Summary - Innate Immunity

The innate immune system provides the first line of host defense against microbes. The

mechanisms of innate immunity exist before exposure to microbes. The cellular components of

the innate immune system include epithelial barriers, leukocytes (neutrophils, macrophages, NK

cells, lymphocytes with invariant antigen receptors, and mast cells).

The innate immune system uses cell-associated pattern recognition receptors, present on plasma

and endosomal membranes and in the cytoplasm, to recognize structures called pathogen-

associated molecular patterns (PAMPs), which are shared by microbes, are not present on

mammalian cells, and are often essential for survival of the microbes, thus limiting the capacity

of microbes to evade detection by mutating or losing expression of these molecules. In addition,

these receptors recognize molecules made by the host but whose expression or location indicates

cellular damage; these are called damage-associated molecular patterns (DAMPs).

TLRs, present on the cell surface and in endosomes, are the most important family of pattern

recognition receptors, recognizing a wide variety of ligands, including bacterial cell wall

components and microbial nucleic acids. Cytoplasmic pattern recognition receptors exist that

recognize microbial molecules. These receptors include the RIG-like receptors (RLRs), which

recognize viral RNA, and the NOD-like receptors (NLRs), which recognize bacterial cell wall

constituents and also sense sodium urate and other crystals.

Soluble pattern recognition and effector molecules are found in the plasma, including pentraxins

(e.g., CRP), collectins (e.g., MBL), and ficolins. These molecules bind microbial ligands and

enhance clearance by complement-dependent and complement-independent mechanisms.

NK cells are lymphocytes that defend against intracellular microbes by killing infected cells and

providing a source of the macrophage-activating cytokine IFN-. NK cell recognition of infected

cells is regulated by a combination of activating and inhibitory receptors. Inhibitory receptors

recognize class I MHC molecules, because of which NK cells do not kill normal host cells but do

kill cells in which class I MHC expression is reduced, such as virus-infected cells.

The complement system includes several plasma proteins that become activated in sequence by

proteolytic cleavage to generate fragments of the C3 and C5 proteins, which promote

inflammation, or opsonize and promote phagocytosis of microbes. Complement activation also

generates membrane pores that kill some types of bacteria. The complement system is activated

on microbial surfaces and not on normal host cells because microbes lack regulatory proteins that

inhibit complement. In innate immune responses, complement is activated mainly spontaneously

on microbial cell surfaces and by mannose-binding lectin to initiate the alternative and lectin

pathways, respectively.

The two major effector functions of innate immunity are to induce inflammation, which

involves the delivery of microbe-killing leukocytes and soluble effector molecules from blood

into tissues, and to block viral infection of cells by the antiviral actions of type 1 interferons.

Both types of effector mechanism are induced by the PAMPs and DAMPs, which initiate

signaling pathways in tissue cells and leukocytes that activate transcription factors and lead to

the expression of cytokines and other inflammatory mediators.

Several cytokines produced mainly by activated macrophages mediate inflammation. TNF and

IL-1 activate endothelial cells, stimulate chemokine production, and increase neutrophil

production by the bone marrow. IL-1 and TNF both induce IL-6 production, and all three

cytokines mediate systemic effects, including fever and acute-phase protein synthesis by the

liver. IL-12 and IL-18 stimulate production of the macrophage-activating cytokine IFN- by NK

cells and T cells. These cytokines function in innate immune responses to different classes of

microbes, and some (IL-1, IL-6, IL-12, IL-18) modify adaptive immune responses that follow

the innate immune response.

Neutrophils and monocytes (the precursors of tissue macrophages) migrate from blood into

inflammatory sites during innate immune responses because of the effects of cytokines and

chemokines produced by PAMP- and DAMP-stimulated tissue cells.

Neutrophils and macrophages phagocytose microbes and kill them by producing ROS, nitric

oxide, and enzymes in phagolysosomes. Macrophages also produce cytokines that stimulate

inflammation and promote tissue remodeling at sites of infection. Phagocytes recognize and

respond to microbial products by several different types of receptors, including TLRs, C-type

lectins, scavenger receptors, and N-formyl met-leu-phe receptors.

Molecules produced during innate immune responses stimulate adaptive immunity and

influence the nature of adaptive immune responses. Dendritic cells activated by microbes

produce cytokines and costimulators that enhance T cell activation and differentiation into

effector T cells. Complement fragments generated by the alternative pathway provide second

signals for B cell activation and antibody production.

Innate immune responses are regulated by negative feedback mechanisms that limit potential

damage to tissues. IL-10 is a cytokine that is produced by and inhibits activation of macrophages

and dendritic cells. Inflammatory cytokine secretion is regulated by autophagy gene products.

Negative signaling pathways block the activating signals generated by pattern recognition

receptors and inflammatory cytokines.