Research Only Immune & Anti-Inflammatory

HD5

also known as: human α-defensin 5, DEFA5, defensin α5, enteric α-defensin 5

The Paneth cell α-defensin — the dominant antimicrobial peptide of the human small intestine, stored at millimolar concentrations in Paneth cell secretory granules and released into the crypt lumen upon cholinergic or bacterial stimulus. Reduced HD5 expression is a recognised feature of ileal Crohn disease.

A 32-amino-acid cationic α-defensin secreted exclusively by Paneth cells at the base of small-intestinal crypts of Lieberkühn, with a disulfide-stabilised β-sheet fold homologous to HNP-1–3. HD5 is the most abundant antimicrobial peptide of the human small bowel (~50 µg per crypt, ~milligram total output per day), shapes ileal microbiota composition, and is stored as an inactive propeptide that is activated extracellularly by trypsin cleavage. Reduced Paneth cell HD5 expression is a well-documented feature of ileal Crohn disease associated with NOD2 mutations.

Mechanism of action

Stored as an inactive 94-residue propeptide in Paneth cell secretory granules, then activated extracellularly by trypsin (in mice, by matrilysin/MMP-7) cleavage that releases the mature 32-residue defensin. Mature HD5 acts on microbial membranes by the classical defensin mechanism — cationic binding to anionic bacterial phospholipids and lipid II, followed by membrane permeabilisation. In vitro HD5 is broadly active against Gram-positive bacteria (including L. monocytogenes, E. faecalis, S. aureus), Gram-negative bacteria (E. coli, Salmonella), fungi (C. albicans), and some enveloped viruses. Beyond direct microbicidal activity, HD5 contributes to the shaping of small-intestinal microbiota (mouse Paneth cell defensin ablation, via CR-2-deficient Defa5-expressing transgenics, produces reproducible dysbiosis) and contributes to the ileal barrier against enteric pathogens.

Primary uses

  • Research reagent for mucosal antimicrobial peptide studies
  • Inflammatory bowel disease research (ileal Crohn disease defensin-deficiency hypothesis)
  • Microbiome research on Paneth cell / defensin / microbiota interactions
  • Clinical biomarker research (Paneth cell HD5 expression by immunohistochemistry in biopsy samples)

Typical dosing

Not established

⚠ No human dosing established. HD5 has never been administered as a therapeutic.

Regulatory status

Not a drug. HD5 is an endogenous human Paneth cell defensin studied as a research reagent for mucosal immunity, microbiome, and inflammatory bowel disease research. Synthetic HD5 is commercially available from peptide vendors. Clinical correlates: reduced Paneth-cell HD5 and HD6 expression in ileal Crohn disease has been one of the most reproduced mucosal-immunity findings of the past 20 years, though the therapeutic implications remain unclear.

References

  1. [pubmed] Jones DE, Bevins CL. "Paneth cells of the human small intestine express an antimicrobial peptide gene." J Biol Chem, 1992;267(32):23216-23225. (First cloning and characterisation of HD5.)
  2. [pubmed] Ghosh D, Porter E, Shen B, et al. "Paneth cell trypsin is the processing enzyme for human defensin-5." Nat Immunol, 2002;3(6):583-590.
  3. [pubmed] Wehkamp J, Salzman NH, Porter E, et al. "Reduced Paneth cell alpha-defensins in ileal Crohn disease." Proc Natl Acad Sci USA, 2005;102(50):18129-18134.

Related peptides

HD6

The Paneth cell α-defensin that does not kill directly — HD6 traps enteric pathogens by self-assembling into fibrillar "nanonets" (Chu et al., Science 2012), a mechanism unique among the defensin family. Poor microbicidal activity in vitro was a decade-long puzzle until the trapping mechanism was discovered.

HNP-1

The prototype human α-defensin — isolated from neutrophil granules by Ganz, Selsted and Lehrer in 1985; the dominant antimicrobial peptide in human neutrophils and a workhorse molecule of innate immunity. Research peptide only: no defensin has ever been developed as an approved drug.

hBD-1

The constitutive epithelial β-defensin — first isolated from haemodialysate urine by Bensch, Schröder and colleagues (FEBS Letters 1995). Constitutively expressed (unlike hBD-2 and hBD-3, which are inducible), salt-sensitive in standard assays, and a major component of urogenital and airway surface antimicrobial defense.

hBD-2

The inducible β-defensin — cloned by Harder, Bartels, Christophers and Schröder (Nature 1997) from the lesional scales of psoriasis patients, with the paper framing psoriatic skin as a paradoxical "almost-never-infected" phenotype driven by massive β-defensin induction. Induced by TLR / NF-κB signalling in response to bacterial lipopolysaccharide and pro-inflammatory cytokines (IL-1, TNF-α).

hBD-3

The broad-spectrum β-defensin — active against Gram-positive, Gram-negative and fungal targets, and largely salt-insensitive (unlike hBD-1). Isolated independently in 2001 by Harder et al. and by García et al. from psoriatic skin and tonsil respectively. The β-defensin most studied for clinical translation because of its salt tolerance.
Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.