I. Introduction Innate immunity acts immediately to effect removal of the pathogen without the development of disease in the host. If the innate immune responses are overwhelmed, bypassed or even evaded by the pathogen, adaptive immune responses are required. Very helpful video: Immune System: Innate and Adaptive Immunity Explained (Links to an external site.) II. Recognising a Pathogen Innate immunity has evolved over millions of years to distinguish "dangerous" things from "innocuous" things. Innate immunity involves the use of receptors that recognise parts of the most common pathogens we are likely to encounter. These proteins are known as Pattern Recognition Receptors (PRRs). Pattern recognition receptors (PRRs) recognise Pathogen-Associated Molecular Patterns (PAMPs). The important features of PAMPs include: · are not produced by the multi-cellular host organism, · are shared by large groups of pathogens, · do not undergo frequent mutation, · are often essential for pathogen's survival, and · are recognised by PRRs in the innate response. Two examples of PAMPs include the: · peptidoglycan in Gram-positive bacteria · lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria. The two main groups of cell-associated membrane PRRs include: · phagocytosis receptors (that are used to bring the particle inside the phagocyte) and · Toll-like Receptors (TLRs, to allow the phagocyte to determine if the particle is dangerous, i.e., a pathogen). III. Toll and Toll-like Receptors (TLRs)
"Toll" is an evolutionarily conserved family of receptors in the invertebrate, Drosophila melanogaster(a fruit fly). Upon binding of an infectious organism to Toll, anti-fungal or anti-microbial peptides are released that are appropriate to the infectious organism. Mammalian TLRs structurally resemble Drosophila Toll. They consist of an · extracellular leucine-rich domain that recognises the PAMP, · transmembrane domain · cytoplasmic domain that is homologous to the IL-1 receptor (a receptor that binds the cytokine, interleukin-1 (IL-1) (see Figure 2.1) Mammalian TLRs are also functionally analogous to DrosophilaToll. The binding of mammalian TLRs also leads to the activation of NF-KB, an important family of transcription activators that bind to the promoters of genes that code for antimicrobial peptides. Thirteen different TLRs have been described in mammals so far (13 in mice, 11 in humans). Each TLR recognises a distinct set of molecular patterns that are not found in the host. TLR function as homodimers or heterodimers. The ability to form heterodimers extends the range of PAMPs that can be recognised. Tri-acylated lipopeptides Leucine-rich repeat (LRR) motif Transmembrane helix 8 3 000000r Cell membrane Intracellular TIR domain - TLR1-TLR2 heterodimer Figure 2.1 The structure of a Toll-like receptor (TLR). The conserved structural features of all TLRs consist of three critical components: (1) leucine-rich repeat (LRR) motif; (2) transmembrane helix; (3) intracellular Toll/Interleukin-1 receptor (TIR) domain. IV. The Complement (C') System The complement system is a set of plasma proteins that act together to attack extracellular pathogens. Activation of a complement component usually involves the
cleavage of the protein to make two smaller proteins. The complement system is activated in a series of reactions, where the product of one