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Chapter: Medical Immunology: The Complement System

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Pathological Situations Associated With Exaggerated Complement Activation

Once the complement cascade is activated, the complement components are under very tight regulation and control.


Once the complement cascade is activated, the complement components are under very tight regulation and control. An important aspect of this regulation is the constant presence of plasma inhibitors for the activated complement components. For each type of activated fragment there is at least one inhibitor or inhibitory mechanism. The tight regulation and rapid neutralization of the active fragments limit their range of action.

In the case of C3a and C5a, there are several serum inhibitors, one of which is be-lieved to be a serum protease that removes the carboxy-terminal arginine residue of the pep-tides and limits their ability to stimulate PMNs, leukocytes, basophils, and mast cells.

The inhibitor for C3b, as described in detail in previous sections, is Factor I, which only works in conjunction with appropriate cofactors (Factor H, CR1, or MCP). C4b is also inhibited by Factor I and a cofactor termed C4-binding protein (C4BP). Factor I cleaves C4b and C3b and prevents their capacity to be involved in binding down-stream components of the complement pathways.

The serum inhibitor for C1 is a serum protein, termed C1 inhibitor (C1-INH), which tends to stabilize the nonactivated C1 macromolecular complex, preventing spontaneous activation. More importantly, C1-INH has the ability to bind irreversibly to the activated form of C1r and C1s, at or near their active site. If a deficiency of any of these complement inhibitors or cofactors exists within an individual, an imbalance in complement regulation occurs and disease may ensue.

A. Hereditary Angioedema

This is a rare genetic disorder due to a genetically inherited C1-INH deficiency, of which two main variants are known. In the most common, the genetic inheritance of a silent gene results in a very low level of C1-INH. The second variant is characterized by normal lev-els of C1-INH protein, but 75% of the molecules are dysfunctional, i.e., will not inhibit ac-tivated C1r or C1s because of an aberrant amino acid substitution. While the lack of C1-INH can be easily detected by a quantitative assay, the synthesis of dysfunctional C1-INH can only be revealed by a combination of quantitative and functional tests. An acquired form of C1 INH deficiency can be detected in certain malignant diseases. Individuals with congenital C1-INH deficiency may present clinically with a disease known as hereditary angioedema, characterized by spontaneous swelling of the face, neck, genitalia, and ex-tremities, often associated with abdominal cramps and vomiting. The disease can be life threatening if the airway is compromised by laryngeal edema, and tracheotomy may be a life-saving measure. This anaphylactoid reaction is due not to IgE-mediated reactions, but rather to spontaneous uncontrolled activation of the complement system by C1. The reac-tion is usually self-limiting and will cease after all C4 and C2 have been consumed. How-ever, in vivo there is not a substantial consumption of the remaining complement sequence (C3-9) due to the action of several other regulatory mechanisms, which are especially ef-fective against the unbound (free) forms of C4b and C3b (i.e., C4b and C3b are not bound to any antigen).

Attacks in patients with C1-INH deficiency occur after surgical trauma, particularly after dental surgery or after severe stress. It is notable that activated Hageman factor, kallikrein, and plasmin are also controlled (in part) by binding to C1-INH. Such binding further depletes the available C1-INH in deficient patients. In the absence of sufficient C1-INH, spontaneous activation of a limited number of C1 molecules will gradually accentu-ate the depletion of C1-INH to the point that activated unbound C1 is in the circulation. Meanwhile the other blood enzymes controlled by C1-INH become less restricted. The continued presence of activated, uninhibited fluid phase C1s will cause spontaneous and continuous activation of the next two components in the sequence, C4 and C2, until their complete consumption. Low C4 levels are considered diagnostic of C1-INH deficiency, and they remain low even when the patients are not experiencing an attack, probably due to a continuously exaggerated C4 catabolism by activated C1. The angioedema-producing peptide has been suggested to be a fragment of C2 (C2a) liberated by the action of C1 on C2 followed by the cleavage of C2 by plasmin. This theory has developed because it is gen-erally accepted that serum C3 levels are not significantly altered during attacks of an-gioedema. However, in vitro evidence has shown that if appropriate levels of antibody to human C1-INH are added to whole human serum, 100% C3 conversion occurs. This com-plete C3 conversion can only be achieved when the function of C1-INH is blocked. Thus, the participation of low levels of C3a in angioedema cannot be ruled out when local C1-INH levels approach zero. As mentioned previously, C1 INH also controls several other blood system enzymes. Therefore during attacks of HAE, when C1 INH is being con-sumed, activation of the kallikrein-kinin system fibrinolysis occurs and this may also con-tribute to the edema scenario.

B. Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder on the surface of se-lected hemopoietic stem cell lines and their erythrocyte progeny. The patients develop hemolytic anemia associated with the intermittent passage of dark urine (due to hemoglobinuria), which usually is more accentuated at night. The spontaneous hemolysis is due to an increased susceptibility of the abnormal population of erythrocytes to comple-ment-mediated lysis. The erythrocytes are not responsible for the activation of the comple-ment system; rather, they are lysed as innocent bystanders when complement is activated.

Detailed studies of the circulating erythrocytes in PNH patients have demonstrated the existence of three erythrocyte subpopulations with varying degrees of sensitivity to complement. The reason for the existence of these subpopulations was elucidated when the molecular basis of PNH was established. Several membrane proteins are attached to cell membranes through phosphatidylinositol “anchors.” The red cell membrane contains two such proteins: the decay-accelerating factor (DAF), which prevents or disrupts the forma-tion of C4b2a and C3bBb, and protectin (CD59), which prevents the proper assembly of the membrane attack complex by binding to C8 and or C9. These two proteins (together with CR1 and MCP) have an important protective role for “bystander” erythrocytes by con-trolling the rate of complement activation on the erythrocyte membrane. The deficiency of the phosphatidylinositol anchoring system is reflected by deficiencies of DAF and pro-tectin. Type I PNH red cells have normal or slightly lowered levels of these two proteins and usually show normal resistance to complement-mediated hemolysis; type III PNH red cells lack both proteins and are very sensitive to hemolysis; type II PNH red cells lack DAF and have intermediate sensitivity to hemolysis.

Phosphatidylinositol is involved in the membrane binding of other proteins, such as the predominant type of Fc receptor in the neutrophil (Fc RIII). Therefore, in these patients neutrophils, platelets, and other cells are deficient both in DAF and in Fc receptors. These deficiencies seem to be the basis of other abnormalities seen in PNH patients: thrombotic complications, attributed to increased complement-induced platelet aggregation, and bac-terial infections and persistence of immune complexes in the circulation, both attributed to a lack of Fc-mediated phagocytosis.

C. Pulmonary Vascular Leukostasis as a Side Effect of Hemodialysis

Passage of heparinized blood over a variety of filter materials (i.e., artificial hemodialysis membranes and nylon fiber substances used in the heart-lung machine) causes varying de-grees of complement activation. The classical pathway may be activated by interfacially (solid-liquid or air-liquid) aggregated immunoglobulins or by direct binding of C1q. Also, membrane (filter)-bound C3b (via C3 turnover and C3b deposition) mediates activation of the alternative pathway. Rapid generation of C5a causes a transient leukopenia with a short-term, reversible accumulation and aggregation of granulocytes in the blood capillar-ies of the lungs, where they release superoxide that damages the tissues surrounding the ar-eas of PMN accumulation. As a result, repeated hemodialyses may lead to chronic fibrosis of the lung.

D.  Pancreatitis, Severe Trauma, and Pulmonary Distress Syndrome

Any mechanism that causes a rapid release of high levels of C5a into the blood may cause massive PMN aggregation and consequent pulmonary distress syndrome. For example, when large amounts of proteases are released into the blood (i.e., pancreatitis or severe tis-sue trauma), pulmonary distress syndrome and sometimes temporary blindness occur due to blockage of small blood vessels with aggregated granulocytes. Similarly, in myocardial infarction, blockage of critical heart capillaries with leukocyte aggregates may extend car-diac damage. Steroids that prevent and reverse leukocyte aggregation have been used to re-tard such damage in experimental animals. Cardiolipin released from the damaged heart tis-sues may directly activate C1 and therein exaggerate the complement activation being induced by the tissue proteases.

E. Septic Shock and C1-INH Depletion

The classical complement pathway, the contact activation system, and the coagulation cas-cade are activated during severe sepsis and septic shock. Activation of these cascades in se-vere sepsis contributes to the development of multiple organ failure (which may or may not be reversible), associated with high mortality rates. This is, at least in part, a consequence of the depletion of C1-INH, as a consequence of the activation of these systems and of degradation by bacterial and host proteases (e.g., leukocyte elastase). Depletion of C1-INH to less than about 10% of its normal serum level allows many bacterial substances and charged host cellular substances to directly activate C1 (which otherwise would be pre-vented from activating complement by C1-INH). In experimental animals, C1-INH substi-tution reduces the mortality by severe sepsis or septic shock.

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