Clinical Assessment of Complement Activation

As products of a triggered activation system, one would expect that the anaphylatoxin fragments would not be detectable in healthy patients, with levels appearing only during complement activation. In truth, C4a, C3a, and C5a are not detectable in vivo, but their degradation products are. Their C-terminal arginines rapidly are cleaved off by a serum carboxypeptidase, generating the less active catabo-lites, designated desArg. The desArg peptides are stable and are the targets of detection in clinical immunoassays. In the case of C4a desArg and C3a desArg, those clinical conditions that affect clearance are not described, and the normal concentration in plasma is surprisingly high at 400 ng/mL and 100 ng/mL, respectively. In contrast, C5a is so avidly ligated to leukocyte cell surface receptors (C5aR) that levels of C5a desArg are not detectable in systems that contain leukocytes, such as any naturally occurring activation event, even with massive complement activation.

Whether complement activation has occurred and to what degree cannot be ascertained solely through analysis of serum concentrations of C3 and other intact complement proteins. C3 is a relatively abundant serum protein (1 to 2 mg/mL), which is synthesized by hepatocytes for plasma levels, by macrophages in the periphery at sites of inflammation, and by intestinal enterocytes. Concentrations of C3 at inflammatory sites cannot be measured clinically. Furthermore, serum C3 concentrations are a balance of synthesis, degradation, and serum dilution, none of which can be measured clinically, in addition to consumption by activation. Those factors that determine the rate of synthesis and degradation of C3 are not characterized well enough to predict C3 levels in a given medical condition. C3 also is an acute-phase reactant, causing concentrations to rise, despite consumption by complement activation. On the other hand, in a state of poor nutrition, concentrations might fall without any complement activation to consume C3. As a plasma protein, C3 concentrations also are dependent on degrees of hemodilution in the ill patients in whom C3 might be

Table I Complement Proteins.

Activation proteins, serum Classical pathway IgM, IgG

C1:C1r, C1s, C1q subunits

Alternative pathway

Lectin pathway MBL

MASP1, MASP2

Terminal proteins, serum C3

Activates complement with antigens Binds to antigen Binds to Ig, cleaves C2 Cleaves C4 With C2, cleaves C3 Binds to target, cleaves C5 Activates complement with membrane charge

Amplifies C3 deposition by other pathways Cleaves B

Binds to C3, cleaves C3/C5 With B, cleaves C3/C5 Stabilizes C3b, Bb enzyme Activates complement with sugars Binds mannose With MBL, cleave C2

Binds to target, cleaves C5, signals leukocytes Cleaves C6, signals leukocytes

Terminal proteins, serum C3

Binds to target, cleaves C5, signals leukocytes Cleaves C6, signals leukocytes

C6-9

Form MAC, attack cell membranes

Control proteins

C1-INH

Serum, inhibits C1r, C1s

C4bp

Serum, inhibits C4

H

Serum, serum, inhibits B

C3-INH

Serum, inhibits C3, cleaves C3

CR1

Membrane, degrades C3 cleaving enzymes

DAF, MCP

Membrane, decay C3 cleaving enzymes

CD59

Membrane, inhibits MAC formation

Signaling proteins

C3a, C4a, C5a

Serum, anaphylatoxins, chemoattractants

CR1

Membrane receptor for C3b, phagocytosis

CR2

Membrane receptor, antibody formation

CR3

Membrane receptor, leukocyte adhesion

C3aR, C5aR

Membrane receptor for anaphylatoxin

measured but in whom hemodilution is rarely considered. Finally, complement activation reactions that consume more than 5 to 10 percent of available serum C3 would be truly massive. Assessments of the functional capability of the complement lytic system using the CH50 assay have been employed as a repetitive measure with which to monitor the activity of a chronic systemic inflammatory disorder, such as systemic lupus erythematosus. However, the CH50 is a highly contrived assay designed to measure differences in red cell hemolysis at limiting dilutions of complement proteins (typically several hundredfold). Whether undiluted serum can ever acquire a complement lytic functional deficiency is doubtful. Thus, the mainstay of assessments for complement activation is the measurement of complement activation-derived cleavage products such as C3a desArg. However, assuming that complement activation has occurred simultaneously with measured elevations of C3a desArg could be misleading, as the factors that influence the rate of C3a desArg degradation are not characterized. Isolated elevations of C3a desArg concentrations alone are thought to indicate alternative pathway activation. Eleva tions of both C3a desArg and C4a desArg indicate that classical pathway activation is occurring but is unable to distinguish whether there is simultaneous alternative pathway activation. In most acute injury settings, complement activation has been alternative-pathway mediated. In most chronic diseases, the classical pathway has been paramount. Additional complement cleavage products, such as C4d, Bb, and the C5b-9 neoantigen, have been reported to be clinically valuable, as well.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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