Antimicrobial Proteins and Peptides molecule is also observed.The abundance and wide cytes.Trace amounts ofa fourth defensin.HNP-4.are also distribution of lysozyme suggest that it is of considerable found in the same compartment.HNP-I and HNP-4 are importance encoded by genes designated D上rAI and DEFA4. gene on chrom some 12 encodes the huma of the DEE4 HNP-2 results from p removal of the N terminal residue from HNP-1 and/or HNP-3.The remain ing a-detensins HD- and HD-6 are expressed by human and are pro boto oreensins s in the small I intestine.Human B-defensin Complement rious epithelia,and The DEFBI.DEFB2 The direct microbicidal effect of blood plasma on many aned the microbial species is mediated by complement.The key luster are neighbours.occup region of about 400- lethal event is the assembly of the membrane 6.9 neutrophils or Paneth cells.epithelial B-defensins tored granule of tare microbes.The insertion of th rimarily by their nth initiating C5b fragment is the end result of complement esis and secretion rates Other members of the defensin family of peptides hav nen t cascades. pathway as abundant uents of granulocytes in surfaces,thea nsters.guinea ternative pathway is triggered by the interaction of C3b with the microbial surface,while the and horses.Epithelial defensins have been found in Paneth contact of Clq-like mannose. ng和 repe disrupts the ionic homcostasis of the microbes.killing HBD.2 is susceptible microbes.Many pathogenic microbes have matory stimuli.Inducible antimicrobial cationic peptides evolved thick cell with six cysteines have been identified in the haemolymph apsu les that make and ot rates and icidal a ment is illustrated by the predisposition of pa tients with a ve tebrate def structure and composition are found in host defence roles deficiency of C6.C7 or C8 to recurrent infections with eisseria gonorrhoed and N.meningitid n plants where they plant anifest broac bial function ready in arthropods (e.g.horseshoe crabs). ions many hact ia.fung and ome enveloped viruses are inactivated by defensins.The nitial interaction of defensins with bac Defensins orces,and i into the target cell.Preferential interaction of defensins Defensins are 3-4-kDa cationic antimicrobial peptides es as opposed to host cells is probably due to with three intramolecular cystine disulfide the microbi men ane composition: largely B sheet struc cture The vere ate and Although similar in shape to-defensins.B-defensins nulocvte defensins.and suffer from rent bact erial slightly larger and differ in the placement and connectivity infections. of their six conserved cysteine residues.Human s produc at e st sD fensins and tw content of phagocytic granules of neutrophilic granulo- ENCYCLOPEDIA OF LIFE SCIENCES/ Publishing Group/www.els.net 3molecule is also observed. The abundance and wide distribution of lysozyme suggest that it is of considerable importance. A single gene on chromosome 12 encodes the human lysozyme enzyme. The mouse has two lysozyme genes, one of which (lysozyme M) is expressed in macrophages and granulocytes, while the other (lysozyme P) is expressed by Paneth cells of the small intestine. In other animals, the number of lysozyme genes and their tissue-specific patterns of expression are highly variable. Complement The direct microbicidal effect of blood plasma on many microbial species is mediated by complement. The key lethal event is the assembly of the membrane attack complex (MAC) consisting of components C5b, C6, C7, C8 with two or more associated C9 molecules in the membranes of target microbes. The insertion of the initiating C5b fragment is the end result of complement activation via one of three complement cascades. The classical pathway is initiated by the binding of C1q molecules to specific antibody clustered on microbial surfaces, the alternative pathway is triggered by the interaction of C3b with the microbial surface, while the lectin pathway depends on contact of C1q-like mannose￾binding protein with specific repeating glycans. The formation of the membrane attack complexes disrupts the ionic homeostasis of the microbes, killing susceptible microbes. Many pathogenic microbes have evolved thick cell walls or capsules that make them partially or completely resistant to complement. The importance of the direct microbicidal activity of comple￾ment is illustrated by the predisposition of patients with a deficiency of C6, C7 or C8 to recurrent infections with Neisseria gonorrhoeae and N. meningitidis. Complement￾like proteolytic cascades appeared early in the evolution of multicellular animals and have a documented antimicro￾bial function already in arthropods (e.g. horseshoe crabs). Defensins Defensins are 3–4-kDa cationic antimicrobial peptides with three intramolecular cystine disulfide bonds and a largely b sheet structure. The vertebrate defensin family contains two branches, designated a- and b-defensins. Although similar in shape to a-defensins, b-defensins are slightly larger and differ in the placement and connectivity of their six conserved cysteine residues. Humans produce at least six different a-defensins and two b-defensins. Three human a-defensins (human neutrophil peptides: HNP-1, HNP-2 and HNP-3) constitute about 30% of the protein content of phagocytic granules of neutrophilic granulo￾cytes. Trace amounts of a fourth defensin, HNP-4, are also found in the same compartment. HNP-1 and HNP-4 are encoded by genes designated DEFA1 and DEFA4, respectively. HNP-3 arises from a single nucleotide substitution in one of the several DEFA1 gene copies. HNP-2 results from posttranslational removal of the N￾terminal residue from HNP-1 and/or HNP-3. The remain￾ing a-defensins HD-5 and HD-6 are expressed by human small-intestinal Paneth cells and are products of the DEFA5 and DEFA6 genes. Paneth cells are specialized, granule-laden secretory epithelial cells located at the bottom of crypts in the small intestine. Human b-defensins HBD-1 and HBD-2 are produced in various epithelia, and are encoded by the DEFB1 and DEFB2 genes, respectively. The DEFB1, DEFB2 gene and the human a-defensin gene cluster are neighbours, occupying a region of about 400– 600 kb on chromosome 8p23. Unlike the a-defensins of neutrophils or Paneth cells, epithelial b-defensins are not stored in cytoplasmic granules. Consequently, their local concentration may be governed primarily by their synth￾esis and secretion rates. Other members of the defensin family of peptides have been found as abundant constituents of granulocytes in rabbits, rats, hamsters, guinea pigs, cows, sheep, chickens and turkeys but are absent from granulocytes of mice, pigs and horses. Epithelial defensins have been found in Paneth cells of mice and rats, and in various epithelia of cows, pigs, sheep and mice. The production of tracheal and lingual antimicrobial peptides (TAP and LAP), as well as that of human epithelial defensin, HBD-2, is induced by inflam￾matory stimuli. Inducible antimicrobial cationic peptides with six cysteines have been identified in the haemolymph of many insects and other invertebrates and have been called ‘insect’ defensins but their evolutionary relationship to vertebrate defensins is uncertain. Peptides of similar structure and composition are found in host defence roles in plants where they are referred to as plant defensins. Defensins manifest broad-spectrum antimicrobial activ￾ity that is characteristically but variably inhibited by increasing salt concentrations. Many bacteria, fungi and some enveloped viruses are inactivated by defensins. The initial interaction of defensins with bacteria or fungi involves electrostatic forces, and is followed by permeabi￾lization of microbial membranes and the entry of defensins into the target cell. Preferential interaction of defensins with microbes as opposed to host cells is probably due to the microbial membrane composition: rich in anionic phospholipids and lacking cholesterol. Patients with ‘specific granule deficiency’ also have a deficiency of granulocyte defensins, and suffer from recurrent bacterial infections. Antimicrobial Proteins and Peptides ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 3