Brief Evolutionary Perspectives

3.1. Antimicrobial synergy

A myriad of reports on peptide antimicrobial properties has demonstrated that each peptide has its own pattern of microbial specificity and dose-response curve. Even minor differences in amino acid sequence may change properties significantly. It is likely that we under-appreciate how these molecules synergize, perhaps not being as creative in our laboratory studies as nature has been during evolution. Peptides may be weakly microbicidal, but may unmask bacterial structures that lead to increased vulnerability to other molecules of innate immunity. For example, in the horseshoe crab, the peptide tachycitin has low antimicrobial activity but synergisti-cally enhances the activity of a defensin-like peptide fifty-fold [88],

Experience in antimicrobial drug therapy has taught us that multi-drug treatment is the most effective approach to minimising the selection of resistant organisms. Apparently, through expression of large families of active peptides at each site of pathogen exposure, nature has been following this approach for thousands of years in optimising the innate immune response.

3.2. Checks and balances

In a number of examples from the inflammatory, clotting and immune cascades, pathway activation also lays the groundwork for limiting the response. Examples in the field of antimicrobial peptides are present as well, with several described below.

In the first case, proinflammatory cytokines IFN- and IL-6 were shown to stimulate syner-gistically the release of LL-37 from human PBMC, T and NK cells [15]. Simultaneously, these same cytokines down-regulated transcription of the LL-37 gene leading to a net decrease in peptide release 24 hours later.

Second, LL-37 administration to mice protects against endotoxemia yet inhibits macrophage stimulation by bacterial LPS and lipoteichoic acid [89], These results suggest that this potent antimicrobial peptide can modulate the host response through limiting release of proinflammatory cytokines. This was confirmed by expression profiling of LL-37-treated human and mouse monocytes/macrophages. In both cases, chemokines but not TNF-a were up-regulated, consistent with the recruitment of immune cells even while limiting the damaging effects of inflammation.

As a third example, neutrophil activation results in the release of antimicrobial propeptides and their activating proteases including elastase and proteinase 3. Coincidentally these cells release antiproteases that function to limit activation [53], At the same site where these proteases are crucial for promoting inflammation through antimicrobial peptide release, there is speculative evidence that they dampen the inflammatory response via entry into endothelial cells and cleavage of NF-kB [90],

Lastly, we had outlined in an earlier section three examples of antimicrobial peptide affects with bell-shaped dose-response curves, i.e., HNP1-3 enhancing cell proliferation, LL-37 promoting mast cell chemotaxis and protegrins catalysing release of active IL-1 (3. This response profile implies that as peptide concentrations move off of their optimum in either direction, e.g., as a response builds or subsides, their effectiveness will diminish and the system will trend back to baseline equilibrium.

3.3. Gene amplification, rearrangement and mutation

From a broad perspective, genes of the adaptive immune system encoding immunoglobulins and T cell receptors are known to undergo a series of genetic amplifications, rearrangements and mutations that generate a protective diversity promoting survival of the individual. Homologous events involving genes of the innate immune system can be seen as generating a protective diversity promoting survival of a population or species. Specific examples are presented below. The mechanisms for this "genome instability" in innate immunity genes remain to be elucidated, but may represent a precursor for the more familiar examples described in the adaptive immune system.

3.3.1 Amplification

Whole genome sequencing in both humans and mice demonstrated a large collection of closely related a- and [3-defensin genes, presumably derived from duplication events that cluster at a single locus on human chromosome 8p23 [91] and its mouse equivalent. The number of genes varies significantly both between species and even between individuals in the case of HNP1-3 [92]. Similar results are found in the cathelicidin family with humans and mice having one classic cathelicidin, while sheep, cows and pigs have variably large cathelicidin gene families, again clustered at a single chromosomal site [11]. The genetic relationship among the multiple genes of these families, hypothesised based on sequence comparisons of the signal and propiece regions, is consistent with gene duplications occurring both before and after speciation [7].

In addition to the gene duplication events expanding the defensins family at the 8p23 locus, sophisticated computational analysis of genome sequence data points to expansion of the (3-defensin gene family to at least 4 additional sites in the genome and subsequent duplication at each of these sites [40],

3.3.2 Rearrangement

One well-documented example of genetic rearrangement altering tissue-specific expression of innate immune peptides is in the human a-defensins [93], The Paneth cell-specific a-defensins HD-5 and 6 are encoded by two exon genes, while the neutrophil a-defensins are encoded by three exon genes. A detailed comparison revealed a specific recombination event that juxtaposed a new 5' exon onto a 2 exon Paneth cell defensin gene, retargeting expression from the GI tract to neutrophils and creating the first 3 exon neutrophil defensin gene.

3.3.3 Mutation

Genetic mutation has led to a family of mouse Paneth cell a-defensins, numbering perhaps 20 or more, that differ at a limited number of amino acid positions and have significant differences in peptide properties [94], The importance of mutations in the (3-defensin gene family can be demonstrated as well with the association between single nucleotide polymorphisms in the hBD-1 gene and COPD in Japanese populations, most specifically with an increased risk of chronic bronchitis (OR 6.1, (2-18.3)) [95],

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