antimicrobial peptides

Heterogeneous group of naturally occurring, so-called "endogenous antibiotics", small, cationic amphiphilic, peptides, consisting of 6-50 amino acids, with broad microbicidal activity. Antimicrobial peptides (AMPs) also known as alarmins, form the host's front line of defense against infection in vertebrates. They are produced in the skin predominantly by keratinocytes. AMPs are part of the innateimmune system and, in addition to their direct antimicrobial function , also have other functions, for example as inflammatory mediators.

Based on their structure, antimicrobial peptides can be classified into different families. In humans, peptides of the following families are found:

• Defensins
• Cathelicidins
• Dermcidins
• Other AMPs

Defensins (AMPs of 30-40 amino acids; depending on their disulfide pattern, defensins are divided into alpha or beta defensins.

• Defensin, alpha 1
• Defensin, alpha 2
• Defensin, alpha 3
• Defensin, alpha 4
• Defensin, alpha 5
• Defensin, alpha 6

The beta-defensins include (keratinocytes produce beta-defensins) the human beta-defensins (HBD-1 to HBD-4).

• Defensin, beta 1
• Defensin, beta 2
• Defensin, beta 3
• Defensin, beta4

Cathelicidins (AMPs including the human cathelicidin LL37). In humans, only LL-37 is produced by neutrophil granulocytes, mast cells and keratinocytes. It exhibits broad antimicrobial activity against both Gram-positive and Gram-negative bacteria. It acts chemotactically on mast cells, neutrophil granulocytes, monocytes, and T cells. LL-37 acts as a Z-cell autoantigen in psoriasis.

Dermcidins (DCD) are antimicrobial peptides produced in human sweat glands and excreted through sweat. One derivative is dermcidin DCD-1L, an antimicrobial peptide.

• Dermcidin D-1 (important AMP in sweat). Proteolytic cleavage produces DCD-1, a peptide of 47 amino acids with broad antimicrobial activity. DCD-1 appears to be decreased in patients with atopic eczema .

Other AMPs of human skin. These include proteinase inhibitors,chemokines, and neuronal peptides. The main representatives of this group are RNase and psoriasin (see below S100A15).

Antimicrobial peptides (AMPs) are small molecules (< than 100 amino acids) synthesized by insects, plants, bacteria, invertebrates, and vertebrates. They play an important role in innate, nonspecific immune defense (see Immunity, innate) within the epithelial barrier function of respiratory, genitourinary, and gastrointestinal tracts as well as the skin in defending against infectious pathogens and modulating the cutaneous microbiota (Schröder 2016).

AMPs can activate cells of the immune system in addition to their original direct defense function, and are therefore referred to as effector substances of the innate immune system. The upregulation of AMP`s in psoriasis might play a role in diser specific inflammatory response. LL-37 is upregulated in psoriasis. LL-37 specific T cells express interferon-gamma as well as Il-17. In patients with rosacea, abnormal processing of cathelicidin LL-37 is thought to be responsible for the inflammatory response.

AMPs are produced in different cell types (especially in macrophages, neutrophil granulocytes, epithelial cells).

Some AMPs such as S100A7/S100A15, beta-defensin-3(HBD-3 = human beta-defensin - 3), and RNAse 7, are constitutively expressed by keratinocytes.

Other AMPs, however, such as HBD1, NBD2, and cathelicidin, are produced on demand. Their expression is mainly induced by microbial factors and inflammatory cytokines.

Cathelicidins and beta-defensins are the best characterized AMP families in the skin.

Diseases with reduced activity of antimicrobial peptides are characterized by immune deficiencies. These include: patients with STAT3 mutation(hyper-IgE syndrome), tumor patients in whom the epidermal growth receptor(EGF receptor) has been therapeutically blocked. Disturbed AMP expressions are also discussed in Crohn's disease and atopic eczema (tendency to infection).

Studies have shown that high concentrations of antimicrobial peptides (e.g. the endogenous antimicrobial peptide LL-37 - belongs to the cathelicidins) were found in extracts of lesional scales of patients with psoriasis vulgaris. This probably explains that psoriatics have less skin infections (see here for atopic eczema).

Physiologically, antimicrobial peptides are also produced on the skin. The protein "RNAse-7" has an antimicrobial potency against vancomycin-resistant enterococci (Enterococcus faecium).

In neonates, there is an increased expression of cathelicidin LL-37 and β-defensin-2 by a factor of 10 to 100 compared to adult skin (compensatory mechanism in still immature immune system).

Pathological colonization of the skin with microbes equally induces antimicrobial control. For example, the saprophytic yeast Malassezia furfur triggers the expression of β-defensin-2 in human keratinocytes. The antimicrobial activity of AMP against multidrug-resistant microorganisms is 1-8 μg/ml in vitro, within the range of conventional synthetic antibiotics; development of resistance is rare.

Patients with atopic eczema show a low concentration of HBD-2 and LL-37 on the skin compared to psoriasis patients (infections e.g. with Staph. aureus may be favoured by this). Probably the reason for this is the up-regulation of the TH-2 cytokines IL-4 and IL-13 which inhibit the AMP`s. The AMP dermidicin is also inhibited in atopic eczema. In principle, the reduction of AMP`s in atopic eczema also leads to reduced control of vaccinia virus replication, which explains the increased susceptibility to generalized herpes simplex infections.

Defensins are also produced in the small intestine, ensuring low bacterial counts. Deficiency of defensins is associated with Crohn's disease.

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