The Role of Human Defensins in Gastrointestinal Diseases

Jost Langhorst; Kyung-Eun Choi

Disclosures

Expert Rev Clin Immunol. 2011;7(6):779-787. 

In This Article

Human Defensins

Human defensins (HDs) contribute to innate immunity at a systemic level.[10] They are presented on nearly every surface of the human body or in human neutrophils, monocytes and lymphocytes; for example, human β-defensin (HBD)-1 is expressed at the respiratory tract, kidney, urogenital epithelium and the colon.[11] Characterized by small cationic arginine-rich peptides with a molecular weight of 3–5 kDa,[12–14] HD have shown antibiotic activity towards Gram-positive and Gram-negative bacteria as well as enveloped viruses and fungi.[4,15–17] Based on the position of three intramolecular disulfide bonds between cysteine residues generating a characteristic tertiary protein structure, HD are classified as α- and β-defensins. The third class of θ-defensins only exists in several species of monkeys, but not in humans.

Human α-defensins

The human neutrophil peptides (α-defensins 1–4) are present in azurophil granules of polymorphonuclear cells. To date, six α-defensins (DEFA1–4 coding for α-defensins 1–4) with stable copy numbers (n = 2)[18] have been isolated in humans and mapped to chromosome 8p22–23.[5,19,20] In man, α-defensins, HD-5 and HD-6 are almost exclusively synthesized and expressed in the small bowel[21] by a specialized form of epithelial cells at the base of the crypts of Lieberkühn – so-called Paneth cells. Their location and properties hint at an essential role for epithelial stem cell protection.[22] Although Paneth cell defensins do not impact the number of bacteria, they do change microbiota composition.[23] While HD-6 has poor antibacterial activity in vitro, HD-5 is active against several bacterial species.[21] Paneth cell antimicrobials, which are stored in secretory granules, are released into the intestinal lumen on stimulation with bacterial products including lipopolysaccharide (LPS) and the specific ligand to nucleotide oligomerization domain 2 (NOD2), muramyl dipeptide (MDP).[3,24] Although many other epithelial defensins are expressed by transcriptional induction in response to infectious stimuli, Paneth cell α-defensins may in fact be expressed continually, even in neonatal and fetal periods before the presence of enteric bacteria.[22]

Human β-defensins

In the gut, the four β-defensins isolated so far in humans (also mapped to chromosome 8p22–23) are expressed by epithelial cells and plasma cells at multiple sites in the lamina propria in the colon.[2,5,18–20] Under physiological conditions, the expression of HBD-1 occurred constitutively, while the expression of HBD-2, -3 and -4 is induced by various bacterial stimuli and proinflammatory cytokines (e.g., IL-1β).[21] HBD-1 was the first defensin to be identified in the human large bowel[25] and its copy number is stable with n = 2.[26] Its antibiotic killing activity has been regarded as being low compared with that of other defensins, but this may be deployed when its disulphide bridges are reduced.[27] HBD-2 as the first inducible human antimicrobial protein discovered was originally isolated from lesional psoriatic skin.[15] With a broad spectrum of antimicrobial and cytokine activity in inflammatory signaling pathways it might promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.[11]

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