Immunology. Richard Coico
Z, Cooper MD. (2007) The evolution of adaptive immunity. Annu Rev Immunol 24: 497.
11 Ricklin D, Lambris JD. (2013) Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol 190: 3831.
12 Song DH, Lee JO. (2012) Sensing of microbial molecular patterns by Toll‐like receptors. Immunol Rev 205: 216.
13 Sonnenberg GF, Artis D. (2015) Innate lymphoid cells in the initiation, regulation, and resolution of inflammation. Nat Med 21:698.
14 Stekel DJ, Parker CE, Nowak MA. (1997) A model for lymphocyte recirculation. Immunol Today 18: 216.
REVIEW QUESTIONS
For each question, choose the ONE BEST answer or completion.
1 Which of the following generally does not apply to bone marrow (a primary lymphoid organ) but does apply to secondary lymphoid organs?cellular proliferationdifferentiation of lymphocytescellular interactionantigen‐dependent response
2 Which of the following is involved in recognition of intracellular pathogens in innate immune cells?Toll‐like receptors (TLRs)antibodyNOD‐like receptors (NLRs)complement
3 Which of the following is a correct statement about NK cells?They proliferate in response to antigen.They kill target cells by phagocytosis and intracellular digestion.They are a subset of polymorphonuclear cells.They kill target cells in an extracellular fashionThey are particularly effective against certain bacteria.
4 Mature dendritic cells are capable of which of the following?activating naïve antigen‐specific T cellsremoving red blood cellsproducing bradykininextracellular killing of target cells
5 Killer‐cell inhibitory receptors (KIRs) expressed by NK cells bind to which of the following to prevent killing of normal cells?complement receptorsMHC class IimmunoglobulinToll‐like receptors
ANSWERS TO REVIEW QUESTIONS
1 D. Cellular proliferation, differentiation of lymphocytes, and cellular interactions can take place in bone marrow. However, antigen‐dependent responses occur in the secondary lymphoid organs, such as the spleen and lymph nodes.
2 C. The NLRs are a group of cytosolic innate receptors that recognize microbes that infect cells. Once ligated, they initiate a set of cellular activities that facilitate inflammatory responses and other host defense mechanisms.
3 D. NK cells are large granular lymphocytes. Their number does not increase in response to antigen. Their killing is extracellular, and their target cells are virus‐infected cells or tumor cells. They are not particularly effective against bacterial cells.
4 A. When immature dendritic cells are activated following their engulfment of pathogens (phagocytosis), they mature and become more efficient at antigen presentation and, in fact, can activate antigen‐specific naïve T cells.
5 B. NK cells express KIRs, which allow them to bind to MHC class I molecules expressed on all nucleated cells that would otherwise be targets for killing when infected with certain viruses that downregulate MHC class I expression.
4 COMPLEMENT
INTRODUCTION
As noted in Chapter 3, the complement system is a major component of innate immunity. Named for some of the earliest observations of its activity—a heat‐sensitive material in serum that “complemented” the ability of antibody to kill bacteria—we now know that complement comprises approximately 30 circulating and membrane‐expressed proteins. Complement components are mainly synthesized by liver hepatocytes and by cells involved in the inflammatory response. A list of the latter cell types and the complement components they produce is shown in Table 4.1.
The biological activities triggered by complement activation enhance pathways that remove microbial pathogens, and they also directly attack the pathogen itself. Because these activities are so powerful, however, they may also damage the host. Thus, under normal conditions, complement activation is tightly regulated. In this chapter we describe the different pathways of complement activation, complement’s key functions, and how complement activation is regulated. We also describe the clinical conditions that result from either inappropriate complement activation or deficiency of complement components.
OVERVIEW OF COMPLEMENT ACTIVATION
There are three pathways of complement activation: the classical, lectin, and alternative pathways. The key features of each are shown in Figure 4.1. Each pathway is initiated when a serum protein binds to the surface of a pathogen. The classical pathway is activated when complement component C1 binds to an antigen–antibody complex (most often, antibody bound to the surface of a pathogen such as a bacterium). The lectin pathway is activated when mannan‐binding lectin (MBL) binds to terminal polysaccharide residues on the surface of many types of microbes (Gram‐positive and Gram‐negative bacteria, fungi, or yeast); the lectin pathway can also be activated by another serum protein, ficolin, which binds to acetylated molecules on microbial surfaces. The alternative pathway is activated when complement component C3b deposits on the surface of a pathogen.
TABLE 4.1. Complement protein synthesis/secretion by various immune cells
| Cell | Complement proteins |
|---|---|
| B cell | C5 |
| T cell | C3, C5, factor B, factor D, factor P |
| Polymorphonuclear leukocyte | C3, C6, C7, ficolin‐1, factor B, factor P |
| Mast cell | C3, C5, C1q |
| Monocyte | C1q, C1r, C3, C5, C6, C7, C8, factor B, factor D |
| Macrophage | C1q, C1r, C3, C5, factor B, factor D |
| Dendritic cell | C1q, C1r, C3, C5, C7, C8, CD9, factor B, factor D |
Although the three pathways are initiated by different activators, the early steps in each have a common general mechanism: complement components are sequentially activated on the surface of the pathogen. That is, activation of the component induces enzymatic function that acts on the next component in the cascade, splitting it into biologically active fragments, and so on. In addition, several activated complement components build up on the surface of the pathogen.
Figure 4.1. Summary of classical, lectin, and alternative complement activation pathways: key activators, initiating complement components, components common to all pathways, and major activities generated.
After the early steps, the pathways converge at the cleavage of complement component C3. Cleavage of C3 forms C3b and a small fragment, C3a. C3b covalently binds to the surface of the pathogen. C3b is an opsonin,