Defensins are members of an evolutionarily old family of related peptides (Ganz et al, 1992, 2005; Lehrer, 2004; Crovella et al, 2005). Zhu (2008) has studied the evolutionary relationships of defensins as a class of effectors of innate immunity in three eukaryotic kingdoms. Computational analysis allows identification of six families of fungal defensin-like peptides (see, for example: Plectasin) in which three known defensin types (antibacterial ancient invertebrate-type defensins (abbr. AITD), antibacterial classical insect-type defensins (abbr. CITD), and antifungal plant/insect-type defensins (abbr. PITD)) can be assigned. Sharing of these defensin types between animals and fungi supports their closer evolutionary relationship.
Based on unique consensus sequences, conserved six cysteine residues with differing tridisulfide motifs one distinguishes Alpha-Defensins and Beta-Defensins (Selsted et al, 1996; Schutte and McCray, 2002). The protein family also includes the so-called Cryptdins (mouse Alpha-Defensins) and Corticostatins. For a related factor see also: RK-1).
Rhesus monkey Delta-Defensins (rhesus monkey) (see also: RTD-1) and Theta-Defensins are circular octadecapeptides that contain an internal tridisulfide ladder and are evolutionarily related to alpha-Defensins and beta-Defensins. They are expressed only in nonprimate monkeys, but synthetic versions of them with antiviral activities have been generated (see: retrocyclins). Minidefensins are antimicrobial peptides with 16-18 residues, approximately half the number found in alpha-Defensins. Some of them are related to Alpha-Defensins or Beta-Defensins, whereas others probably arose independently (Cole and Lehrer, 2003).
Defensins were found initially in invertebrates as constituents of a primitive immune system (Froy and Gurevitz, 2003; Froy, 2005; Hoffmann and Hetru, 1992; Rodriguez de la Vega and Possani, 2005; Bulet et al, 2004) but have been found also in other species, including plants and humans (Broekaert et al, 1995). Humans express these factors mainly in neutrophils (Date et al, 1994).
For insect defensins see: Defensin A, Defensin B. For structurally and functionally related peptides from plants see: plant defensins.
Multiple forms of Defensins exist in humans (Bateman et al, 1991). They are obtained by processing of larger precursors (Harwig et al, 1992; Michaelson et al, 1992). Liu et al (1997) have shown that human alpha-Defensins and Beta-Defensins are encoded by adjacent genes. The human gene locus encoding defensins, DEF, maps to chromosome 8p23 (Sparkes et al, 1989). Functional proteins arise by sequential posttranslational processing of a preproprotein of 93-95 amino acids, removing 64 aminoterminal amino acids (Daher et al, 1988; Valore and Ganz, 1992).
Defensin-1 (Alpha-Defensin-1, defensin-alpha-1) is called also HNP-1 (human neutrophil peptide-1, human neutrophil granule peptide-1; abbr. also: HP-1, gene symbol DEFA1, DEF1). It is the same as MRS (myeloid-related sequence).
Defensin-2 (Alpha-Defensin-2, defensin-alpha-2; abbr. DEFA2, DEF2) is called also HNP-2 (human neutrophil peptide-2, human neutrophil granule peptide-2; abbr. also: HP-2).
Defensin-3 (Alpha-Defensin-3, defensin-alpha-3; abbr. DEFA3, DEF3) is called also HNP-3 (human neutrophil peptide-3, human neutrophil granule peptide-3; abbr. also: HP-3). Another human defensin of neutrophils, designated HNP-4 (human neutrophil peptide-4), is approximately 100-fold less abundant and may serve functions other than host defense (Wilde et al, 1989). For a related defensin-like protein from horseshoe crab see also: Big Defensin.
Human Alpha-Defensin family members, HD-5 (Defensin-5, defensin-alpha-5; abbr. DEFA5, DEF5) and HD-6 (Defensin-6, defensin-alpha-6; abbr. DEFA6, DEF6) have been cloned by Mallow et al (1996). These two defensins appear to be expressed predominantly in the Paneth cells of the small intestines. Both proteins are vesicular proteins of Paneth cells (Jones and Bevins, 1992). They are expressed as proforms that require proteolytic activation by trypsin (Ghosh et al, 2002).
Human beta-Defensin-1 (defensin-beta-1, HBD-1, DEFB1, DEFB101) has been isolated from blood filtrates (Bensch et al, 1995) and cloned by Liu et al (1997). Human beta-Defensin-2 (defensin-beta-2, DEFB4, HBD-2), has been cloned by Liu et al, 1998). It has been described also as SAP-1 [skin antimicrobial peptide 1]. Human beta-Defensin-3 (defensin-beta-3, HBD-3, DEFB103 (Boniotto et al, 2003) has been described by Harder et al (2001) and cloned by Jia et al (2001). Human beta-Defensin-4 (defensin-beta-4, DEFB104, HBD-4) has been described by Garcia et al (2001) and Garcia et al (2001). HE2 (human epididymis secretory protein-2) (Jia et al, 2001) has a splice variant (HE2-beta-1) which encodes a beta-Defensin consensus cysteine motif and probably represents a defensin gene product.
Schutte et al (2002) have identified at least 28 other human beta-Defensin genes, many of which are thought to be transcribed. Schutte et al (2002) have identified at least 43 mouse beta-Defensin genes, many of which are thought to be transcribed. Maxwell et al (2003) have identified 14 murine beta-Defensins.
Selsted et al (1993) and Rosen et al (2004) have isolated a series of Beta-Defensins from bovine neutrophils (BNBD = Bovine neutrophil Beta-Defensin; BNBD-1, BNBD-2, BNBD-3, BNBD-4, BNBD-5, BNBD-6, BNBD-7, BNBD-8, BNBD-9, BNBD-10, BNBD-11, BNBD-12, BNBD-13) Bovine BNBD-4 (41 residues) derives from a 63 amino acid prepropeptide. Bovine BNBD-12 (38 residues) and BNBD-13 (42 residues) derive from a common 60 amino acid precursor (BNBD-12/13). The peptides are encoded by genes that are closely related to bovine epithelial beta-Defensin genes (Yount et al, 1999).
Chicken defensins belong to the family of Beta-Defenbsins and have been called gallinacins. THP 1 (turkey heterophil peptide 1) and THP 2 (turkey heterophil peptide 2) are turkey defensins (Brockus et al, 1998).
Defenins from cows have been isolated by Selsted et al (1996). TAP (Tracheal antimicrobial peptide) is the bovine homolog of human beta-Defensin-2 and has been isolated from ciliated epithelium of the bovine trachea (Diamond et al, 2000).
Rabbit microbicidal cationic protein-1 (see: MCP-1) and microbicidal cationic protein-2 (see: MCP-2) are identical with defensins.
Human defensin from neutrophils has been shown to form complexes with serine protease inhibitors (serpins) in mammalian plasma. Complexation abolishes the biological activities of defensins and serpins (Panyutich et al, 1995).
At least nine mouse strains (A/HeJ, AKR/J, BALB/c/J, SWR/J, Swiss Webster outbred, C57BL/10J, C3H/HeJ, CBA/J, DBA/2J) have been described that almost entirely lack defensins in their neutrophils, suggesting that these strains may be imperfect experimental models of infection in which the functions of neutrophils is significant (Eisenhauer and Lehrer, 1992).
Defensin mRNA is detected in normal bone marrow cells but not in peripheral blood leukocytes (Daher et al, 1988). Defensins are found mainly in segmented neutrophilic granulocytes and constitute approximately 30-50 % of all proteins of azurophilic granules. Defensins are released from these granules by transport into vacuoles generated after ingestion of micro-organisms. They destroy these micro-organisms in an oxygen-independent manner by permeabilization of the outer and inner membrane. In micromolar concentrations defensins are bactericidal for a variety of Gram-negative and Gram-positive micro-organism, mycobacteria, and yeasts, and some enveloped viruses. Defensins also possess a nonspecific cytotoxic activity against a wide range of normal and malignant cells, including cells that are resistant to TNF-alpha and NKCF (natural killer cytotoxic factor). They kill cells by inserting themselves into the cell membrane, permeabilizing the membranes by the creation of voltage-regulated channels (Hill et al, 1991; Lichtenstein, 1991). Intestinal beta-Defensins play a major role as broad spectrum immune effector molecules in the defence against bacterial pathogens in the gut (O'Neil, 2003).
Apart from their activity on membranes defensins may act also on DNA, introducing single-strand breaks, and this may, at least in part, also account for some of their biological activities (Gera and Lichtenstein, 1991).
At nanomolar concentrations defensins (HNP-1 and HNP-2, but not HNP-3) are specific potent chemoattractants for monocytes (see also: Chemotaxis) (Territo et al, 1989). The release of defensins by neutrophils may facilitate, therefore, the local accumulation of monocytes in areas of infection and/or inflammation.
HNP-1, the most abundant representative of human defensins, has been found to form very stable complexes with Alpha-2-Macroglobulin which may function as a scavenger of defensins in inflamed tissues and may constitute an important mechanism for the regulation and containment of inflammation (Panyutich and Ganz, 1991).
In addition, defensins may modulate immune responses (Bowdish et al, 2006). For example, human beta-Defensins, Beta-Defensin-2, Beta-Defensin-3, and Beta-Defensin-4 have been shown to stimulate human keratinocytes to express the interleukins IL6 and IL10 and the chemokines, CXCL10, CCL2, CCL5, CCL20, and RANTES (Niyonsaba et al, 2007). defensin-alpha-1 and defensin-beta-1 have been shown to upregulate expression of CD91 in dendritic cells and to enhance the production of the proinflammatory cytokines TNF-alpha, IL6, and IL12p70 (but not IL10) (Presicce et al, 2009)