Clinical Focus Question Explain why complement disorders involving regulatory components such as PNH may be more serious than deficiencies in the active complement components.
1. Indicate whether each of the following statements is true or false. If you think a statement is false, explain why.
a. A single molecule of bound IgM can activate the C1q component of the classical complement pathway.
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Review and quiz of key terms b. C3a and C3b are fragments of C3.
c. The C4 and C2 complement components are present in the serum in a functionally inactive proenzyme form.
d. Nucleated cells tend to be more resistant to complement-mediated lysis than red blood cells.
e. Enveloped viruses cannot be lysed by complement because their outer envelope is resistant to pore formation by the membrane-attack complex.
f. C4-deficient individuals have difficulty eliminating immune complexes.
2. Explain why serum IgM cannot activate complement by itself.
3. Would you expect a C1 or C3 complement deficiency to be more serious clinically? Why?
4. Some microorganisms produce enzymes that can degrade the Fc portion of antibody molecules. Why would such enzymes be advantageous for the survival of microorganisms that possess them?
5. Complement activation can occur via the classical, alternative, or lectin pathway.
a. How do the three pathways differ in the substances that can initiate activation?
b. Which portion of the overall activation sequence differs in the three pathways? Which portion is similar?
c. How do the biological consequences of complement activation via these pathways differ?
6. Enucleated cells, such as red blood cells, are more susceptible to complement-mediated lysis than nucleated cells.
a. Explain why the red blood cells of an individual are not normally destroyed as the result of innocent-bystander lysis by complement.
b. Under what conditions might complement cause lysis of an individual's own red blood cells?
7. Briefly explain the mechanism of actionl of the following complement regulatory proteins. Indicate which pathway(s) each protein regulates.
a. C1 inhibitor (C1Inh)
b. C4b-binding protein (C4bBP)
c. Homologous restriction factor (HRF)
d. Decay-accelerating factor (DAF)
e. Factor H
f. Membrane cofactor protein (MCP)
8. For each complement component(s) or reaction (a-l), select the most appropriate description listed below (1-13). Each description may be used once, more than once, or not at all.
Complement Component(s)/Reactions a. _C3b b. _C1, C4, C2, and C3
(1) Reaction that produces major amplification during activation
(2) Are early components of alternative pathway
(3) Compose the membrane-attack complex
(4) Mediates opsonization
(5) Are early components of classical pathway
(6) Has perforin-like activity
(7) Binds to Fc region of antibodies
(8) Have chemotactic activity
(9) Has C3 convertase activity
(10) Induce degranulation of mast cells (are anaphylatoxins)
(11) Has C5 convertase activity
(12) Reaction catalyzed by factor D
(13) Reaction catalyzed by C1qr2s2
9. You have prepared knockout mice with mutations in the genes that encode various complement components. Each knockout strain cannot express one of the complement components listed across the top of the table below. Predict the effect of each mutation on the steps in complement activation and on the complement effector functions indicated in the table below using the following symbols: NE = no effect; D = process/function decreased but not abolished; A = process/function abolished.
Component knocked out
C1q C4 C3 C5 C6 C9 Factor B
Formation of C3 convertase in classical pathway
Formation of C3 convertase in alternative pathway
Formation of C5 convertase in classical pathway
Formation of C5 convertase in alternative pathway
Cell-Mediated Effector Responses
The cell-mediated and humoral branches of the immune system assume different roles in protecting the host. The effectors of the humoral branch are secreted antibodies, highly specific molecules that can bind and neutralize antigens on the surface of cells and in the extracellular spaces. The primary domain of antibody protection lies outside the cell. If antibodies were the only agents of immunity, pathogens that managed to evade them and colonize the intracellular environment would escape the immune system. This is not the case. The principal role of cell-mediated immunity is to detect and eliminate cells that harbor intracellular pathogens. Cell-mediated immunity also can recognize and eliminate cells, such as tumor cells, that have undergone genetic modifications so that they express antigens not typical of normal cells.
Both antigen-specific and -nonspecific cells can contribute to the cell-mediated immune response. Specific cells include CD8+cytotoxic T lymphocytes (TC cells or CTLs) and cytokine-secreting CD4+ TH cells that mediate delayed-type hypersensitivity (DTH). The discussion of DTH reactions and the role of CD4+ T cells in their orchestration appears in Chapter 16. Nonspecific cells include NK cells and non-lymphoid cell types such as macrophages, neutrophils, and eosinophils. The activity of both specific and nonspecific components usually depends on effective local concentrations of various cytokines. T cells, NK cells, and macrophages are the most important sources of the cytokines that organize and support cell-mediated immunity. Finally, although humoral and cell-mediated immunity have many distinctive features, they are not completely independent. Cells such as macrophages, NK cells, neutrophils, and eosinophils can use antibodies as receptors to recognize and target cells for killing. Also, chemotactic peptides generated by the activation of complement in response to antigen-antibody complexes can contribute to assembling the cell types required for a cell-mediated response.
In the preceding chapters, various aspects of the humoral and cell-mediated effector responses have been described. This chapter addresses cytotoxic effector mechanisms mediated by TC cells, NK cells, antibody-dependent cell-mediated cytotoxi-city (ADCC), and the experimental assay of cytotoxicity.
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