Knowledge about the ability of vitamin D to function outside its established role in skeletal homeostasis is not a new phenomenon. Nonclassical immunomodulatory and antiproliferative responses triggered by active 1,25-dihydroxyvitamin D were first reported more than a quarter of a century ago. It is only in recent years, however, that there has been a significant improvement in our understanding of how these nonclassical effects of vitamin D can influence the pathophysiology and possible prevention of human disease. Three particular strands of evidence have been prominent: firstly, population studies have revised our interpretation of normal vitamin D status in humans, suggesting, in turn, that vitamin D insufficiency is a clinical problem of global proportions; secondly, epidemiology has linked vitamin D status with disease susceptibility and/or mortality; and, thirdly, expression of the machinery required to synthesize 1,25-dihydroxyvitamin D in normal human tissue seems to be much more widespread than originally thought. Collectively, these observations suggest that nonclassical metabolism and response to vitamin D might have a significant role in human physiology beyond skeletal and calcium homeostasis. Specific examples of this will be detailed in the current Review, with particular emphasis on the immunomodulatory properties of vitamin D.

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Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity.

Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally occurring peptides that can combat infections through their direct microbicidal properties and/or by influencing the host's immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been used to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies.

/pdf/antimicrobial-host-defence-peptides-functions-and-clinical-48oa63nlrk.pdf

Antimicrobial host defence peptides: functions and clinical potential

In the last 5 years, there has been a remarkable change in our understanding of the health benefits of vitamin D. The classical actions of vitamin D as a determinant of mineral metabolism and rachitic bone disease have been expanded to include a broader role in skeletal homoeostasis and prevalent bone disorders such as osteoporosis. However, it is the nonskeletal function of vitamin D that has attracted most attention. Although pluripotent responses to vitamin D have been recognized for many years, our new perspective on nonclassical vitamin D function stems from two more recent concepts. The first is that impaired, vitamin D status is common to many populations across the globe. This has prompted studies to explore the health impact of suboptimal circulating levels of vitamin D, with association studies linking vitamin D 'insufficiency' to several chronic health problems including autoimmune and cardiovascular disease, hypertension and common cancers. In support of a broader role for vitamin D in human health, studies in vitro and using animal models have highlighted immunomodulatory and anticancer effects of vitamin D that appear to depend on localized activation of vitamin D. The conclusion from these reports is that many nonclassical actions of vitamin D are independent of conventional vitamin D endocrinology and are therefore more sensitive to variations in vitamin D status. The current review summarizes these developments, with specific reference to the newly identified effects of vitamin D on the immune system, but also highlights the challenges in translating these observations to clinical practice.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2265.2011.04261.x

An update on vitamin D and human immunity.

As the key components of innate immunity, human host defense antimicrobial peptides and proteins (AMPs) play a critical role in warding off invading microbial pathogens. In addition, AMPs can possess other biological functions such as apoptosis, wound healing, and immune modulation. This article provides an overview on the identification, activity, 3D structure, and mechanism of action of human AMPs selected from the antimicrobial peptide database. Over 100 such peptides have been identified from a variety of tissues and epithelial surfaces, including skin, eyes, ears, mouths, gut, immune, nervous and urinary systems. These peptides vary from 10 to 150 amino acids with a net charge between −3 and +20 and a hydrophobic content below 60%. The sequence diversity enables human AMPs to adopt various 3D structures and to attack pathogens by different mechanisms. While α-defensin HD-6 can self-assemble on the bacterial surface into nanonets to entangle bacteria, both HNP-1 and β-defensin hBD-3 are able to block cell wall biosynthesis by binding to lipid II. Lysozyme is well-characterized to cleave bacterial cell wall polysaccharides but can also kill bacteria by a non-catalytic mechanism. The two hydrophobic domains in the long amphipathic α-helix of human cathelicidin LL-37 lays the basis for binding and disrupting the curved anionic bacterial membrane surfaces by forming pores or via the carpet model. Furthermore, dermcidin may serve as ion channel by forming a long helix-bundle structure. In addition, the C-type lectin RegIIIα can initially recognize bacterial peptidoglycans followed by pore formation in the membrane. Finally, histatin 5 and GAPDH(2-32) can enter microbial cells to exert their effects. It appears that granulysin enters cells and kills intracellular pathogens with the aid of pore-forming perforin. This arsenal of human defense proteins not only keeps us healthy but also inspires the development of a new generation of personalized medicine to combat drug-resistant superbugs, fungi, viruses, parasites, or cancer. Alternatively, multiple factors (e.g., albumin, arginine, butyrate, calcium, cyclic AMP, isoleucine, short-chain fatty acids, UV B light, vitamin D, and zinc) are able to induce the expression of antimicrobial peptides, opening new avenues to the development of anti-infectious drugs.

https://www.mdpi.com/1424-8247/7/5/545/pdf

Human Antimicrobial Peptides and Proteins

The active metabolite of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25(OH)2D3], is involved in calcium and phosphate metabolism and exerts a large number of biological effects. Vitamin D3 inhibits parathyroid hormone secretion, adaptive immunity and cell proliferation, and at the same time promotes insulin secretion, innate immunity and stimulates cellular differentiation. The role of vitamin D3 in immunoregulation has led to the concept of a dual function as both as an important secosteroid hormone for the regulation of body calcium homeostasis and as an essential organic compound that has been shown to have a crucial effect on the immune responses. Altered levels of vitamin D3 have been associated, by recent observational studies, with a higher susceptibility of immune-mediated disorders and inflammatory diseases. This review reports the new developments with specific reference to the metabolic and signalling mechanisms associated with the complex immune-regulatory effects of vitamin D3 on immune cells.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2567.2011.03482.x

Vitamin D3: a helpful immuno-modulator

The antimicrobial peptide LL-37 is the only cathelicidin that has been described in humans. LL-37 exerts chemotactic, immunomodulatory and angiogenic effects; activities that are mediated through binding to the formyl peptide receptor like (FPRL)-1 receptor. Agonistic ligation of FPRL-1 can also induce down-regulation of HIV-1 chemokine receptors and reduce susceptibility to HIV-1 infection in vitro. Therefore, we have evaluated the capacity of LL-37 to inhibit HIV-1 infection in vitro. Here we demonstrate that LL-37 inhibits HIV-1 replication in PBMC, including primary CD4(+) T cells. This inhibition was readily reproduced using various HIV-1 isolates without detectable changes in the target cell expression of HIV-1 chemokine receptors. Accordingly, the HIV-1 inhibitory effect was shown to be independent of FPRL-1 signalling. Given the epithelial expression of LL-37, it may contribute to the local protection against HIV-1 infection.

Lilian Walter-Jallow

Papers

The Antimicrobial Peptide LL-37 Inhibits HIV-1 Replication