Hereditary angioedema

read clinical case 31 and and answer the two following questions. 

179

Complement is a system of plasma proteins that participates in a cascade of reac-
tions, generating active components that allow pathogens and immune complexes
to be destroyed and eliminated from the body. Complement is part of the innate
immune defenses of the body and is also activated via the antibodies produced in
an adaptive immune response. Complement activation is generally confined to the
surface of pathogens or circulating complexes of antibody bound to antigen.

Complement is normally activated by one of three routes: the classical pathway,
which is triggered by antigen:antibody complexes or antibody bound to the surface
of a pathogen; the lectin pathway, which is activated by mannose-binding lectin
(MBL) and the ficolins; and the alternative pathway, in which complement is acti-
vated spontaneously on the surface of some bacteria. The early part of each pathway
is a series of proteolytic cleavage events leading to the generation of a convertase,
a serine protease that cleaves complement component C3 and thereby initiates the
effector actions of complement. The C3 convertases generated by the three path-
ways are different, but evolutionarily homologous, enzymes. Complement compo-
nents and activation pathways, and the main effector actions of complement, are
summarized in Fig. 31.1.

The principal effector molecule, and a focal point of activation for the system, is
C3b, the large cleavage fragment of C3. If active C3b, or the homologous but less
potent C4b, accidentally becomes bound to a host cell surface instead of a patho-
gen, the cell can be destroyed. This is usually prevented by the rapid hydrolysis of

Case 31
Hereditary angioedema

Regulation of complement activation.

This case was prepared by Raif Geha, MD, in collaboration with Arturo Borzutzky, MD, and
Andrew Maginnitie, MD.

topics bearing
on tHis case:

Classical pathway
of complement
activation

Inhibition of C1
activation

Alternative pathway
of complement
activation

Inflammatory effects
of complement
activation

Regulation of C4b

case31.indd 179 23/12/2015 14:47

180 Case 31: Hereditary Angioedema

active C3b and C4b if they do not bind immediately to the surface where they were
generated. Protection against inappropriate activation of complement is also pro-
vided by regulatory proteins.

One of these, and the most potent inhibitor of the classical pathway, is the C1
inhibitor (C1INH). This belongs to a family of serine protease inhibitors (called
serpins) that together constitute 20% of all plasma proteins. In addition to being
the sole known inhibitor of C1, C1INH contributes to the regulation of serine pro-
teases of the clotting system and of the kinin system, which is activated by injury to
blood vessels and by some bacterial toxins. The main product of the kinin system is
bradykinin, which causes vasodilation and increased capillary permeability.

C1INH intervenes in the first step of the complement pathway, when C1 binds
to immunoglobulin molecules on the surface of a pathogen or antigen:antibody
complex (Fig. 31.2). Binding of two or more of the six tulip-like heads of the C1q
component of C1 is required to trigger the sequential activation of the two asso-
ciated serine proteases, C1r and C1s. C1INH inhibits both of these proteases, by
presenting them with a so-called bait-site, in the form of an arginine bond that they
cleave. When C1r and C1s attack the bait-site they covalently bind C1INH and dis-
sociate from C1q. By this mechanism, the C1 inhibitor limits the time during which
antibody-bound C1 can cleave C4 and C2 to generate C4b2a, the classical pathway
C3 convertase.

Activation of C1 also occurs spontaneously at low levels without binding to an
antigen:antibody complex, and can be triggered further by plasmin, a protease of
the clotting system, which is also normally inhibited by C1INH. In the absence of
C1INH, active components of complement and bradykinin are produced. This is
seen in hereditary angioedema (HAE), a disease caused by a genetic deficiency of
C1INH.

Case Studies in Immunology | Raif Geha
ISBN: 978-0-8153-4512-1 | 7th edition
Hereditary Angioedema | CS-31.01 | Figure 31-1
© Garland Science design by blink studio limited

Removal of
immune complexes

Binds to complement
receptors on phagocytes

Opsonization
of pathogens

Peptide mediators
of in�ammation,

phagocyte recruitment

Membrane-attack
complex,

lysis of certain
pathogens and cells

Terminal
complement components

C5b
C6
C7
C8
C9

C3a, C5a C3b

C3 convertase

CLASSICAL PATHWAY ALTERNATIVE PATHWAY

C3
B
D

C1q, C1r,

C1s

C4
C2

Antigen:antibody complexes
(pathogen surfaces) Pathogen surfaces

LECTIN PATHWAY

Mannose-binding lectin or
�colin binds carbohydrate

on pathogen surfaces

MBL/�colin, MASP-2
C4
C2

Fig. 31.1 Overview of the main
components and effector actions of
complement. The early events of all
three pathways of complement activation
involve a series of cleavage reactions
that culminate in the formation of an
enzymatic activity called a C3 convertase,
which cleaves complement component
C3 into C3b and C3a. The production of
the C3 convertase is the point at which
the three pathways converge and the
main effector functions of complement are
generated. C3b binds covalently to the
bacterial cell membrane and opsonizes
the bacteria, enabling phagocytes
to internalize them. C3a is a peptide
mediator of local inflammation. C5a
and C5b are generated by the cleavage
of C5b by a C5 convertase formed by
C3b bound to the C3 convertase (not
shown in this simplified diagram). C5a
is also a powerful peptide mediator of
inflammation. C5b triggers the late events
in which the terminal components of
complement assemble into a membrane-
attack complex that can damage the
membrane of certain pathogens. Although
the classical complement activation
pathway was first discovered as an
antibody-triggered pathway, it is now
known that C1q can activate this pathway
by binding directly to pathogen surfaces,
as well as paralleling the lectin activation
pathway by binding to antibody that is
itself bound to the pathogen surface.
In the lectin pathway, MASP stands
for mannose-binding lectin-associated
serine protease.

case31.indd 180 23/12/2015 14:47

Case 31: Hereditary Angioedema 181

The case of Richard Crafton: a failure of
communication as well as of complement
regulation.

Richard Crafton was a 17-year-old high-school senior when he had an attack of
severe abdominal pain at the end of a school day. The pain came as frequent sharp
spasms and he began to vomit. After 3 hours, the pain became unbearable and he
went to the emergency room at the local hospital.

At the hospital, the intern who examined him found no abnormalities other than
dry mucous membranes of the mouth, and a tender abdomen. There was no point
tenderness to indicate appendicitis. Richard continued to vomit every 5 minutes and
said the pain was getting worse.

Case Studies in Immunology | Raif Geha
ISBN: 978-0-8153-4512-1 | 7th edition
Hereditary Angioedema | CS-31.02 | Figure 31-2
© Garland Science design by blink studio limited

C1INH dissociates C1r and C1s from the active C1 complex

Binding of C1q to Ig activates C1r, which cleaves
and activates the serine protease C1s

C1q binds to at least two IgG molecules
on bacterial surface

C1q binds to IgM on bacterial surface

C1s

C1r

C1INH

C1s

C1r

C1INH

Fig. 31.2 activation of the classical pathway of complement and intervention by
C1INH. In the left panel, one molecule of IgM, bent into the ‘staple’ conformation by
binding several identical epitopes on a pathogen surface, allows binding by the globular
heads of C1q to its Fc pieces on the surface of the pathogen. In the right panel, multiple
molecules of IgG bound to the surface of the pathogen allow binding by C1q to two
or more Fc pieces. In both cases, binding of C1q activates the associated C1r, which
becomes an active enzyme that cleaves the proenzyme C1s, a serine protease that
initiates the classical complement cascade. Active C1 is inactivated by C1INH, which
binds covalently to C1r and C1s, causing them to dissociate from the complex. There
are in fact two C1r and two C1s molecules bound to each C1q molecule, although for
simplicity this is not shown here. It takes four molecules of C1INH to inactivate all the
C1r and C1s molecules.

Richard, age 17, presents as an

acute abdominal emergency.

case31.indd 181 23/12/2015 14:47

182 Case 31: Hereditary Angioedema

A surgeon was summoned. He agreed with the intern that Richard had an acute
abdominal condition but was uncertain of the diagnosis. Blood tests showed an
elevated red blood cell count, indicating dehydration. An ultrasound examination of
the abdomen was inconclusive. The surgeon decided to proceed with a laparoscopic
appendectomy. Intestinal edema was noted, but no other cause for his pain was
seen. The surgeon removed Richard’s appendix, which was normal, and Richard
recovered and returned to school 5 days later.

What Richard had not mentioned to the intern or to the surgeon was that, although
he had never had such severe pains as those he was experiencing when he went to
the emergency room, he had had episodes of abdominal pain since he was 14 years
old. No one in the emergency room asked him if he was taking any medication,
or took a family history or a history of prior illness. If they had, they would have
learned that Richard’s mother, his maternal grandmother, and a maternal uncle,
also had recurrent episodes of severe abdominal pain, as did his only sibling, a
19-year-old sister.

As a newborn, Richard was prone to severe colic. When he was 4 years old, a bump
on his head led to abnormal swelling. When he was 7, a blow with a baseball bat
caused his entire left forearm to swell to twice its normal size. In both cases, the
swelling was not painful, nor was it red or itchy, and it disappeared after 2 days. At
age 14 years, he began to complain of abdominal pain every few months, sometimes
accompanied by vomiting and, more rarely, by clear, watery diarrhea.

Richard’s mother had taken him at age 4 years to an immunologist, who listened to
the family history and immediately suspected hereditary angioedema. The diagno-
sis was confirmed on measuring key complement components. C1INH levels were
16% of the normal mean and C4 levels were markedly decreased, while C3 levels
were normal.

When Richard returned for a routine visit to his immunologist a few weeks after his
surgical misadventure, the immunologist, noticing Richard’s abdominal scar, asked
what had happened. When Richard explained, he prescribed purified C1INH to be
infused intravenously for acute attacks. Richard has utilized C1INH on several occa-
sions and is considering changing to one of the other recently approved products for
treatment of HAE attacks. He is also aware that C1INH can be given prophylactically
to prevent attacks either before surgical and dental procedures or routinely.

Richard subsequently married and had two children. The C1INH level was found to
be normal in both children.

Hereditary angioedema.

Individuals like Richard with a hereditary deficiency of C1INH are subject to recur-
rent episodes of circumscribed swelling of the skin (Fig. 31.3), intestine, and airway.
Attacks of subcutaneous or mucosal swelling most commonly affect the extremi-
ties, but can also involve the face, trunk, genitals, lips, tongue, or larynx. Cutaneous
attacks cause temporary disfigurement but are not dangerous. When the swell-
ing occurs in the intestine it causes severe abdominal pain, and may obstruct the
intestine causing vomiting. When the colon is affected, watery diarrhea may occur.
Laryngeal swelling is most dangerous as it can lead to asphyxiation. HAE attacks
do not usually involve itching or hives, which is useful to differentiate this disease
from allergic angioedema. However, a serpiginous, or linear and wavy, rash (called
erythema marginatum) is sometimes seen before the onset of swelling symptoms.
HAE attacks may be triggered by trauma, menstrual periods, excessive exercise,
exposure to extremes of temperature, mental stress, and some medications such as
angiotensin-converting enzyme inhibitors and oral contraceptives.

Appendectomy performed.

Appendix appears normal.

Family history of colic.

Case Studies in Immunology | Raif Geha
ISBN: 978-0-8153-4512-1 | 7th edition
Hereditary Angioedema | CS-31.03 | Figure 31-3
© Garland Science design by blink studio limited

Fig. 31.3 Hereditary angioedema.
Transient localized swelling that occurs in
this condition often affects the face.

case31.indd 182 23/12/2015 14:47

Case 31: Hereditary Angioedema 183

HAE is not an allergic disease, and attacks are not mediated by histamine. Rather,
generation of bradykinin by the enzyme kallikrein leads to HAE symptoms. As seen
in Figure 31.4, activated Factor XII generates active kallikrein from its precursor.
Kallikrein, which circulates bound to high-molecular-weight kininogen (HMWK)
then cleaves bradykinin from HMWK. Bradykinin is the main mediator respon-
sible for HAE attacks by causing vasodilation and increasing the permeability of
the postcapillary venules by causing contraction of endothelial cells so as to create
gaps in the blood vessel wall (Fig. 31.5). This is responsible for the edema; move-
ment of fluid from the vascular space into another body compartment, such as the
gut, causes the symptoms of dehydration as the vascular volume contracts.

Treatment of HAE can focus on preventing attacks or on resolving acute episodes.
Purified C1INH can be used either routinely to prevent attack or before known trig-
gers such as surgery or dental work. Attenuated androgens, such as danazol, are
also indicated for prophylaxis. Purified or recombinant C1INH are effective ther-
apy in terminating acute attacks. A kallikrein inhibitor and a bradykinin receptor
antagonist have also been developed, which reverse HAE symptoms.

Questions.

1 Activation of the complement system results in the release of histamine and
chemokines, which normally produce pain, heat, and itching. Why is the edema fluid
in HAE free of cellular components, and why does the swelling not itch?

2 Richard has a markedly decreased amount of C4 in his blood. This is because
it is being rapidly cleaved by activated C1. What other complement component
would you expect to find decreased? Would you expect the alternative pathway
components to be low, normal, or elevated? What about the terminal components?

3 Despite the complement deficiency in patients with HAE, they are not unduly
susceptible to infection. Why not?

Fig. 31.5 Contraction of endothelial
cells creates gaps in the blood
vessel wall. A guinea pig was injected
intravenously with India ink (a suspension
of carbon particles). Immediately
thereafter the guinea pig was injected
intradermally with a small amount of
activated C1s. An area of angioedema
formed about the injected site, which
was biopsied 10 minutes later. An
electron micrograph reveals that the
endothelial cells in post-capillary venules
have contracted and formed gaps
through which the India ink particles
have leaked from the blood vessel. L
is the lumen of the blood vessel; P is
a polymorphonuclear leukocyte in the
lumen; rbc is a red blood cell that has
leaked out of the blood vessel. End is
endothelial cell. Arrows point to India ink
particles Scale bar: 10 μM. Micrograph
courtesy of Kaethe Willms.

Case Studies in Immunology | Raif Geha
ISBN: 978-0-8153-4512-1 | 7th edition
Hereditary Angioedema | CS-31.04 | Figure 31-4
© Garland Science design by blink studio limited

Angiodema

kallikrein

+ bradykinin

factor XIIa

HMW kininogen

kallikrein

HMW kininogenHMW kininogen

prekallikrein

Endothelial
cell

B2R

C1INH

Case Studies in Immunology | Raif Geha
ISBN: 978-0-8153-4512-1 | 7th edition
Hereditary Angioedema | CS-31.05 | Figure 31-5
© Garland Science design by blink studio limited

rbc

L

P

end

Fig. 31.4 Pathogenesis of hereditary angioedema. Activation of Factor XII leads
to the activation of kallikrein, which cleaves kininogen to produce the vasoactive
peptide bradykinin; bradykinin binds to its receptor on the surface of endothelial cells,
triggering the edema characteristic of HAE.

case31.indd 183 23/12/2015 14:47

184 Case 31: Hereditary Angioedema

4 Emergency treatment for HAE cases is sometimes necessary because of
airway obstruction. In most cases, however, a patient with obstruction of the
upper airways is likely to be suffering from an anaphylactic reaction. The treatment
in this case would be epinephrine. How might you decide whether to administer
epinephrine or intravenous C1INH?

5 Fig. 31.6 shows Richard’s family tree. What is the mode of inheritance
(dominant or recessive, sex-linked or not) of HAE? Can Richard’s two children pass
the disease onto their offspring?

Case Studies in Immunology | Raif Geha
ISBN: 978-0-8153-4512-1 | 7th edition
Hereditary Angioedema | CS-31.06 | Figure 31-6
© Garland Science design by blink studio limited

affected female

affected male

normal female

normal male

propositus
(Richard Crafton)

chromosome 11
bearing
C1INH mutation

normal
chromosome 11

Fig. 31.6 The inheritance of hereditary
angioedema in Richard’s extended
family.

case31.indd 184 23/12/2015 14:47