eliminate invading pathogens from the host, in some individuals with complement inhibitor deficiency, complement may lyse host red blood cells and cause a disease called paroxysmal nocturnal hemoglobinuria (PNH). These patients can be treated with a monoclonal antibody (Mab) that binds the C5 component of complement (see Mab section below), disrupting the lytic cascade. Patients taking a C5 inhibitor are at risk of life-threatening meningococcal infections.
During the inflammatory response triggered by infection, neutrophils and monocytes enter the tissue sites from the peripheral circulation. This cellular influx is mediated by the action of chemoattractant cytokines (chemokines) (eg, interleukin-8 [IL-8; CXCL8], macrophage chemotactic protein-1 [MCP-1; CCL2], and macrophage inflammatory protein-1α [MIP-1α; CCL3]) released from activated endothelial cells and immune cells (mostly tissue macrophages) at the inflammatory site. Egress of the immune cells from blood vessels into the inflammatory site is mediated by adhesive interactions between cell surface receptors (eg, l-selectin, integrins) on the immune cells and ligands (eg, sialyl-Lewis x, intercellular adhesion molecule-1 [ICAM-1]) on the activated endothelial cell surface. The tissue macrophages as well as dendritic cells express pattern recognition receptors (PRRs) that include Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), scavenger receptors, mannose receptors, and lipopolysaccharide (LPS)-binding protein, which recognize key evolutionarily conserved pathogen components referred to as pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include microbe-derived unmethylated CpG DNA, flagellin, double-stranded RNA, peptidoglycan, and LPS. The PRRs recognize PAMPs in various components of pathogens and stimulate the release of pro-inflammatory cytokines, chemokines, and interferons. If the innate immune response is successfully executed, the invading pathogen is ingested, degraded, and eliminated, and disease is either prevented or is of short duration.
In addition to monocytes and neutrophils, natural killer (NK), natural killer-T (NKT), and gamma-delta T (fc T) cells recruited to the inflammatory site contribute to the innate response by secreting interferon-gamma (IFN-γ) and interleukin-17 (IL-17), * which activate resident tissue macrophages and dendritic cells and recruit neutrophils, respectively, to successfully eliminate invading pathogens. NK cells are so called because they are able to recognize and destroy virus-infected normal cells as well as tumor cells without prior stimulation. This activity is regulated by “killer cell immunoglobulin-like receptors” (KIRs) on the NK cell surface that are specific for major histocompatibility complex (MHC) class I molecules. When NK cells bind self MHC class I proteins (expressed on all nucleated cells), these receptors deliver inhibitory signals, preventing them from killing normal host cells. Tumor cells or virus-infected cells that have downregulated MHC class I expression do not engage these KIRs, resulting in activation of NK cells and subsequent destruction of the target cell. NK cells kill target cells by releasing cytotoxic granules such as perforins and granzymes that induce programmed cell death.
NKT cells express T-cell receptors as well as receptors commonly found on NK cells. NKT cells recognize microbial lipid antigens presented by a unique class of MHC-like molecules * Interferons and interleukins are cytokines, which are discussed later in this chapter.
known as CD1 and have been implicated in host defense against microbial agents, autoimmune diseases, and tumors.