Abstract
Defensins represent an evolutionary ancient family of antimicrobial peptides that play diverse roles in human health and disease. Defensins are cationic cysteine-containing multifunctional peptides predominantly expressed by epithelial cells or neutrophils. Defensins play a key role in host innate immune responses to infection and, in addition to their classically described role as antimicrobial peptides, have also been implicated in immune modulation, fertility, development, and wound healing. Aberrant expression of defensins is important in a number of inflammatory diseases as well as modulating host immune responses to bacteria, unicellular pathogens, and viruses. In parallel with their role in immunity, in other species, defensins have evolved alternative functions, including the control of coat color in dogs. Defensin genes reside in complex genomic regions that are prone to structural variations and some defensin family members exhibit copy number variation (CNV). Structural variations have mediated, and continue to influence, the diversification and expression of defensin family members. This review highlights the work currently being done to better understand the genomic architecture of the β-defensin locus. It evaluates current evidence linking defensin CNV to autoimmune disease (i.e., Crohn’s disease and psoriasis) as well as the contribution CNV has in influencing immune responses to HIV infection.
Highlights
The defensins represent a class of cationic antimicrobial peptides that play pivotal roles in innate and adaptive immunity as well as roles in non-immunological processes
The term “Defensins” was coined in 1985 after granule rich sediments were purified from human and rabbit neutrophils. This resulted in the characterization of the primary structure of the first six neutrophils defensins [1,2,3]. These early studies highlighted the structural hallmarks of defensins: that is, despite poor sequence identity across family members, all defensins possesses a highly conserved motif of six cysteine residues that is key to their antimicrobial function
The complex genetic variation that underlies the evolutionary history of defensins and their biology is gradually being elucidated, suggesting defensin copy number variation (CNV) is an important contributor to maximizing the host innate and adaptive response
Summary
The defensins represent a class of cationic antimicrobial peptides that play pivotal roles in innate and adaptive immunity as well as roles in non-immunological processes. Recent studies have suggested that some β-defensin gene products including hBD1 and hBD3, can interact with a family of melanocortin receptors, modulating pigment expression in dogs and possibly in humans [28]. The variation in the number of repeat units between individuals in the population and likely sequence variation between copies suggests that CNV of defensins may play a role in modulating defensin expression [86, 87] and function. The consequences of CNV have been explored for a number of years and may include increased gene product, the production of fusion genes, the formation of extra coding domains, or a position effect that alters expression of the gene product [88] This extensive structural genome variation in humans is pertinent to diseases where defensins may be implicated in their pathology. A model suggested to explain this apparently paradoxical result was that high CN may promote increased recruitment of CCR6 expressing cell types that are highly permissive for HIV-1 infection amplifying the foci of HIV-1 infection
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