IMMUNOLOGY - Roit I. - Mir 2000

Chapter 21. Primary Immunodeficiency

COMPLEMENT SYSTEM PROTEIN DEFICIENCIES

Complement components and their interaction with The Immune System are described in Chapter 4. Genetically determined deficiencies of various complement Proteins occur in humans (Fig. 21.11); studying such conditions helps to elucidate the normal Functions of The Complement System.

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Fig. 21.11. Genetically determined complement defects in humans. (Inheritance patterns: AR - autosomal recessive, AD - autosomal dominant, XR - X-linked recessive).

Defects in the complement system can impair the clearance of immune complexes, inflammation, phagocytosis, and bacteriolysis

Deficiencies in the Components of the classical complement activation pathway — C1q, C1r and C1s, C4, or C2 — predispose individuals to diseases caused by impaired formation and clearance of immune complexes, such as systemic lupus erythematosus. This correlates with the well-known role of the classical pathway in immune complex clearance. Deficiencies in C3, factor B, or factor I lead to increased susceptibility to pyogenic infections, which aligns with data on the critical importance of C3 in the opsonization of these pathogens. Deficiencies of terminal components — C5, C6, C7, and C8 — as well as components of the alternative complement activation pathway — factor D and properdin — confer a specific predisposition to Infections caused by two Neisseria species: N. gonorrhoeae and N. meningitidis. This clearly indicates the crucial role of the alternative complement pathway and the membrane attack complex in eliminating these bacterial species.

All of the listed complement component deficiencies are inherited as autosomal recessive traits, with the exception of properdin deficiency (X-linked recessive inheritance) and C1 inhibitor deficiency (Autosomal dominant inheritance).

Hereditary angioneurotic edema (HAE) As a result of C1 inhibitor deficiency

The most severe clinical manifestations are associated with complement dysfunction caused by C1 inhibitor deficiency. This molecule causes the dissociation of activated C1 by binding to C1r₂C1s₂. C1 inhibitor deficiency is the cause of hereditary angioneurotic edema (HAE), a well-characterized disease (Fig. 21.12) that is transmitted as an autosomal dominant trait. The condition is characterized by the periodic onset of localized edema in various PARTS OF THE body. When the process involves the intestine, it causes extremely sharp abdominal cramps and pain accompanied by uncontrollable vomiting. Edema of the Upper Respiratory Tract can lead to fatal asphyxia and requires immediate medical intervention to restore normal breathing.

Fig. 21.12. Hereditary angioneurotic edema. The photograph shows the transient local edema characteristic of this pathology.

The C1 inhibitor not only blocks the classical complement activation pathway but also suppresses The activity of functionally linked kinin and plasmin systems, as well as the Blood Coagulation SYSTEM. The onset of edema is mediated by two Peptides generated as a result of uninhibited complement activation and its associated systems. One peptide, C2 kinin, is a product of C2 component activation, while the other, bradykinin, is generated through the activation of the kinin system (Fig. 21.13). The action of these peptides on postcapillary venules causes endothelial Cells to contract, forming gaps between them through which plasma leaks into the Tissues (see Chapter 5).

Fig. 21.13. The C1 inhibitor is involved in the inactivation of elements of the blood coagulation, kinin, plasmin, and complement systems. It can be activated following surface-dependent activation of factor XII (Hageman factor). Red areas indicate sites of C1 inhibitor action. Unregulated activation of all these processes leads to the generation of bradykinin and C2 kinin, which induce edema.

There are two genetically distinct forms of HAE. Type I HAE is caused by a defect in the C1 inhibitor Gene that prevents The formation of RNA transcripts. In Type II HAE, the inhibitor gene carries point Mutations, and inhibitor molecules are synthesized but are defective. Distinguishing between the Two Types of HAE is important because Type II disease cannot be diagnosed solely by quantitative measurement of serum C1 inhibitor. It is also necessary to examine the level of the C4 component. The level of the latter in the serum of HAE patients is invariably reduced due to its consumption by uninhibited, activated C1.

C1 inhibitor deficiency can manifest later in life. In some cases, this is accompanied by autoantibodies to the C1 inhibitor, while in others it is associated with B-Cell monoclonal proliferation (as seen in chronic Lymphocytic Leukemia), multiple myeloma, or B-cell lymphoma. Patients possess anti-idiotypic Antibodies directed against the overproduced immunoglobulin; for reasons that remain unclear, the idiotype-anti-idiotype interaction is accompanied by the consumption of C1, C4, C2, and C1 inhibitor without the formation of an effective C3 convertase (which mediates C3 deposition and the clearance of complement complexes).