1. Introduction
Selenium was discovered by the Swedish chemist Jöns Jakob Berzelius in 1817 and was considered a toxic element for humans and livestock for nearly 150 years [1]. However, in 1957, the benefits of selenium for humans and other mammals were revealed in landmark studies by Klaus Schwartz and Calvin Foltz who demonstrated that dietary selenium protected rats against liver necrosis [2]. Since then, the role of selenium as a trace mineral nutrient in human health and the mechanisms by which it exerts its biological effects have become better understood.
The U.S. recommended dietary allowance for selenium for adults is 55 μg/day and most individuals achieve this level while several other countries have higher recommended allowances due to a lower average selenium status in their populations [7]. For example, adults in the U.K. are recommended to ingest 60 μg/day for adult women and 75 μg/day for lactating women and adult men [8]. Commonly used measures of a selenium status include plasma and serum selenium concentrations as well as selenoprotein P levels and glutathione peroxidase activity [9,10].
The predominant form of selenium ingested by humans is selenomethionine. However, other forms of selenium are also present in foods.
Most of the effects of dietary selenium on immune functions are attributable to the insertion of this element into a family of proteins called seleno-proteins. What separates selenium from other nutritional elements is the fact that it is incorporated directly into proteins as the 21st amino acid, selenocysteine (Sec).
Therefore, the selenium status is directly related to levels of different selenoproteins in different tissues.
In humans, 25 selenoproteins have been identified and 24 of those exist as Sec-containing proteins in rodents [21], which highlights the value of rodent models for determining roles for members of this protein family in immune responses.
The most completely characterized selenoprotein enzymes related to immune functions include glutathione peroxidases (GPXs), thioredoxin reductases (TXNRDs), iodothyronine deiodinases (DIOs), methionine-R-sulfoxide reductase B1 (MSRB1), and selenophosphate synthetase 2 (SPS2). For non-enzymatic selenoproteins, the best characterized in terms of immune cell function is selenoprotein K (SELENOK).
2. Selenium and Immunobiology
The importance of adequate levels of dietary selenium and its efficient incorporation into selenoproteins in immunity has been demonstrated in cell culture models, in rodent models, in livestock and poultry studies, and in humans. Selenium deficiency can give rise to immune-incompetence that leads to increased susceptibility to infections and possibly to cancers. There is some evidence that selenium can modulate the pathology that accompanies chronic inflammatory diseases in the gut and liver as well as in inflammation-associated cancers [83,84]. Selenium deficiency and suppressed selenoprotein expression have been implicated in higher levels of inflammatory cytokines in a variety of tissues including the gastrointestinal tract [85,86], the uterus [87], mammary gland tissues [88], and others.
Selenium supplementation, for the most part, is immuno-stimulatory, which is measured by a wide range of parameters including T cell proliferation, NK cell activity, innate immune cell functions, and many others [91]. This depends on the baseline selenium status and the strongest effects can be seen when supplementation boosts selenium levels from inadequate to adequate while the benefits of increasing an adequate selenium level to supra-nutritional levels is less clear.
3. Leukocyte Functions
Adaptive immunity is affected by selenium intake including the activation and functions of T and B cells. One immunological feature of selenium levels in vivo is the positive effect that higher selenium has on the proliferation and differentiation of cluster of differentiation(CD)4+ T helper (Th) cells. There are several reports of the skewing of T cell immunity toward Th1 phenotypes.
In a more recent study involving Selenoprotein F (SELENOF) knockout mice, elevated levels of immunoglobulins were detected in the sera that were nonfunctional [38]. The authors of this study concluded that SELENOF functions as a gatekeeper of immunoglobulins in the endoplasmic reticulum (ER), which supports the redox quality control of these proteins and likely other proteins.
Innate immune cell functions have also been shown to be impacted by selenium levels. Macrophages are affected by selenium levels in terms of their inflammatory signaling capacity and anti-pathogen activities. Activation of macrophages through pathogen-associated molecular patterns like lipopolysaccharide (LPS) generates an oxidative burst. Additionally, macrophage activation involves the release of cytokine mediators and arachidonic acid-derived prostaglandins like prostaglandin E2 (PGE2), thromboxane A2 (TXA2), and prostaglandin D2 (PGD2) as well as its metabolite 15-Deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2). It was shown that selenium induces a phenotypic switch in macrophage activation from a classically activated, pro-inflammatory phenotype (M1) toward an alternatively activated, anti-inflammatory phenotype (M2) [105]. Regarding the latter phenotype, selenium was shown to be pivotal for cyclooxygenase-dependent 15d-PGJ2 generation and M2-mediated clearance of helminthic parasite infections [106].
Natural Killer (NK) cells are impacted by dietary selenium intake both directly and indirectly. Serum selenium concentration was positively associated with peripheral CD16+ NK cells in older humans [112]. However, functional capacity of these NK cells, e.g., cytotoxicity, was not determined. A separate study in mice showed that selenium supplementation increased the cytotoxic functions of NK cells [113].
4. Immune Responses to Pathogens
Innate and adaptive immune responses against bacterial and parasitic infections rely on sufficient selenium for eliminating these pathogens. For example, selenium deficiency in mice was shown to impair innate immunity and induce susceptibility to Listeria monocytogenes infection [116].
Selenium is one of many nutrients implicated in the severity and progression of tuberculosis (TB) caused by the bacterium Mycobacterium tuberculosis [124]. Pulmonary TB patients have lower selenium statuses when compared to healthy controls [125].
The most compelling data available regarding the role of selenium in anti-viral immunity are those related to HIV infection, which is a global pandemic that particularly afflicts persons with inadequate nutrition and directly impairs immunity [136]. Selenium is one micronutrient implicated in disease progression. Low selenium intake has been associated with HIV prevalence [137,138] .
Several cohort studies have illustrated an association between selenium deficiency and progression to AIDS-related mortality [147]. Remarkably, randomized controlled trials demonstrated that selenium supplementation minimized hospitalizations and diarrheal morbidity and improved CD4+ T cell counts [141,148].
5. Selenium and Its Effects on a Shift toward Anti-Cancer Immunity
The effects of the selenium status on carcinogenesis or tumor progression have been intensely studied and results have led to a wide variety of conclusions. In humans, there have been several epidemiological studies as well as intervention studies involving different types of cancer, which suggests beneficial effects of higher selenium status [150,151,152]. On the other hand, the selenium status was not found to be a factor in cancer progression in a number of other studies [153,154,155,156]. From the perspective of research in humans, it has proven difficult to separate the direct effects that selenium has on carcinogenesis from its impact on the growth of established tumors as well as its influence on cancer immunity.
6. Specific Mechanisms by Which Selenoproteins Regulate Immunity
There have been some investigations into molecular mechanisms underlying the effects of selenium on the immune system. Because selenium can impact so many cellular functions, it is very difficult to dissect out the many different pathways and individual molecules regulated by this micronutrient. Despite these caveats, the generation of transgenic and knockout mouse models has revealed some intriguing mechanisms involving individual selenoproteins. Two examples shown below involve roles elucidated for two selenoproteins in regulating immune cell functions.
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Referência:
Nutrients. 2018;10(9):1203.
