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The innate immune system evolved several strategies of self/nonself discrimination that are based on the recognition of molecular patterns demarcating infectious nonself, as well as normal and abnormal self. These patterns are deciphered by receptors that either induce or inhibit an immune response, depending on the meaning of these signals.
The innate immune system of vertebrate animals uses three strategies of immune recognition that can be described in terms of recognition of "microbial nonself," recognition of "missing self," and recognition of "induced or altered self." The basis of microbial nonself recognition lies in the ability of the host to recognize conserved products of microbial metabolism that are unique to microorganisms and are not produced by the host. This strategy allows the innate immune system to discriminate between "infectious nonself" and "noninfectious self."
The second strategy, recognition of "missing self," relies on the detection of "markers of normal self." Such recognition is coupled with various inhibitory pathways that block initiation of immune responses against self. Markers of normal self are dedicated gene products and products of metabolic pathways that are unique to the host and absent from microorganisms.
The third strategy, recognition of induced self is based on the detection of markers of abnormal self that are induced upon infection (in particular, viral infection) and cellular transformation. Markers of abnormal self tag the affected cells for elimination by the immune system.
Recognition of Microbial Nonself
Recognition of microbial nonself, which evolved early in metazoan evolution, plays a crucial role in host defense (1). This recognition strategy is based on the detection of conserved molecular patterns that are essential products of microbial physiology. These invariant structures are referred to as pathogen-associated molecular patterns (PAMPs), although they are not unique to pathogens and are produced by all microorganisms, pathogenic or not (see below). PAMPs are unique to microbes (and are not produced by the host), and invariant among microorganisms of a given class (1, 2). The best known examples of PAMPs include lipopolysaccharide (LPS) of gram-negative bacteria and peptidoglycan of gram-positive bacteria. These and other PAMPs are recognized by receptors of the innate immune system called pattern recognition receptors (PRRs). Because PAMPs are produced only by microorganisms, they are perceived by the innate immune system as molecular...