Inflammation will be discussed later in this chapter. In this capacity, inflammasomes meaningfully contribute to the healthy resolution of infections. However, activation of inflammasomes also contributes to cytokine‐driven inflammation central to the pathology of autoimmune and autoinflammatory diseases. Consequently, inflammasomes are now major drug targets for autoimmune and chronic inflammatory diseases. Moreover, recent studies have described the genetic association of mutations in NLR genes with several chronic inflammatory barrier diseases, such as Crohn’s disease and asthma, and with rare autoinflammatory syndromes including familial cold urticaria, Muckle–Wells syndrome, and Blau syndrome.
RIG‐I‐Like Receptors.
RIG‐I‐like receptors (RLRs) constitute a family of three cytoplasmic RNA helicases that are critical for host antiviral responses. They sense double‐stranded RNA, a replication intermediate for RNA viruses, leading to production of type I interferons (interferon‐α and interferon‐β) in infected cells.
Figure 3.6. Binding of pathogen‐associated molecular patterns (PAMPs) to the core form of an inflammasome. Binding of PAMPs to leucine‐rich repeats (LRRs) on cytoplasmic inflammasomes causes the core form to bind to an adaptor protein and caspase‐1. This is followed by oligomerization of the inflammasome, which enables it to catalyze the conversion of inactive IL‐1β to active IL‐1β
COMPLEMENT
Another major soluble element of the innate immune system is the complement system. Complement will be discussed in detail in Chapter 4. Briefly, it is made up of approximately 25 proteins, most of which are produced in the liver. They work together to assist or “complement” the action of antibodies in destroying bacteria. Complement also helps to rid the host of antibody‐coated antigens (so‐called opsonized antigens). Certain complement proteins that cause blood vessels to become dilated and then leaky contribute to the redness, warmth, swelling, pain, and loss of function that characterize inflammatory responses.
Complement proteins circulate in the blood in an inactive form. Each component takes its turn in a precise chain of steps known as the complement cascade (Figure 3.7). The end‐products are molecular cylinders called the membrane attack complex (MAC), which are inserted into the cell walls that surround the invading bacteria. This results in the development of puncture holes causing fluids to flow in and out of the bacteria. Consequently, the bacterial cell walls swell and burst (lysis), and the bacteria are killed.
Figure 3.7. The three complement activation pathways: classical, alternative, and lectin.
There are three complement activation pathways, as discussed in detail in Chapter 4. When the first protein in the complement series (C1q) is activated by an antibody that has been made in response to a microbe (e.g., bacteria), this initiates the chain of events resulting in the generation of MAC that causes lysis of the microbe. This is known as the classic activation pathway and is part of complement’s participation in the adaptive immune response. However, the alternative activation pathway involves direct binding of certain complement components, such as C3, to the surfaces of pathogens without the participation of antibody. This binding triggers a conformational change in the protein that initiates the downstream cascade leading to the generation of MAC followed by lysis of the microbe. Finally, the lectin activation pathway involves other complement components such as C2 and C4, which are lectins that also bind directly, in this case to mannan moieties expressed on pathogens. As with the other two pathways, this results in activation of other complement components leading to MAC production and lysis of the pathogen.
By directly binding to bacteria, other components of the complement system make bacteria more susceptible to phagocytosis by innate immune cells. Phagocytic cells express complement receptors, and when they encounter complement‐coated bacteria (opsonized bacteria), this greatly facilitates their binding to and phagocytosis of the bacteria. Complement components generated during the complement cascade can attract other immune cells (phagocytes and other leukocytes) to the area where invading bacteria are present. Thus, complement plays a role in locally mobilizing host defense mechanisms. Finally, like all biologically complex systems involving activation of proteins with the ability to promote potentially harmful consequences to the host (e.g., inflammation), the complement system is endowed with regulatory proteins that help to terminate the process.
TABLE 3.1. Proteins Involved in the Complement Cascade
| Binding to Ag:Ab complexes | C1q |
|---|---|
| Activating enzymes | C1r, C1s, C2b, Bd, D, MASP1,2 |
| Membrane‐binding opsonins | C4b, C3b, MBP |
| Mediators of inflammation | C5a, C3a, C4a |
| Membrane attack | C5b, C6, C7, C8, C9 |
| Complement receptors | CR1, CR2, CR3, CR4, C1qR |
| Complement‐regulatory proteins | C1INH, C4bp, CR1, MCP, DAE,H, I, P, CD59 |
Table 3.1 summarizes the functional properties of the proteins involved in the complement cascade. These will be discussed further in Chapter 4.
Intracellular and Extracellular Killing of Microorganisms
Another hallmark of innate immunity is the ability of certain innate immune cells to sample their environment by engulfing macroparticles (endocytosis) or individual cells (phagocytosis). Endocytosis is the process whereby macromolecules present in extracellular tissue fluid are ingested by cells. This can occur either by pinocytosis, which involves nonspecific membrane invagination, or by receptor‐mediated endocytosis, a process involving the selective binding of macromolecules to specific membrane receptors. In both cases, ingestion of the foreign macromolecules generates endocytic vesicles filled with the foreign material, which then fuse with acidic compartments called endosomes. Endosomes then fuse with lysosomes containing degradative enzymes (e.g., nucleases, lipases, proteases) to reduce the ingested macromolecules to small breakdown products, including nucleotides, sugars, and peptides (Figure 3.8).
Phagocytosis.
Phagocytosis is the ingestion by individual
