The alternative pathway shows points of similarity with the classic sequence. Both pathways generate a C3 convertase that activates C3 to provide the pivotal event in the final common pathway of both systems. However, in contrast to the classic pathway, which is initiated by the formation of antigen- antibody reactions, the alternate complement pathway is pre dominantly a non–antibody-initiated pathway.

Microbial and mammalian cell surfaces can activate the alternative pathway in the absence of specific antigen-antibody complexes. Factors capable of activating the alternative pathway include inulin, zymosan (polysaccharide complex from surface of yeast cells), bacterial polysaccharides and endotoxins, and the aggregated IgG2, IgA, and IgE. In paroxysmal nocturnal hemoglobinuria (PNH), the patient’s erythrocytes act as an activator and result in excessive lysis of these erythrocytes. This nonspecific activation is a major physiologic advantage because host protection can be generated before the induction of a humoral immune response.

A key feature of the alternative pathway is that the first three proteins of the classic activation pathway—C1, C4, and C2—do not participate in the cascade sequence. The C3a com ponent is considered to be the counterpart of C2a in the classic pathway. C2 of the classic pathway structurally resembles fac tor B of the alternative pathway. The omission of C1, C4, and C2 is possible because activators of the alternative pathway catalyze the conversion of another series of normal serum proteins, which leads to the activation of C3. It was previously believed that properdin, a normal protein of human serum, was the first protein to function in the alternative pathway; thus, the pathway was originally named after this protein.

T he uptake of factor B onto C3b occurs when C3b is bound to an activator surface. However, C3b in the fluid phase or attached to a nonactivator surface will preferentially bind to and therefore prevent C3b,B formation. C3b and factor B combine to form C3b,B, which is converted into an active C3 convertase, C3b,Bb. This results from the loss of a small fragment, Ba (glycine-rich α2-globulin believed to be physiologically inert), through the action of the enzyme, factor D. The C3b,Bb complex is able to convert more C3 to C3b, which binds more factor B and the feedback cycle continues.

The major controlling event of the alternative pathway is factor H, which prevents the association between C3b and factor B. Factor H blocks the formation of C3b,Bb, the catalytically active C3 convertase of the feedback loop. Factor H (formerly β1-H) competes with factor B for its combining site on C3b, eventually leading to C3 inactivation. Factors B and H apparently occupy a common site on C3b. The factor that is preferentially bound to C3b depends on the nature of the surface to which C3b is attached. Polysaccharides are called activator surfaces and favor the uptake of factor B on the chain of C3b, with the corresponding displacement of factor H. In this situation, binding of factor H is inhibited, and consequently factor B will replace H at the common binding site. When factor H is excluded, C3b is thought to be formed continuously in small amounts. Another controlling point in the amplification loop depends on the stability of the C3b,Bb convertase. Ordinarily, C3b,Bb decays because of the loss of Bb, with a half-life of approximately 5 minutes. However, if properdin (P) binds to C3b,Bb, forming C3b,BbP, the half-life is extended to 30 minutes.

T he association of numerous C3b units, factor Bb, and properdin on the surface of an aggregate of protein or the surface of a microorganism has potent activity as a C5 convertase. With the cleavage of C5, the remainder of the complement cascade continues as in the classic pathway

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مواضيع ذات صلة

Hematopoietic Stimulators

The Complement System: Diagnostic Evaluation

Biological Functions of Complement Proteins

The Complement System: Classic Pathway

The Complement System

Immune-Mediated Disease

Evaluation of Immunodeficiency Syndromes

Plasma Cell Biology

B Lymphocyte Subsets

Natural Killer and K-Type Lymphocytes

Antigen Recognition by T Cells

Antigen Processing and Antigen Presentation to T Cells