**Bradykinin-Mediated Angioedema Across the History**

Jesús Jurado-Palomo, Irina Diana Bobolea,

Alexandru Daniel Vlagea and Teresa Caballero

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67714

#### **Abstract**

[73] Farkas H, Zotter Z, Csuka D, Szabó E, Nébenfuhrer Z, Temesszentandrási G, et al. Shortterm prophylaxis in hereditary angioedema due to deficiency of the C1-inhibitor--a long-

[74] Zuraw B, Bersntein J, Lang D. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibito-associated

term survey. Allergy 2012;67:1586–93.

204 A Comprehensive Review of Urticaria and Angioedema

angioedema. J Allergy Clin Immunol. 2013;131:1491–3.

The origins of the discovery of the "Complement System" date from the second half of the nineteenth century. The official paternity of the Complement System is attributed to Jules Bordet. The complement system can be activated through three major pathways. The classical pathway, the alternative pathway, and the lectin pathway converge in a common final lytic pathway. Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) was first described by Robert Graves in his clinical lectures. The autosomal dominant pattern of HAE was recognized by Sir William Osler. The pathophysiologic basis of C1-INH-HAE as a deficiency of a plasma inhibitor was discovered in the early 1960s. In 1986, the C1NH gene was identified, which encodes the C1-INH protein. Although the possible relationship between angioedema and estrogens in women was described as early as 1986, it was not until the first decade of the twenty-first century when several series of patients with HAE were described with normal levels of the fractions of the complement system. In the last decade, several drugs have been approved and marketed in Europe, in the United States, and in other countries, contributing to the improved management of C1-INH-HAE and patient's quality of life.

**Keywords:** acquired angioedema, angioedema, bradykinin, c1 inhibitor, complement system, factor XII, hereditary angioedema, hereditary angioedema with mutation in *F12* gene, history, immunodeficiency

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

The origins of the discovery of the "Complement System" date from the second half of the nineteenth century. The official paternity of the Complement System is attributed to Jules Bordet. The complement system can be activated through three major pathways. The classical pathway, the alternative pathway, and the lectin pathway converge in a common final lytic pathway. This chapter describes the historical discovery of biochemistry pathways implicated in the pathophysiology of bradykininergic angioedema (BK-AE).

### **2. Historical review of the Complement System**

The origins of the discovery of the "Complement System" date from the second half of the nineteenth century. In that era, the works of Louis Pasteur (1822–1895), Robert Koch (1843– 1910) [1], and Joseph Lister (1827–1912) [2] contributed to the knowledge needed to consider many microorganisms as producers of lethal effects in humans. It was obvious that the human body, despite being constantly exposed to microorganisms, successfully overcame their assaults, discovering that many of them were destroyed in the blood, one of whose effector systems of defense was the "complement system" [3] (**Figure 1**).

Taube and Gscheidlen made one of the first observations that the blood of various mammals possessed bactericidal activity [4]. These authors injected microorganisms in the bloodstream, sampling at 24 and 48 hours while preserving them aseptically. Even months after storage, bacterial multiplication was not observed. Wyssokowitsch [5] and von Fodor [6, 7] repeated the experiment, injecting microorganisms in the blood of mammals, noting that within minutes there were no viable organisms; they thought that they had been cleared by the blood cells. Metschnikoff [8] found phagocytes that engulfed and destroyed microorganisms, but soon discovered that blood cells were not solely responsible. Grohmann [9] was the first scientist who discovered that *in vitro* plasma (cell-free) was capable of lysing bacteria and fungi.

Nuttal [10], in experiments similar to those conducted previously by Wyssokowitsch [5] and von Fodor [6, 7], observed morphological changes in microorganisms (anthrax bacillus) that had escaped phagocytosis, concluding that they had been damaged by a noncellular process. After inoculating defibrinated sheep blood with bacteria, the bactericidal activity was preserved both *in vivo* and *in vitro*, but disappeared if the blood was heated to 45°C or was stored for several days at room temperature. A year later, Buchner [11, 12] reported that fresh serum was able to lyse bacteria, but if heated for 30 minutes at 55°C, this capacity was lost. He also found that the dialysis of fresh serum against water at 0°C for 18–36 hours abolished the lytic activity, but there was no loss when dialyzed against bicarbonate buffer containing 0.75–0.8% NaCl. He called fresh factor serum with bactericidal activity "alexina," concluding that it was due to proteins with enzymatic activity.

Pfeiffer and Issaeff [13] reported that the activity of alexina was due to the joint action of specific antibodies and specific serum factor. In their experiment, the blood of guinea pigs that recovered from cholera infection protected normal guinea pigs if they were injected alexina

**Figure 1.** Historical review of the Complement System (from 1850 to 1930) [3].

**1. Introduction**

206 A Comprehensive Review of Urticaria and Angioedema

The origins of the discovery of the "Complement System" date from the second half of the nineteenth century. The official paternity of the Complement System is attributed to Jules Bordet. The complement system can be activated through three major pathways. The classical pathway, the alternative pathway, and the lectin pathway converge in a common final lytic pathway. This chapter describes the historical discovery of biochemistry pathways implicated

The origins of the discovery of the "Complement System" date from the second half of the nineteenth century. In that era, the works of Louis Pasteur (1822–1895), Robert Koch (1843– 1910) [1], and Joseph Lister (1827–1912) [2] contributed to the knowledge needed to consider many microorganisms as producers of lethal effects in humans. It was obvious that the human body, despite being constantly exposed to microorganisms, successfully overcame their assaults, discovering that many of them were destroyed in the blood, one of whose effector

Taube and Gscheidlen made one of the first observations that the blood of various mammals possessed bactericidal activity [4]. These authors injected microorganisms in the bloodstream, sampling at 24 and 48 hours while preserving them aseptically. Even months after storage, bacterial multiplication was not observed. Wyssokowitsch [5] and von Fodor [6, 7] repeated the experiment, injecting microorganisms in the blood of mammals, noting that within minutes there were no viable organisms; they thought that they had been cleared by the blood cells. Metschnikoff [8] found phagocytes that engulfed and destroyed microorganisms, but soon discovered that blood cells were not solely responsible. Grohmann [9] was the first scientist who discovered that *in vitro* plasma (cell-free) was capable of lysing bacteria and fungi. Nuttal [10], in experiments similar to those conducted previously by Wyssokowitsch [5] and von Fodor [6, 7], observed morphological changes in microorganisms (anthrax bacillus) that had escaped phagocytosis, concluding that they had been damaged by a noncellular process. After inoculating defibrinated sheep blood with bacteria, the bactericidal activity was preserved both *in vivo* and *in vitro*, but disappeared if the blood was heated to 45°C or was stored for several days at room temperature. A year later, Buchner [11, 12] reported that fresh serum was able to lyse bacteria, but if heated for 30 minutes at 55°C, this capacity was lost. He also found that the dialysis of fresh serum against water at 0°C for 18–36 hours abolished the lytic activity, but there was no loss when dialyzed against bicarbonate buffer containing 0.75–0.8% NaCl. He called fresh factor serum with bactericidal activity "alexina," concluding that it was

Pfeiffer and Issaeff [13] reported that the activity of alexina was due to the joint action of specific antibodies and specific serum factor. In their experiment, the blood of guinea pigs that recovered from cholera infection protected normal guinea pigs if they were injected alexina

in the pathophysiology of bradykininergic angioedema (BK-AE).

systems of defense was the "complement system" [3] (**Figure 1**).

due to proteins with enzymatic activity.

**2. Historical review of the Complement System**

mixed with live bacteria. *In vitro* data showed that vibrios were eliminated only by fresh immune serum, but not by heat-inactivated immune serum. Protection against cholera present during injections of heat-inactivated immune serum was due to the antibody. Therefore, bacterial lysis was due to the association of the antibody plus complement. Bacteriolytic ability of serum from animals immunized with a particular microorganism was higher than that of animals immunized against this microorganism.

The official paternity of the Complement System is attributed to Jules Bordet, who performed the critical experiments that identified the "complement system" in 1894 [14, 15]. Bordet [16, 17] showed that increased immune serum bactericidal activity was due to the action of two factors [3]:


Ferrata [18] showed that the complement consisted of several serum factors that could be separated by physicochemical means, but it was Brand [19] the following year who best characterized both fractions [3]:


Brand's works established a number of assumptions:


Both the mid-piece and the end-piece are temperature sensitive.

#### **2.1. Historical development of the classical complement pathway**

Ritz [20] and Coca [21] were the first to demonstrate the existence of a third component other than the mid- and end-piece following observation of the destructive effect of cobra venom on the complement [3] (**Figure 2**). Coca treated fresh serum with yeast, concluding that the third component was capable of combining with yeast and he called it C′3. Gordon et al. [22] showed a fourth component, which he called C′4 when observing that the ammonium destroyed a thermostable

mixed with live bacteria. *In vitro* data showed that vibrios were eliminated only by fresh immune serum, but not by heat-inactivated immune serum. Protection against cholera present during injections of heat-inactivated immune serum was due to the antibody. Therefore, bacterial lysis was due to the association of the antibody plus complement. Bacteriolytic ability of serum from animals immunized with a particular microorganism was higher than

The official paternity of the Complement System is attributed to Jules Bordet, who performed the critical experiments that identified the "complement system" in 1894 [14, 15]. Bordet [16, 17] showed that increased immune serum bactericidal activity was due to the action of

(a) Thermostable factor increased by immunization, specifically reacting with the microor-

(b) Thermolabile factor present in normal and immune sera, nonspecific (at least in the way the thermostable factor was). Bordet quickly identified such a factor with the bactericidal activity or alexina described by Buchner [11, 12]. He was also able to lyse erythrocytes

Ferrata [18] showed that the complement consisted of several serum factors that could be separated by physicochemical means, but it was Brand [19] the following year who best char-

(a) He called the activity in the precipitate (euglobulins) "mid-piece" because he found that

(a) He called the activity in the supernatant (pseudo-globulins) "end-piece" because it acted

(b) Interaction of erythrocytes with the antibody, mid-piece, and end-piece, in that order,

Ritz [20] and Coca [21] were the first to demonstrate the existence of a third component other than the mid- and end-piece following observation of the destructive effect of cobra venom on the complement [3] (**Figure 2**). Coca treated fresh serum with yeast, concluding that the third component was capable of combining with yeast and he called it C′3. Gordon et al. [22] showed a fourth component, which he called C′4 when observing that the ammonium destroyed a thermostable

sensitized with specific antibodies against erythrocyte antigens.

it acted after the antibody (front-piece) would bind to the cell (RBC).

(b) An intermediate product as a function of hemolysis was generated.

Both the mid-piece and the end-piece are temperature sensitive.

**2.1. Historical development of the classical complement pathway**

that of animals immunized against this microorganism.

two factors [3]:

ganism used to immunize.

208 A Comprehensive Review of Urticaria and Angioedema

acterized both fractions [3]:

produced hemolysis.

only after the "mid-piece" had acted.

Brand's works established a number of assumptions:

(a) The action of the complement is sequential.

**Figure 2.** Historical review of the discovery of the Complement System (from 1930 to 1985) [3].

factor from serum other than C′3 (the mid-piece was called C′1 and the end-piece was renamed C′2). It should be noted at this point that C′1 and C′2 do not correspond to the current fractions C1 and C2, since both constitute the full complement including C′3 and C′4. Ueno [23] established the order of performance of the components known up to that time. Pillemer [24] managed to separate the four serum fractions into different components and set the activation sequence C′1, C′4, C′2, and C′3. It was not until the early 1960s, once chromatographic methods were developed, that the various components could be purified. Nelson [25, 26] showed that in reality the third component C′3 was formed by at least six factors (C′3c, C′3b, C′3e, C′3f, C′3a, and C′3d). Having established that these were proteins not related to C′3 acting at a later stage, he called them C′5, C′6, C′7, C′8, and C′9, respectively. As of 1968, World Health Organization (WHO) annulled the symbol "′" leaving it currently C1, C2, and so on.

#### **2.2. Historical development of the alternative complement pathway**

The heavy reliance of the study of the classical complement pathway using erythrocytes sensitized with antibodies for activation did not even consider the possibility of activation by other substances [3]. However, since the early twentieth century, there were data suggesting that it was possible to lyse erythrocytes with cobra venom without antibodies and with the participation of various components other than those of the classical pathway. Pillemer [27] was the father of the discovery of the alternative pathway upon describing a protein or a new component called "properdin," which when absent diminished the bactericidal potency of serum against certain bacteria.

#### **2.3. Historical development of the final common lytic complement pathway**

Green et al. [28] suggested that the cytolysis mediated by complement involved the production of pores in the cell membrane on the grounds that large molecules (dextrans and albumin) prevented cell lysis when present in high concentration in the reaction medium; on the contrary, but small molecules did not [3] (**Figure 2**). Cell rupture was thought to be due to a colloid-osmotic swelling process that finally finished by lysing the cell. Borsos et al. [29], with the use of electron microscopy, visualized ultrastructural lesions etched into cell membranes, showing that the lesions were associated with the cytolytic complement activity. Lachman [30] showed that the five terminal components C5, C6, C7, C8, and C9 were necessary and sufficient to cause such lesions. Haxby [31] and Kinsky [32] were the first to demonstrate that the lipid bilayer was the target of the "membrane attack complex" (MAC), noting that C5-C9 directly damaged the integrity of the bilayer without any enzymatic activity. Mayer [33] formulated the "donut hypothesis" where cell damage is achieved through the formation of a structure described as a donut, forming stable transmembrane pores. Lysis would be explained by the osmotic difference between the exterior and the interior cell through the transmembrane channel. Bhadki [34] and Podack [35] observed that the MAC was due to C5-C9 multimolecular assembly. Bieseker [36] initially postulated a dimeric structure (C5-9)2, but Bhakdi [37] suggested a monomeric complex with the same structure as the complex SC5b-9 ("S" was one of the proteins that control the MAC). The C9 alone forms complexes structurally similar to the full MAC [38].
