;
4. Ying S, et al. J Allergy ClinImmunol2002;109:694–700;
5. ZuberbierT, et al. Allergy 2009;64:1417–26;
6. Ito Y et al. Allergy 2011;66:1107–13; 7. Schocket AL. AllergyAsthma Proc. 2006; 27:90–95.
• PMN & monocytes secrete histamine releasing factors
that activate human skin and lung mast cell
• B cells produce histamine release inhibitory factor that
block histamine release
• Different stimuli: immunological stimuli and
neuropeptides causes similar amounts of histamine
release but roughly 20 fold more than PGD2 and LTC4
 different stimuli may activate different mast cell
biochemical pathway and accordingly may explain the
varied clinical manifestation of urticaria and
angioedema
• >>>> chronic recurrent urticaria: mononuclear cell
infiltrate (others manifests PMNs)
• >> PMNs rich infiltrate have autoantibodies that bind
to mast cell FceRl receptors & surface bound IgE
(immunologic or non immunologic) ~ type of
infiltrate
• Mast cells in different sites "skin-lung and intestine“
may differ in the irreaction and stimulation to the
same stimulator
Degranulation of mast cells & basophils causes there lease of:
1) Preformed granule-associated substances, e.g.histamine,
tryptase, chymase, carboxypeptidase, and cytokine.
Histamine effects account for many of the clinical and
histologic findings of urticaria. Histamine acts on 4
receptors HI, H2, H3 and H4.

2) Newly-generated mediators e.g. PGD2, leukotriene (LT) B4,

LTC4, LTD4, LTE4, neutrophils and eosinophils chemotactic
factors and platelet activating factor
• Mast cells in close apposition to the peripheral nerve fibers in
the upper dermis & invade nerve bundles in the lower dermis
leading to intimate mast cells & unmyelinated dermal nerves or
Schwann cells
• The degranulation of mast cells in peripheral nerve bundles and
edema of the nerve bundle provoking / aggravating itching
• The role of neuro peptides in the pathogenesis of urticaria:
capsaicin pre-treatment of the skin block hives formation in
patients with cold and heat induced urticaria
• Histamine released from mast cells stimulate nerves to produce
neuro peptides and it appears that nerves can stimulate mast
cells indicating a bi directional communication

Mast cell nerves

 Mast cells are the key effector cells of acute & chronic urticaria
Mediator pathway: similar;initiating cause : different

Activation
IgE Fc RI IL-1, IL-2,
IL-3, IL-4,
PRURITUS
SCF Kit

C
IgG Fc R IL-5, IL-6,
LPS TLRs IL-8, IL-10,
Complement CR1/2, CR3 IL-13, TNF,
MIPs, IFN-,

A
Anaphylatoxins C3aR, C5aR
Neuropeptides NK1 GM-CSF, Vasodilation ERYTHEMA
Endothelin-1 ETA /ETB TGF-,
Bacteria CD48 bFGF,

U Interleukins
Chemokines
Oxytocine
IL-3,4,15R
CCR3
OTRs
MC VPF/VEGF,
PGD2, LTB4,
LTC4, PAF, Extravasation
S Leukotriene
POMCs
Prostaglandins
CysLT1R
MC-1/MC5
EP1/EP3
histamine,
serotonine,
heparin,
WHEAL

E
Cannabinoids CB1/CB2
chondroitin-
Adenosine A2b/A3
sulfate,
Urokinase uPAR
chymase,
Capsaicin VR
? PIRA/PIRB tryptase, CPA Recruitment INFILTRATE

Urticaria & Angioedema. Zuberbier T, Gattan C , Maurer S. Springer2010

Grattan CEH. Aetiopeathogenesis of urticarial. In: Zuberbier T, Grattan C, Maurer M,
editors. Urticaria and angioedema. Heidelberg: Springer; 2010. p. 9-24.
1
2
 Pathophysiology of Angioedema
1
Pathophysiology of Angioedema
2
The complement cascade after activation by pathogens. Tthe complement cascade is usually activated by antibody complexes
(classical pathway) or high-density mannose (lectin pathway) on the surface of pathogens. This activation leads opsonization and
phagocytosis, as well as lysis as a result of the formation of the membrane attack complex (MAC). These combined actions of
complement lead to the elimination of pathogenic cells (Ricklin and Lambris 2007)
Grattan CEH. Aetiopeathogenesis of urticarial. In: Zuberbier T, Grattan C, Maurer M,
editors. Urticaria and angioedema. Heidelberg: Springer; 2010. p. 9-24.
Grattan CEH. Aetiopeathogenesis of urticarial. In: Zuberbier T, Grattan C, Maurer
M, editors. Urticaria and angioedema. Heidelberg: Springer; 2010. p. 9-24.
• Urticaria & Angioedema: diverse clinical presentations &
etiologies
• Functional autoantibodies: 45% CSU patients
• The cutaneous mast cell: primary effector cell
• Histamine: the most important performed mediator
• Leukotrienes: pseudoallergic reactions
• Bradykinin: angioedema (C1est deficiency & ACE inhibitor tx)
• Mast cell degranulation immunological stimuli (the high FcεRI)
& non-immunological stimuli (opiates)
• Activation of FcεRI: Type I hypersensitivity or IgE autoantibodies
• The role for inflammatory cells needs further investigation