α‐Defensins in human innate immunity

Abstract

Defensins are small, multifunctional cationic peptides. They typically contain six conserved cysteines whose three intramolecular disulfides stabilize a largely β-sheet structure. This review of human α-defensins begins by describing their evolution, including their likely relationship to the Big Defensins of invertebrates, and their kinship to the β-defensin peptides of many if not all vertebrates, and the θ-defensins found in certain non-human primates. We provide a short history of the search for leukocyte-derived microbicidal molecules, emphasizing the roles played by luck (good), preconceived notions (mostly bad), and proper timing (essential). The antimicrobial, antiviral, antitoxic, and binding properties of human α-defensins are summarized. The structural features of α-defensins are described extensively and their functional contributions are assessed. The properties of HD6, an enigmatic Paneth cell α-defensin, are contrasted with those of the four myeloid α-defensins (HNP1-4) and of HD5, the other α-defensin of human Paneth cells. The review ends with a decalogue that may assist researchers or students interested in α-defensins and related aspects of neutrophil function.

Functional Determinants of Human Enteric α-Defensin HD5

“…Moreover, MeGlu 21 -HD5 activity was comparable with HD5 activity against E. coli, indicating that E. coli killing is independent of defensin dimerization. We and others have shown that a number of Gram-negative bacterial strains can be killed effectively independent of ␣-defensin structure and chirality (1). The present study further underscores the mechanistic difference in the bactericidal activity of ␣-defensins against these two bacterial strains, one mediated by achiral electrostatic attractions, such as to membrane phosphate groups, and the other mediated partially by hydrophobic interactions that result in specific binding to molecules, such as lipid II.…”

“…The molecular basis of the myriad ␣-defensin functions is gradually being elucidated (1). Many of the prior studies have been focused on two model systems: HNP1 and ␣-defensins from mouse crypts, also known as cryptdins (50).…”

“…Defensins are multifunctional peptides of innate immunity (1)(2)(3)(4)(5). These small, 2-5-kDa peptides are classified into ␣, ␤, and families based on sequence homology and the connectivity of disulfide bonds linking the six conserved cysteine residues (6,7).…”

Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression

“…These data support the involvement of CD30 in the negative control of immune responses directed against self-antigens, a setting largely including tumor-specific T cells. In addition to CD30, other genes were upregulated in SNBs from progressing patients: HMGA1, a transcriptional factor regulating the IFN, IL2, and IL4 genes and recently reported to play a role in transcriptional silencing of the CD4/CD8 loci in the T-cell lineage (30); BSG, which encodes the CD4 þ Foxp3 þ Tregactivation marker CD147 (15), here resulting expressed by nodal CD30 þ lymphocytes; and DEFA1, which encodes defensin a, which has been reported to attract immature DCs and sustain chronic inflammation (31). In addition to the upregulation of defined immune-related genes, GSEA demonstrated that SNBs from patients with poor outcomes displayed a prominent pattern of the reduced expression of genes associated with immunologic responses, thus indicating transcriptional downregulation associated with immune-function impairment.…”

Defensin-chemokine heteromeric complexes derived from heterocellular activation—a possible target to inhibit CCL5 in cardiovascular settings

“…HNP1 belongs to the α-defensin family and is contained within azurophilic granules of neutrophils with other HNPs (HNP 2−4). When these granules fuse with phagosomes, HNPs are thought to be released to pathogen or phagocytic surfaces and cause disruption of microbial membrane to kill bacteria (22).…”