**4. What is the complement system?**

However, this classification has some limitations such as the noninclusion of AE caused by non‐steroidal anti‐inflammatory drugs (NSAIDs), which often occurs without associated urticaria [10]. These drugs act by inhibiting the enzyme cyclooxygenase in the metabolic

A classification of AE according to endotypes was proposed later [11]. In this classification, three subtypes of AE were included: (1) mast cell and basophil‐driven AE, (2) bradykininergic AE, and (3) idiopathic AE [11]. It has the advantage that NSAIDs induced or exacerbated AE and

C1‐INH is a serine protease inhibitor (serpin) that regulates the following closely interrelated proteolytic pathways: complement system, coagulation system, contact system, and fibrinolysis system [12, 13] (**Figure 2**). It is also known as SERPING1, belongs to the

First, C1‐INH inhibits C1r, C1s, and mannose‐binding‐lectin‐associated serine proteases (MASP1, MASP2) in the complement system. The inhibition of C1r and C1s is the function that gives name to this protein, "C1 inhibitor." The C1 fraction of complement, also known as C1 esterase, is the first protein of the complement system, and circulates in an inactive form. C1 esterase is activated during immunological processes, initiating the complement cascade and splitting off proteins from the classical pathway (C4 and C2) [9]. In patients with C1‐INH deficiency, an increase in C1 esterase functioning produces decreased C2, C4 levels, the natural substrates of the complement C1s fraction, which diminish much more during AE attacks [9]. C3, the protein that follows C2 in the classical complement cascade, is usually normal in patients with C1‐INH‐HAE, since it is

**Figure 2.** C1‐INH regulates different pathways: (A) complement system, (B) contact system, and (C) fibrinolysis system.

pathways of arachidonic acid and increasing leukotrienes.

**3. C1‐inhibitor deficiency**

154 A Comprehensive Review of Urticaria and Angioedema

not controlled by C1‐INH [9].

allergic AE are both included within the mast cell and basophil‐driven AE.

SERPIN superfamily, and is mainly synthesized in hepatocytes [9].

The "Complement System" is one of the effector pathways of the immune system against microorganisms and tumor cells, consisting of about 30 molecules, part of the comple‐ ment factors enhance "inflammation" and "phagocytosis," producing lysis of cells and microorganisms. The sequential activation through the generation of complex enzymes from inactive zymogens produces a cascade in which a capable enzyme generates a large number of active downstream molecules. Very strict regulation of downstream activation processes can be expected to restrict such activation to the foci where it started, thereby preventing possible tissue damage [15, 16]. This set of molecules, those involved in the acti‐ vation and the regulators (distinguishing between "triggers"—those able to bypass con‐ trol systems—and "nontriggers"), is called the "complement system." The need for both "amplification" and "regulation" with strict control gives an idea of the complexity of the "Complement System."
