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A single-center, randomized, double-blind, placebo-controlled study was conducted in 72 volunteers who received a synergistic combination of yeast-based ingredients with a unique β-1,3/1,6-glucan complex and a consortium of heat-treated probiotic Saccharomyces cerevisiae rich in selenium and zinc (ABB C1 ® ) or placebo on the next day after getting vaccinated against influenza (Chiromas ® ) ( n = 34) or the COVID-19 (Comirnaty ® ) ( n = 38). The duration of treatment was 30 and 35 days for the influenza and COVID-19 vaccine groups, respectively. Mean levels of CD4+T cells increased from 910.7 at baseline to 1000.2 cells/µL after the second dose of the COVID-19 vaccine in the ABB C1 ® group, whereas there was a decrease from 1055.1 to 929.8 cells/µL in the placebo group. Changes of CD3+T and CD8+T lymphocytes showed a similar trend. In the COVID-19 cohort, the increases in both IgG and IgM were higher in the ABB C1 ® supplement than in the placebo group. Serum levels of selenium and zinc showed a higher increase in subjects treated with the active product than in those receiving placebo. No serious adverse events related to ABB C1 ® or tolerance issues were reported. The study findings validate the capacity of the ABB C1 ® product to stimulate trained immunity.

Non-canonical inflammasome activation by mouse caspase-11 (or human CASPASE-4/5) is crucial for the clearance of certain gram-negative bacterial infections, but can lead to severe inflammatory damage. Factors that promote non-canonical inflammasome activation are well recognized, but less is known about the mechanisms underlying its negative regulation. Herein, we identify that the caspase-11 inflammasome in mouse and human macrophages (Mϕ) is negatively controlled by the zinc (Zn 2+ ) regulating protein, metallothionein 3 (MT3). Upon challenge with intracellular lipopolysaccharide (iLPS), Mϕ increased MT3 expression that curtailed the activation of caspase-11 and its downstream targets caspase-1 and interleukin (IL)-1β. Mechanistically, MT3 increased intramacrophage Zn 2+ to downmodulate the TRIF-IRF3-STAT1 axis that is prerequisite for caspase-11 effector function. In vivo , MT3 suppressed activation of the caspase-11 inflammasome, while caspase-11 and MT3 synergized in impairing antibacterial immunity. The present study identifies an important yin-yang relationship between the non-canonical inflammasome and MT3 in controlling inflammation and immunity to gram-negative bacteria., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chowdhury, Gardner, Satpati, Nookala, Mukundan, Porollo, Landero Figueroa and Subramanian Vignesh.)

Food supplements (FS) are a concentrated source of vitamins, minerals, or other ingredients with nutritional or other physiological effects. Due to their easy availability, widespread advertising, and sometimes low price, increased consumption of this group of preparations has been observed. Therefore, the aim of the study was to assess the knowledge and intake of FS during the COVID-19 pandemic in Poland, with particular reference to FS containing zinc and vitamin D. It was noted that both of the above ingredients were used significantly more often by people with higher education (59.0%), with a medical background or related working in the medical field (54.5%), and/or exercising at home (60.1%). Preparations containing vitamin D were used by 22.8% of the respondents in the first wave, 37.6% in the second wave, and 32.9% in the third wave. To sum up, we showed the highest consumption of vitamin and mineral supplements, and preparations containing zinc and vitamin D were taken significantly more often by people with higher medical and related education. This indicates a high awareness of health aspects and the need for preventive measures in these groups.

The significance of zinc for an efficient immune response is well accepted. During zinc deficiency, an increase in the myeloid to lymphoid immune cells ratio was observed. This results in a disturbed balance of pro- and anti-inflammatory processes as well as defects in tolerance during infections. Consequently, instead of efficiently defending the body against invading pathogens, damage of host cells is frequently observed. This explains the increased susceptibility to infections and their severe progression observed for zinc deficient individuals as well as the association of autoimmune diseases with low serum zinc levels. Together with the advances in techniques for investigating cellular development, communication and intracellular metabolism, our understanding of the mechanisms underlying the benefits of zinc for human health and the detriments of zinc deficiency has much improved. As analyses of the zinc status and effects of zinc supplementation were more frequently included into clinical studies, our knowledge of the association of zinc deficiency to a variety of diseases was strongly improved. Still there are several areas in zinc biology that require further in-depth investigation such as the interaction with other nutritional elements, the direct association between zinc transportation, membrane-structure, receptors, and signaling as well as its role in cell degeneration. This article will describe our current understanding of the role of zinc during the immune response focusing on the most recent findings and underlying mechanisms. Research questions that need to be addressed in the future will be discussed as well., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival., Objective: The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19., Methods: We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020., Results: Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials., Conclusions: Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Periparturient period induces stress in cows which fluctuates hormonal and metabolic function and causes immune suppression. Apart from impairing the health, production, and reproduction of cows, it also influences the well-being of newborn calves by decreasing the colostrum quality. Micronutrients are known for optimal health and production and their effects on parturition stress, immune response in both cow and its calf need to be explored., Aim: The aim of this study was to see the effect of oral supplementation of micronutrients during the prepartum period on the health status of crossbred dairy cows and subsequently on their newborn calves., Methods: A total of 42 healthy multiparous cows were selected and randomly divided into five groups with seven cows in each group, i.e. control (Basal Diet, BD), VA group (BD + vitamin A, 10 5 IU), Zn group (BD + zinc sulphate, 60 ppm), VE group (BD + vitamin E, 2500 IU), and combined supplementation (CS) group (BD + combination of VA, Zn, and VE). The supplements were offered in compounded concentrate DM (100 g) to individual cows once daily before the morning feeding and the remaining portion was incorporated in the TMR. Feeding was started one month before the expected days of calving till calving. Blood samples were collected from cows at days -15, -7, -3, 0, +3, +7, and +15 relative to the day of calving. Blood samples from newborn calves and milk samples of cows were collected at days 0, +3, +7, and +15. Milk somatic cell counts (SCC) were estimated using a cell counter. Cortisol was estimated by ELISA kit in blood and milk plasma of cows and in the blood plasma of their calves. Total immunoglobulins (Ig) were estimated in milk of cows and serum of calves using zinc sulphate turbidity method. Blood neutrophils from cows and calves were studied for phagocytic activity (PA) using nitro blue tetrazolium (NBT) assay.Data were analysed by repeated-measures two-way ANOVA using the mixed procedure of SAS, and the pairwise comparison was performed using a multiple comparison test (Tukey)., Results: Combined supplementation of micronutrients decreased (P < 0.05) maternal blood plasma (control vs. CS group, 5.98 ± 0.20 vs. 3.86 ± 0.23 ng/mL) and milk plasma (3.96 ± 0.13 vs. 2.71 ± 0.10 ng/mL) cortisol, milk SCC (3.05 ± 0.11 vs. 2.12 ± 0.10 × 10 5 cells/mL) and increased (P < 0.05) total milk Ig concentration (18.80 ± 0.11 vs. 23.04 ± 0.57 mg/mL) and the PA of blood neutrophils (0.84 ± 0.03 vs. 1.07 ± 0.03). Similarly, lower blood cortisol concentration (9.69 ± 0.35 vs. 6.02 ± 0.18 ng/mL) and higher (P < 0.05) total Ig (23.26 ± 0.11 vs. 30.34 ± 0.70 mg/mL) and PA of blood neutrophils (0.37 ± 0.02 vs. 0.52 ± 0.02) were observed in the calves born to CS group of cows as compared to the control. Highest (P < 0.05) positive effects (lower stress levels and higher immune response) of treatment were noticed in CS group followed by VE group and then Zn group. However, VA group didn't differ from the control group., Conclusion: Our results indicate that micronutrient interventions during the prepartum period can improve the health status of dairy calves and subsequently the well-being of their calves., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Background & Aims: The micronutrient zinc is essential for proper immune function. Consequently, zinc deficiency leads to impaired immune function, as seen in decreased secretion of interleukin (IL)-2 by T cells. Although this association has been known since the late 1980s, the underlying molecular mechanisms are still unknown. Zinc deficiency and reduced IL-2 levels are especially found in the elderly, which in turn are prone to chronic diseases. Here, we describe a new molecular link between zinc deficiency and reduced IL-2 expression in T cells., Methods: The effects of zinc deficiency were first investigated in vitro in the human T cell lines Jurkat and Hut-78 and complemented by in vivo data from zinc-supplemented pigs. A short- and long-term model for zinc deficiency was established. Zinc levels were detected by flow cytometry and expression profiles were investigated on the mRNA and protein level., Results: The expression of the transcription factor cAMP-responsive-element modulator α (CREMα) is increased during zinc deficiency in vitro, due to increased protein phosphatase 2A (PP2A) activity, resulting in decreased IL-2 production. Additionally, zinc supplementation in vivo reduced CREMα levels causing increased IL-2 expression. On epigenetic levels increased CREMα binding to the IL-2 promoter is mediated by histone deacetylase 1 (HDAC1). The HDAC1 activity is inhibited by zinc. Moreover, deacetylation of the activating histone mark H3K9 was increased under zinc deficiency, resulting in reduced IL-2 expression., Conclusions: With the transcription factor CREMα a molecular link was uncovered, connecting zinc deficiency with reduced IL-2 production due to enhanced PP2A and HDAC1 activity., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Zinc is an essential micronutrient in human body and a vital cofactor for the function of numerous proteins encoded by the human genome. Zinc has a critical role in maintaining many biochemical and physiological processes at the molecular, cellular, and multiple organ and systemic levels. The alteration of zinc homeostasis causes dysfunction of many organs and systems. In the immune system, zinc regulates the differentiation, proliferation and function of inflammatory cells, including T cells, eosinophils, and B cells, by modifying several signaling pathways such as NFκB signaling pathways and TCR signals. An adequate zinc level is essential for proper immune responses and decreased zinc levels were reported in many allergic inflammatory diseases, including atopic dermatitis, bronchial asthma, and chronic rhinosinusitis. Decreased zinc levels often enhance inflammatory activation. On the other hand, the inflammatory conditions alter the intracellular homeostasis of zinc, often decreasing zinc levels. These findings implied that there could be a vicious cycle between zinc deficiency and inflammatory conditions. In this review, we present recent evidence on the involvement of zinc in atopic dermatitis, bronchial asthma, and chronic rhinosinusitis, with insights into the involvement of zinc in the underlying molecular and cellular mechanisms related to these allergic inflammatory diseases., (Copyright © 2020 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

TLR-inducible zinc toxicity is an antimicrobial mechanism utilized by macrophages, however knowledge of molecular mechanisms mediating this response is limited. Here, we show that E. coli exposed to zinc stress within primary human macrophages reside in membrane-bound vesicular compartments. Since SLC30A zinc exporters can deliver zinc into the lumen of vesicles, we examined LPS-regulated mRNA expression of Slc30a/SLC30A family members in primary mouse and human macrophages. A number of these transporters were dynamically regulated in both cell populations. In human monocyte-derived macrophages, LPS strongly up-regulated SLC30A1 mRNA and protein expression. In contrast, SLC30A1 was not LPS-inducible in macrophage-like PMA-differentiated THP-1 cells. We therefore ectopically expressed SLC30A1 in these cells, finding that this was sufficient to promote zinc-containing vesicle formation. The response was similar to that observed following LPS stimulation. Ectopically expressed SLC30A1 localized to both the plasma membrane and intracellular zinc-containing vesicles within LPS-stimulated THP-1 cells. Inducible overexpression of SLC30A1 in THP-1 cells infected with the Escherichia coli K-12 strain MG1655 augmented the zinc stress response of intracellular bacteria and promoted clearance. Furthermore, in THP-1 cells infected with an MG1655 zinc stress reporter strain, all bacteria contained within SLC30A1-positive compartments were subjected to zinc stress. Thus, SLC30A1 marks zinc-containing compartments associated with TLR-inducible zinc toxicity in human macrophages, and its ectopic over-expression is sufficient to initiate this antimicrobial pathway in these cells. Finally, SLC30A1 silencing did not compromise E. coli clearance by primary human macrophages, suggesting that other zinc exporters may also contribute to the zinc toxicity response., (©2020 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)

Chronic obstructive pulmonary disease is characterized by progressive, irreversible airflow obstruction resulting from an abnormal inflammatory response to noxious gases and particles. Alveolar macrophages rely on the transcription factors, nuclear factor κB and mitogen-activated protein kinase, among others, to facilitate the production of inflammatory mediators designed to help rid the lung of foreign pathogens and noxious stimuli. Building a kinetic model using queuing networks, provides a quantitative approach incorporating an initial number of individual molecules along with rates of the reactions in any given pathway. Accordingly, this model has been shown useful to model cell behavior including signal transduction, transcription, and metabolic pathways. The aim of this study was to determine whether a queuing theory model that involves lipopolysaccharide-mediated macrophage activation in tandem with changes in intracellular Cd and zinc (Zn) content or a lack thereof, would be useful to predict their impact on immune activation. We then validate our model with biologic cytokine output from human macrophages relative to the timing of innate immune activation. We believe that our results further prove the validity of the queuing theory approach to model intracellular molecular signaling and postulate that it can be useful to predict additional cell signaling pathways and the corresponding biological outcomes., (© 2020 Wiley Periodicals LLC.)

The world is currently in the grips of the coronavirus disease (COVID-19) pandemic, caused by the SARS-CoV-2 virus, which has mutated to allow human-to-human spread. Infection can cause fever, dry cough, fatigue, severe pneumonia, respiratory distress syndrome and in some instances death. COVID-19 affects the immune system by producing a systemic inflammatory response, or cytokine release syndrome. Patients with COVID-19 have shown a high level of pro-inflammatory cytokines and chemokines. There are currently no effective anti-SARS-CoV-2 viral drugs or vaccines. COVID-19 disproportionately affects the elderly, both directly, and through a number of significant age-related comorbidities. Undoubtedly, nutrition is a key determinant of maintaining good health. Key dietary components such as vitamins C, D, E, zinc, selenium and the omega 3 fatty acids have well-established immunomodulatory effects, with benefits in infectious disease. Some of these nutrients have also been shown to have a potential role in the management of COVID-19. In this paper, evidence surrounding the role of these dietary components in immunity as well as their specific effect in COVID-19 patients are discussed. In addition, how supplementation of these nutrients may be used as therapeutic modalities potentially to decrease the morbidity and mortality rates of patients with COVID-19 is discussed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background & Aims: The COVID-19 infection can lead to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mainly affecting patients aged 60 and older. Preliminary data suggest that the nutritional status can change the course of the infection, and on the matter, zinc is crucial for growth, development, and the maintenance of immune function. In the absence of treatment for this virus, there is an urgent need to find alternative methods that can contribute to control of disease. The aim of this paper is to establish the relation between zinc and COVID-19., Methods and Results: From the prior scientific knowledge, we have performed a review of the literature and examine the role of zinc in immune function in the infection by COVID-19. Our findings are that the zinc as an anti-inflammatory agent may help to optimize immune function and reduce the risk of infection., Conclusions: Zinc supplementation can be a useful strategy to reduce the global burden of infection in the elderly, there is a need the increased reporting to improve our understanding of COVID-19 and the care of affected patients., Competing Interests: Declaration of Competing Interest No conflict of interest to declare., (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Colonization by pathogenic bacteria depends on their ability to overcome host nutritional defenses and acquire nutrients. The human pathogen group A streptococcus (GAS) encounters the host defense factor calprotectin (CP) during infection. CP inhibits GAS growth in vitro by imposing zinc (Zn) limitation. However, GAS counterstrategies to combat CP-mediated Zn limitation and the in vivo relevance of CP-GAS interactions to bacterial pathogenesis remain unknown. Here, we report that GAS upregulates the AdcR regulon in response to CP-mediated Zn limitation. The AdcR regulon includes genes encoding Zn import ( adcABC ), Zn sparing ( rpsN.2 ), and Zn scavenging systems ( adcAII , phtD , and phtY ). Each gene in the AdcR regulon contributes to GAS Zn acquisition and CP resistance. The Δ adcC and Δ rpsN.2 mutant strains were the most susceptible to CP, whereas the Δ adcA , Δ adcAII , and Δ phtD mutant strains displayed less CP sensitivity during growth in vitro However, the Δ phtY mutant strain did not display an increased CP sensitivity. The varied sensitivity of the mutant strains to CP-mediated Zn limitation suggests distinct roles for individual AdcR regulon genes in GAS Zn acquisition. GAS upregulates the AdcR regulon during necrotizing fasciitis infection in WT mice but not in S100a9 -/- mice lacking CP. This suggests that CP induces Zn deficiency in the host. Finally, consistent with the in vitro results, several of the AdcR regulon genes are critical for GAS virulence in WT mice, whereas they are dispensable for virulence in S100a9 -/- mice, indicating the direct competition for Zn between CP and proteins encoded by the GAS AdcR regulon during infection., (Copyright © 2020 American Society for Microbiology.)

During the current corona pandemic, new therapeutic options against this viral disease are urgently desired. Due to the rapid spread and immense number of affected individuals worldwide, cost-effective, globally available, and safe options with minimal side effects and simple application are extremely warranted. This review will therefore discuss the potential of zinc as preventive and therapeutic agent alone or in combination with other strategies, as zinc meets all the above described criteria. While a variety of data on the association of the individual zinc status with viral and respiratory tract infections are available, study evidence regarding COVID-19 is so far missing but can be assumed as was indicated by others and is detailed in this perspective, focusing on re-balancing of the immune response by zinc supplementation. Especially, the role of zinc in viral-induced vascular complications has barely been discussed, so far. Interestingly, most of the risk groups described for COVID-19 are at the same time groups that were associated with zinc deficiency. As zinc is essential to preserve natural tissue barriers such as the respiratory epithelium, preventing pathogen entry, for a balanced function of the immune system and the redox system, zinc deficiency can probably be added to the factors predisposing individuals to infection and detrimental progression of COVID-19. Finally, due to its direct antiviral properties, it can be assumed that zinc administration is beneficial for most of the population, especially those with suboptimal zinc status., (Copyright © 2020 Wessels, Rolles and Rink.)

Background and Aims: Patients with inflammatory bowel disease [IBD], especially Crohn's disease, often develop zinc deficiency. However, the precise mechanisms by which zinc deficiency affects IBD pathology, particularly intestinal macrophage function, remain unclear. We studied the effects of zinc deficiency on the development and progression of colitis in mice., Methods: To induce colitis, mice were treated with 2,4,6-trinitrobenzene sulphonic acid. Rag1-/- mice were then given injections of naïve CD4+CD62L+ T cells. The respective degrees of mucosal injury of mice that had received a zinc chelator (TPEN; N,N,N',N'-tetrakis [2-pyridylmethyl]ethylenediamine) and of control mice were subsequently compared. Colonic lamina propria mononuclear cells were isolated by enzymatic digestion and were examined using flow cytometry. To generate mouse bone marrow-derived macrophages [BMDMs], bone marrow cells were stimulated with mouse macrophage-colony stimulating factor., Results: Zinc deficiency aggravates colonic inflammation through the activation of type 17 helper T [Th17] cells in mice. Flow cytometric analysis revealed that zinc deficiency significantly increases the proportion of pro-inflammatory [M1] macrophages in colonic lamina propria mononuclear cells obtained from inflamed colon. Interferon-γ plus lipopolysaccharide-mediated M1 skewing alters the expression of zinc transporters in BMDMs and thereby decreases the intracellular free zinc. TPEN treatment mimicking the effects of the M1 skewing up-regulates IL-23p19 expression, which is strongly related to Th17 development. Furthermore, the nuclear accumulation of interferon-regulatory factor 5 is closely involved in IL-23p19 induction in zinc-deficient macrophages., Conclusions: Zinc deficiency aggravates colonic inflammation through activation of the IL-23/Th17 axis. This activation is controlled by subcellular distribution of interferon-regulatory factor 5., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Macrophages are key phagocytic cells and play an important role in eliminating external microorganisms and endogenous danger signals. Dysregulation in macrophage functions have been reported in patients with asthma. Zinc homeostasis is critical in maintaining macrophage functions. The solute carrier (SLC) protein SLC39A7, a Zn2+ importer, has recently been linked to asthma. However, the roles of SLC39A7 in macrophage phagocytosis are not well understood. Here we found that phagocytosis efficiency was significantly decreased in SLC39A7-knockdown THP-1 cells, however the phagocytosis capability could be reversed with zinc supplementation. SLC39A7 deficiency skewed macrophages towards alternative activation, as indicated by increased expression of M2 activation marker CD206 and decreased expression of M1 activation marker NOS2. Consistent to this result, SLC39A7-knockdown cells produced reduced amounts of proinflammatory cytokines TNF- and IL-6. Furthermore, the mRNA level of receptor Clec4e previously known to be involved in phagocytosis of BCG was significantly reduced in SLC39A7 knockdown cells. Importantly, all these defects due to SLC39A7 deficiency could be reversed by zinc supplementation. Thus, zinc transporter SLC39A7 provide support for phagocytosis and classical macrophage activation., Competing Interests: The authors have declared that no competing interests exist.

Background: The etiology of ulcerative colitis (UC) remains elusive even though many genetic and environmental pathogenic factors have been reported. Aberrant inflammatory responses mediated by specific subsets of T cells have been observed in ulcerative lesions of UC patients., Objectives: To elucidate the involvement of a delayed-type hypersensitivity reaction in UC, we focused on dental metal hypersensitivity, a T cell-mediated, delayed-type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation., Method: We recruited 65 Japanese UC patients and 22 healthy controls (HC) and used the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium - the metals that have been widely used in dentistry. All subjects were users of metallic dental implants and/or prostheses containing zinc, gold, nickel, and/or palladium as major constituents., Results: Sixty percent of the UC patients were hypersensitive to at least one metal species, whereas 32% of the HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for UC patients than for HC. Furthermore, a significantly greater proportion of UC patients were hypersensitive to nickel or palladium. The severity of the sensitivity to nickel and palladium was also significantly greater for UC patients than for HC., Conclusions: This pilot study demonstrates that UC patients have a significantly higher incidence of hypersensitivity to nickel and palladium, suggesting the possible involvement of dental metal hypersensitivity in UC pathogenesis., (© 2020 S. Karger AG, Basel.)

Zinc is an essential cofactor required for life and, as such, mechanisms exist for its homeostatic maintenance in biological systems. Despite the evolutionary distance between vertebrates and microbial life, there are parallel mechanisms to balance the essentiality of zinc with its inherent toxicity. Vertebrates regulate zinc homeostasis through a complex network of metal transporters and buffering systems that respond to changes in nutritional zinc availability or inflammation. Fine-tuning of this network becomes crucial during infections, where host nutritional immunity attempts to limit zinc availability to pathogens. However, accumulating evidence demonstrates that pathogens have evolved mechanisms to subvert host-mediated zinc withholding, and these metal homeostasis systems are important for survival within the host. We discuss here the mechanisms of vertebrate and bacterial zinc homeostasis and mobilization, as well as recent developments in our understanding of microbial zinc acquisition., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background : Asthma is a common childhood disorder with complex pathobiologic components that may include aspects of nutritional deficit. The contribution of vitamin deficiency, specifically vitamin A, as part of the disease complex has not been well studied, particularly among at risk children. In this study, we examined the prevalence of vitamin A as well as zinc deficiency in conjunction with visual function among an urban pediatric population sample with moderate-severe persistent asthma. Methods : A cross-sectional case-control assessment of serum vitamin A, zinc and visual function among urban children with and without asthma was undertaken. Inclusion criteria involved (1) well-controlled pediatric asthmatic patients between the ages of 8-18 with corrected vision of at least 20/25 in each eye and (2) chronic use of a combination beta agonist-steroid inhaler. Visual function was assessed by Snellen visual acuity and Peli Robson contrast sensitivity assessment. Results : Overall, 24 patients were enrolled for study with body mass index and age matched between asthmatic and control groups. Median serum vitamin A and zinc levels among control subjects was statistically higher compared to asthmatics ( p  = 0.0303 and p  = 0.0111, respectively). Based on age-based reference levels there was no evidence of vitamin A or zinc deficiency among asthmatics or controls. Serum vitamin A and zinc were found to directly correlate with body mass index ( p  = 0.0074 and p  = 0.0474, respectively), but not age or measures of visual function. Contrast sensitivity was however significantly reduced among asthmatic subjects ( p  = 0.0003). Conclusions : Children with chronic asthma demonstrate reduced levels of vitamin A and zinc that may be related to disease pathobiology however, evidence of frank zinc or vitamin A deficiency was not demonstrated. Reduced contrast sensitivity found in the asthmatic group appears unrelated to serum vitamin A and/or zinc levels.

(1) Background: Zinc is an essential micronutrient and zinc deficiency is associated with immune dysfunction. The neonatal immune system is immature, and therefore an optimal neonatal zinc status may be important. The aim of this study was to investigate the possible association between neonatal whole blood (WB)-Zinc content and several immune markers. (2) Methods: In total, 398 healthy newborns (199 who later developed type 1 diabetes and 199 controls) from the Danish Newborn Screening Biobank had neonatal dried blood spots (NDBS) analyzed for WB-Zinc content and (i) cytokines: Interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-12 (p70), interferon gamma, tumor necrosis factor alpha, and transforming growth factor beta; (ii) adipokines: leptin and adiponectin; (iii) other immune response proteins: C-reactive protein (CRP), and mannose-binding lectin (MBL), and soluble triggering receptors expressed on myeloid cells1 (sTREM-1). WB-Zinc content was determined using laser ablation inductively coupled plasma mass spectrometry. For each analyte, the relative change in mean level was modelled by a robust log-normal model regression. (3) Results: No association was found between WB-Zinc content and all the immune response markers in either the unadjusted or adjusted models overall or when stratifying by case status. (4) Conclusions: In healthy Danish neonates, WB-Zinc content was not associated with cytokines, adipokines, CRP, MBL or sTREM, which does not indicate a strong immunological function of neonatal zinc status.

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn 2+ in modulating B cell receptor signal strength and positive selection.

Background: Normal immune functioning requires sufficient levels of trace elements including zinc and selenium, while elements such as nickel can be immunotoxic., Aim: To assess long-term abnormalities in zinc, selenium and nickel levels in patients with chronic recurrent warts., Methods: Toenail samples were taken from 28 patients with chronic recurrent warts and 30 apparently healthy matching controls were analysed. Toenail concentrations of zinc, selenium and nickel were measured using inductively-coupled plasma-optical emission spectroscopy., Results: Selenium levels were significantly higher in patients than in controls (P = 0.03). Levels of trace elements did not correlate with the number or duration of warts. Toenail nickel levels in all subjects were higher than globally reported values., Limitations: A small sample size and the absence of regional reference ranges for concentrations of trace elements in toenails., Conclusion: Zinc does not seem to be involved in the chronicity of warts, and it is unclear if selenium has a protective role against warts. Our finding of high concentrations of nickel in both patients and controls raises concerns about environmental exposure., Competing Interests: None

Zinc is an essential micronutrient known to play a vital role in host defense against pathogens. Diets that are deficient in zinc lead to impaired immunity and delayed recovery from and worse outcomes following infection. Sustained insufficient zinc intake leads to dysregulation of the innate immune response and increases susceptibility to infection whereas zinc supplementation in at-risk populations has been shown to restore host defense and reduce pathogen-related morbidity and mortality. Upon infection, zinc deficiency leads to increased pathology due to imbalance in key signaling networks that result in excessive inflammation and collateral tissue damage. In particular, zinc impacts macrophage function, a critical front-line cell in host defense, in addition to other immune cells. Deficits in zinc adversely impact macrophage function resulting in dysregulation of phagocytosis, intracellular killing, and cytokine production. An additional work in this field has revealed a vital role for several zinc transporter proteins that are required for proper bioredistribution of zinc within mononuclear cells to achieve an optimal immune response against invading microorganisms. In this review, we will discuss the most recent developments regarding zinc's role in innate immunity and protection against pathogen invasion.

Background: Zinc deficiency may play an important role in the development of atopic asthma., The Aim of the Work: To assess serum zinc levels in adult atopic, non-atopic asthmatic patients, and in healthy controls and to investigate its modulatory effect on production of interferon gamma (IFN-γ) and interleukin-10 (IL-10) by peripheral blood mononuclear cells (PBMCs) in vitro., Methods: Sixty asthmatics and 30 apparently healthy volunteers were included in this study. All patients were subjected to history taking, clinical examination, pulmonary function tests, skin prick test (SPT), serum zinc assessment by a colorimetric method as well as serum total IgE measurement by Enzyme-linked immunosorbent assay (ELISA). PBMCs were activated in vitro in the presence and absence of zinc, and then cell culture supernatants were analyzed for IFN-γ and IL-10 by ELISA., Results: Serum zinc levels were significantly lower in atopic asthmatics than non-atopic asthmatics and healthy controls. In atopic asthmatics, highly significant correlations were found between zinc levels and total Ig E levels as well as FEV1. In culture, zinc triggers IFN-γ and inhibits IL-10 production by PBMCs, in atopic asthmatics. In non atopic asthmatics and healthy controls, IFN-γ and IL-10 were slightly affected by zinc supplementation in culture., Conclusion: Serum zinc levels affect asthma phenotypes. Atopic asthmatics might benefit from zinc supplements., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In response to microbial infection, the human host deploys metal-sequestering host-defense proteins, which reduce nutrient availability and thereby inhibit microbial growth and virulence. Calprotectin (CP) is an abundant antimicrobial protein released from neutrophils and epithelial cells at sites of infection. CP sequesters divalent first-row transition metal ions to limit the availability of essential metal nutrients in the extracellular space. While functional and clinical studies of CP have been pursued for decades, advances in our understanding of its biological coordination chemistry, which is central to its role in the host-microbe interaction, have been made in more recent years. In this review, we focus on the coordination chemistry of CP and highlight studies of its metal-binding properties and contributions to the metal-withholding innate immune response. Taken together, these recent studies inform our current model of how CP participates in metal homeostasis and immunity, and they provide a foundation for further investigations of a remarkable metal-chelating protein at the host-microbe interface and beyond.

Zinc is an essential trace element for living organisms and their biological processes. Zinc plays a key role in more than 300 enzymes and it is involved in cell communication, proliferation, differentiation and survival. Zinc plays also a role in regulating the immune system with implications in pathologies where zinc deficiency and inflammation are observed. In order to examine the experimental evidence reported in the literature regarding zinc levels in the body of patients with autoimmune disorders compared to control individuals, a systematic review and meta-analysis were performed. From 26,095 articles identified by literature search, only 179 of them were considered potentially relevant for our study and then examined. Of the 179 articles, only 62 satisfied the inclusion criteria. Particularly for Fixed Model, Zn concentration in both serum (mean effect = -1.19; confidence interval: -1.26 to -1.11) and plasma (mean effect = -3.97; confidence interval: -4.08 to -3.87) samples of autoimmune disease patients was significantly lower than in controls. The data presented in our work, although very heterogeneous in the manner of collecting and investigating samples, have proved to be extremely consistent in witnessing a deficiency of zinc in serum and plasma of patients compared to controls., Competing Interests: The authors declare no conflict of interest.

Wound care is a major healthcare expenditure. Treatment of burns, surgical and trauma wounds, diabetic lower limb ulcers and skin wounds is a major medical challenge with current therapies largely focused on supportive care measures. Successful wound repair requires a series of tightly coordinated steps including coagulation, inflammation, angiogenesis, new tissue formation and extracellular matrix remodelling. Zinc is an essential trace element (micronutrient) which plays important roles in human physiology. Zinc is a cofactor for many metalloenzymes required for cell membrane repair, cell proliferation, growth and immune system function. The pathological effects of zinc deficiency include the occurrence of skin lesions, growth retardation, impaired immune function and compromised would healing. Here, we discuss investigations on the cellular and molecular mechanisms of zinc in modulating the wound healing process. Knowledge gained from this body of research will help to translate these findings into future clinical management of wound healing., Competing Interests: J.M. is a founder of TRIM-edicine, Inc., a biotechnology company developing rhMG53 as a therapeutic protein. All other authors declare no competing financial interests.

After the discovery of zinc deficiency in the 1960s, it soon became clear that zinc is essential for the function of the immune system. Zinc ions are involved in regulating intracellular signaling pathways in innate and adaptive immune cells. Zinc homeostasis is largely controlled via the expression and action of zinc "importers" (ZIP 1-14), zinc "exporters" (ZnT 1-10), and zinc-binding proteins. Anti-inflammatory and anti-oxidant properties of zinc have long been documented, however, underlying mechanisms are still not entirely clear. Here, we report molecular mechanisms underlying the development of a pro-inflammatory phenotype during zinc deficiency. Furthermore, we describe links between altered zinc homeostasis and disease development. Consequently, the benefits of zinc supplementation for a malfunctioning immune system become clear. This article will focus on underlying mechanisms responsible for the regulation of cellular signaling by alterations in zinc homeostasis. Effects of fast zinc flux, intermediate "zinc waves", and late homeostatic zinc signals will be discriminated. Description of zinc homeostasis-related effects on the activation of key signaling molecules, as well as on epigenetic modifications, are included to emphasize the role of zinc as a gatekeeper of immune function., Competing Interests: The authors declare that they have no conflict of interest.

Zinc (Zn) is an essential trace element that plays important roles in the immune system. There is little known about the role of trace elements in allergic diseases, and previous reports have shown conflicting results. The aim of this study was to investigate the relationship between serum Zn levels and total or allergen-specific immunoglobulin E (IgE) levels. The initial candidates for this study were those who participated in the 5 th Korean National Health and Nutrition Examination Survey 2010 (n = 8,958), and 1,867 adults who had serum total and allergen specific-IgE levels measured were included. Upon adjusting for covariates, mean total IgE, Dermatophagoides farinae and dog-specific IgE levels increased significantly as the Zn levels decrease from the highest to the lowest quartile (p = 0.009, 0.004, and < 0.001, respectively). The multiple logistic regression analyses showed significant negative linear correlations between serum Zn levels and total, D. farinae-, cockroach-, and dog-specific IgE levels (p-value for linear trend = 0.004, 0.006, 0.027, and < 0.001, respectively). This study demonstrated that total/allergen specific IgE and Zn levels are significantly inversely related.

Malnutrition is one of the risk factors in tuberculosis (TB) infection. Mineral levels perturbation is seen in patients with TB. Moreover there are some strategies to starve pathogens of essential metals. Here we decided to conclude association between some essential elements and TB. Copper, calcium and iron are essential for hosts' immune system although calcium and iron are necessary for Mycobacterium tuberculosis vitality. Changing these elements alongside with anti-TB therapy is suggested for better treatment outcomes., (Copyright © 2017 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Objectives: Zinc (Zn) has major effects on immune system activation while Cadmium (Cd) has anti-inflammatory and anti-proliferative effects in several chronic inflammatory contexts. The aim of this work was to investigate by which mechanisms Zn could compete with Cd and eventually counteract its deleterious effects. Rheumatoid arthritis (RA) synoviocytes exposed to cytokines were used as a model of chronic inflammation; osteoarthritis (OA) synoviocytes were used as control., Methods: Cell/medium fractionation constants were analyzed for different metals by inductively-coupled-plasma mass-spectrometry by comparison to the 70Zn spike. Interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were used to mimic inflammation. Gene expression of ZIP-8 importer, metallothioneins-1 (MT-1s) and the ratio between metalloprotease-3 and the tissue inhibitor of metalloproteinases (MMP-3)/TIMP-1) were evaluated after pre-exposure to cytokines and Cd, with or without the addition of exogenous Zn (0.9 ppm). Cell viability was measured by neutral red assay and IL-6 production by ELISA., Results: Synoviocytes selectively absorbed and retained Cd in comparison to Zn. Metal import increased with IL-17/TNF-α exposure, through the enhanced ZIP-8 expression. Zn did not modify ZIP-8 expression, while Cd reduced it (p<0.05). Zn induced a reduction of Cd-induced MT-1s expression, in particular of MT-1X (3-fold), and subsequently the final intra-cellular content of Cd. By reducing Cd accumulation in cells, Zn reversed Cd anti-proliferative and anti-inflammatory effects but preserved the low MMP-3/TIMP-1 ratio induced by Cd, which was enhanced by inflammatory conditions., Conclusion: Zinc counteracts the deleterious effect of Cd by reducing its import and accumulation in the cell, without the reactivation of destructive pathways such as MMPs.

The importance of Zn ions (Zn) in regulating development and functions of the immune system is well established. However, recent years have witnessed a surge in our knowledge of how immune cells choreograph Zn regulatory mechanisms to combat the persistence of pathogenic microbes. Myeloid and lymphoid populations manipulate intracellular and extracellular Zn metabolism via Zn binding proteins and transporters in response to immunological signals and infection. Rapid as well as delayed changes in readily exchangeable Zn, also known as free Zn and the Zn proteome are crucial in determining activation of immune cells, cytokine responses, signaling and nutritional immunity. Recent studies have unearthed distinctive Zn modulatory mechanisms employed by specialized immune cells and necessitate an understanding of the Zn handling behavior in immune responses to infection. The focus of this review, therefore, stems from novel revelations of Zn intoxication, sequestration and signaling roles deployed by different immune cells, with an emphasis on innate immunity, to challenge microbial parasitization and cope with pathogen insult., (Published by Elsevier Inc.)

The significance of the essential trace element zinc for immune function has been known for several decades. Zinc deficiency affects immune cells, resulting in altered host defense, increased risk of inflammation, and even death. The micronutrient zinc is important for maintenance and development of immune cells of both the innate and adaptive immune system. A disrupted zinc homeostasis affects these cells, leading to impaired formation, activation, and maturation of lymphocytes, disturbed intercellular communication via cytokines, and weakened innate host defense via phagocytosis and oxidative burst. This review outlines the connection between zinc and immunity by giving a survey on the major roles of zinc in immune cell function, and their potential consequences in vivo., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aims: The proportion of serum carnosinase (CN-1) recognized by RYSK173 monoclonal antibody negatively correlates with CN-1 activity. We thus hypothesized that the epitope recognized by RYSK173 is accessible only in a catalytically incompetent conformation of the zinc dependent enzyme and we mapped its position in the CN-1 structure. Since patients with kidney failure are often deficient in zinc and other trace elements we also assessed the RYSK173 CN-1 proportion in serum of these patients and studied the influence of hemodialysis hereon in relation to Zn2+ and Cu2+ concentration during hemodialysis., Methods and Results: Epitope mapping using myc-tagged CN-1 fragments and overlapping peptides revealed that the RYSK173 epitope directly contributes to the formation of the dinuclear Zn center in the catalytic domain of homodimeric CN-1. Binding of RYSK173 to CN-1 was however not influenced by addition of Zn2+ or Cu2+ to serum. In serum of healthy controls the proportion of CN-1 recognized by RYSK173 was significantly lower compared to end-stage renal disease (ESRD) patients (1.12 ± 0.17 vs. 1.56 ± 0.40% of total CN-1; p<0.001). During hemodialysis the relative proportion of RYSK173 CN-1 decreased in parallel with increased serum Zn2+ and Cu2+ concentrations after dialysis., Conclusions: Our study clearly indicates that RYSK173 recognizes a sequence within the transition metal binding site of CN-1, thus supporting our hypothesis that metal binding to CN-1 masks the epitope. The CN-1 RYSK173 proportion appears overall increased in ESRD patients, yet it decreases during hemodialysis possibly as a consequence of a relative increase in transition metal bound enzyme.

Background and Aims: Current guidelines favor the use of chelating agents (d-penicillamine, trientine) in first line therapy of symptomatic Wilson disease patients. Development of chelator induced immunological adverse events are a concern especially under d-penicillamine therapy. This study assessed the prevalence of co-existing or therapy-related immune-mediated diseases in Wilson disease patients, and evaluated the role of antinuclear antibodies in therapy monitoring., Methods: We retrospectively analyzed 235 Wilson disease patients. Medical regimens were classified and analyzed in relation to adverse events and antinuclear antibody courses., Results: Coexisting immune-mediated diseases were evident in 19/235 (8.1%) patients, of which 13/235 (5.5%) had pre-existing autoimmune diseases. Six patients (2.6%) developed an autoimmune disease under therapy, all of them under long-term d-penicillamine treatment. Data relating to antinuclear antibody courses during treatment and adverse events were available for patients treated with d-penicillamine (n = 91), trientine (n = 58), and zinc salts (n = 58). No significant increase in antinuclear antibody titers in patients treated with d-penicillamine (16/91; 17.6%), trientine (12/58; 20.7%), and zinc (7/58; 12.1%) were found., Conclusion: Under long-term d-penicillamine therapy a minority of patients developed immune-mediated disease. Elevations in antinuclear antibodies were found frequently, but no correlations were evident between increases in antinuclear antibodies and the development of immune-mediated diseases or medical regimes. Thus, the value of antinuclear antibodies for monitoring adverse events under chelator therapy seems to be limited.

Zinc (Zn) is an essential nutrient, and Zn deficiency causes immunodeficiency and skin disorders. Basophils express FcɛRI on their surface and release multiple mediators after receptor cross-linking, including large amounts of IL-4. However, the mechanisms involved in the FcɛRI-mediated regulation of basophil IL-4 production are currently unclear. Here, we show that the Zn-binding metallothionein (MT) proteins are essential for the FcɛRI-induced basophil production of IL-4. Basophils from MT-I/II(-/-) mice produced significantly less FcɛRI-induced IL-4 than did wild-type basophils. The MTs were involved in maintaining intracellular Zn levels, thereby regulated the calcineurin activity and nuclear factor of activated T-cell (NFAT)-mediated IL-4 production. These results suggest that the MT-dependent control of Zn homeostasis is a novel mechanism for regulating basophil IL-4 production., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Paraquat (PQ), one of the most widely used herbicides, has been used for several decades in agriculture. Some studies suggest that PQ has effects on the immune system. Moreover, previous studies have shown that PQ imparted some immunosuppressive effects. In the present study, cytotoxicity assays using splenic NK cells from mice treated for 28 days with PQ (at 0.2, 1, and 5 mg/kg) were performed to determine whether PQ altered the function of NK cells. Given that PQ was expected to induce an immunosuppressive effect, it was hypothesized that a gene involved in cellular metal ion homeostasis, metallothionein-1 (MT-1), could play an important role in this outcome. This belief was based on the fact that MT1 encodes a protein responsible for zinc ion homeostasis, and that a reduction in free zinc ion levels impairs NK cell function. The results showed that PQ treatments led to increased MT expression in several organs (liver, kidneys, testes) and in splenocytes, caused a reduction of both free zinc ions in sera and in free intracellular zinc, and reduced the expression of GATA-3, a zinc-finger transcription factor important for maturation and activity of T-cells and NK cells. These results provide a basis for a new molecular mechanism to describe potential immunosuppressive effects of PQ in vivo.

Dietary zinc deficiency has been associated with an increased risk of infection. It has been reported that zinc-deficient rats have fewer New T-cells (TCRαβ(+)CD90(+)) compared to diet-restricted and control rats, which over time could adversely affect the ability of the organism to fight off infections. We hypothesized that the lower proportion of New T-cells in zinc deficiency is due to an increased susceptibility to apoptosis. Weanling, Sprague Dawley rats were assigned to one of four dietary treatment groups for 3 weeks: zinc-deficient (ZD, <1mg zinc/kg, ad libitum), diet-restricted (DR, 30mg zinc/kg, limited to the amount of feed as consumed by ZD), marginally zinc-deficient (MZD, 10mg zinc/kg, ad libitum) or control (CTL, 30mg zinc/kg, ad libitum). Thymocytes and splenocytes were labeled for flow cytometric determination of cell surface markers and DNA staining (for simultaneous determination of the phenotype of apoptotic cells) and assessed by Western blotting for apoptotic markers. Cells were analyzed immediately, or after incubation for 7h with or without dexamethasone. There was no difference in the proportion of CD90(+) thymocytes; however ZD rats had a higher proportion of Cytotoxic (CD90(+)4(-)8(+)) thymocytes compared to MZD and CTL. ZD had a lower proportion of splenic New T-cells compared to DR, MZD and CTL. There was no effect of diet on the proportion of apoptotic thymocytes or splenocytes, except ZD splenoctyes had a lower Bax/Bcl-xl ratio compared to DR and CTL. We characterized the splenic New T-cells into Helper and Cytotoxic subsets and found that ZD had a higher ratio of Helper to Cytotoxic New T-cells compared to MZD and CTL. These results do not support the hypothesis of increased apoptotic removal of New T-cells in ZD in growing rats. The regulation of CD90 expression should be explored in future studies., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

In this review the current conceptions concerning zinc biology, its metabolism and transport into the cells, its homeostasis, a role in the functioning of the human immune and endocrine systems, participation in cell signaling and its cytotoxicity, as well as the biophysical mechanisms of action of zinc ions action at the elevated concentrations on human blood cells were analyzed.

IgA nephropathy (IgAN) shows diverse epidemiological characteristics, resulting from both genetic and acquired (e.g., environmental) causes. Environmental factors, such as diet or exposure to exogenous antigens, may prescribe the progression or prognosis of IgAN. It remains unclear as to how diet and infection influence susceptibility to IgAN. A relationship, such as Toll-like receptors (TLRs), especially TLR9 and TLR4, was demonstrated between IgAN and pathogen-recognition molecules. Recently, zinc (Zn) was discovered to be involved in various immune-related diseases, affecting B, T, and dendritic cells (DCs). This study investigates the relationship between dietary Zn and IgAN development in IgAN-prone mice. Seven-week-old IgAN-prone mice were divided into low, normal, and high Zn diet groups. To assess exogenous pathogen-mediated immune responses, lipopolysaccharide (LPS) was nasally administered. The activity of IgAN was biochemically and pathologically evaluated during the disease course. We also examined in vitro IgA production in spleen cells or in combinations of cocultured B, T, and DCs under various Zn conditions with or without LPS. Dietary conditioning with Zn affected serum immunoglobulins and urinary albumin levels, and mesangial deposition of IgA and IgG. Zn deficiency is associated with IgAN progression through the activation of the TLR4/TIR-domain-containing adapter-inducing interferon-β (TRIF), but not the TLR9, in DCs. Zn supplementation prevented disease aggravation. Our findings indicate that immune conditioning with dietary Zn alters nephritogenic IgA production after mucosal infection.

It has been hypothesized that micronutrient levels play a role in the immune response to vaccination; however, population-level research on the association between micronutrient levels and immune response to influenza vaccination is needed. In this study, we hypothesized that decreasing levels of nutrients would be associated with decreased hemagglutination inhibition (HAI) responses to influenza vaccination. Therefore, the purpose of this study was to determine whether serum vitamin A, vitamin E, or zinc levels are associated with influenza vaccine response determined by HAI titer in adults 65 years or older. Participants in this study included 205 community-dwelling adults 65 years or older who resided in Marshfield, WI, USA, from fall 2008 through spring 2009. Participants received trivalent influenza vaccine and donated blood samples before and 21 to 28 days after vaccination. Prevaccination levels of serum retinol, α-tocopherol, and zinc as well as prevaccination and postvaccination HAI titer levels were measured. No participants were vitamin A or vitamin E deficient; 20% had low serum zinc levels (<70 μg/dL). Continuous variables and categorical quartiles coding for vitamin A, vitamin E, and zinc levels were not related to prevaccination or postvaccination seroprotection or seroconversion for any of the vaccine components (influenza A [H1N1], A [H3N2], or B), after adjusting for age, sex, body mass index, and prevaccination HAI geometric mean titer. In conclusion, our study population showed no association between variations in levels of serum vitamin A, vitamin E, or zinc and influenza vaccine response as measured by HAI in adults older than 65 years. Thus, associations between micronutrients and other measures of vaccine response, such as cell-mediated immune parameters, should also be explored., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Diabetes mellitus has been increasing rapidly worldwide, making it a huge health pressure on society in both the developed and developing countries. During the last thirty years, diabetes mellitus, a chronic metabolic disease characterized by hyperglycemia is proving itself to be fatal. Periodontitis was considered as one of the main, oral health problems encountered in patients with diabetes mellitus. There exists a direct relation between the risk of complications of diabetes and periodontitis over time. The present review gives an outline of the features that govern the interrelationship between zinc and diabetes mellitus with periodontal disease, including the physiologic mechanisms and clinical studies, and presents scientific evidences. The disturbance in the zinc micronutrient and increased oxidative stress in type 2 diabetes may bring about insulin resistance and the creation of diabetic complications. The progression of diabetes mellitus may bring about perturbation in micronutrient metabolism and status.

Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like zinc (Zn). The pleiotropic cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF-activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription-factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7; the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H⁺ channel function and triggered reactive oxygen species generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The outer membrane of Gram-negative bacteria functions as a permeability barrier that protects these bacteria against harmful compounds in the environment. Most nutrients pass the outer membrane by passive diffusion via pore-forming proteins known as porins. However, diffusion can only satisfy the growth requirements if the extracellular concentration of the nutrients is high. In the vertebrate host, the sequestration of essential nutrient metals is an important defense mechanism that limits the growth of invading pathogens, a process known as "nutritional immunity." The acquisition of scarce nutrients from the environment is mediated by receptors in the outer membrane in an energy-requiring process. Most characterized receptors are involved in the acquisition of iron. In this study, we characterized a hitherto unknown receptor from Neisseria meningitidis, a causative agent of sepsis and meningitis. Expression of this receptor, designated CbpA, is induced when the bacteria are grown under zinc limitation. We demonstrate that CbpA functions as a receptor for calprotectin, a protein that is massively produced by neutrophils and other cells and that has been shown to limit bacterial growth by chelating Zn²⁺ and Mn²⁺ ions. Expression of CbpA enables N. meningitidis to survive and propagate in the presence of calprotectin and to use calprotectin as a zinc source. Besides CbpA, also the TonB protein, which couples energy of the proton gradient across the inner membrane to receptor-mediated transport across the outer membrane, is required for the process. CbpA was found to be expressed in all N. meningitidis strains examined, consistent with a vital role for the protein when the bacteria reside in the host. Together, our results demonstrate that N. meningitidis is able to subvert an important defense mechanism of the human host and to utilize calprotectin to promote its growth.

Rationale: Alcohol use disorders cause oxidative stress in the lower airways and increase susceptibility to pneumonia and lung injury. Currently, no therapeutic options exist to mitigate the pulmonary consequences of alcoholism., Objectives: We recently determined in an animal model that alcohol ingestion impairs pulmonary zinc metabolism and causes alveolar macrophage immune dysfunction. The objective of this research is to determine the effects of alcoholism on zinc bioavailability and alveolar macrophage function in human subjects., Methods: We recruited otherwise healthy alcoholics (n = 17) and matched control subjects (n = 17) who underwent bronchoscopy for isolation of alveolar macrophages, which were analyzed for intracellular zinc, phagocytic function, and surface expression of granulocyte-macrophage colony-stimulating factor receptor; all three of these indices are decreased in experimental models., Measurements and Main Results: Alcoholic subjects had normal serum zinc, but significantly decreased alveolar macrophage intracellular zinc levels (adjusted means [SE], 718 [41] vs. 948 [25] RFU/cell; P < 0.0001); bacterial phagocytosis (adjusted means [SE], 1,027 [48] vs. 1,509 [76] RFU/cell; P < 0.0001); and expression of granulocyte-macrophage colony-stimulating factor receptor β subunit (adjusted means [SE], 1,471 [42] vs. 2,114 [35] RFU/cell; P < 0.0001]. Treating alveolar macrophages with zinc acetate and glutathione in vitro increased intracellular zinc levels and improved their phagocytic function., Conclusions: These novel clinical findings provide evidence that alcohol abuse is associated with significant zinc deficiency and immune dysfunction within the alveolar space and suggest that dietary supplementation with zinc and glutathione precursors could enhance airway innate immunity and decrease the risk for pneumonia or lung injury in these vulnerable individuals.

Zinc signals, i.e. changes in the free intracellular Zn(2+)concentration, are an integral component of signal transduction in several immune cells. The aim of the present study was to investigate if this is also the case in neutrophil granulocytes. One neutrophil function is NETosis, the release of a matrix composed of DNA, chromatin and granule proteins to capture extracellular bacteria within so-called neutrophil extracellular traps (NET). NETosis can be induced by the protein kinase C (PKC) activator 12-myristate 13-acetate (PMA). PMA treatment led to a zinc signal in neutrophil granulocytes. NETosis was inhibited when the zinc signal was sequestered by the membrane permeable high affinity chelator N,N,N',N',-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN). PKC-mediated NET formation depends on the production of reactive oxygen species (ROS) by NADPH oxidase. Inhibition of NADPH oxidase with diphenyleneiodonium chloride blocked ROS formation and NETosis, as well as the zinc signal. TPEN, however, had no effect on PKC activity and ROS production, indicating that Zn(2+) is not required for activation of PKC, but for signals downstream of ROS production. In conclusion, zinc signals are an essential component of the ROS-dependent signal transduction leading to NETosis.

Immunological discordance in HIV-infected patients is associated with a higher risk of mortality and disease progression. Zinc is an essential micronutrient for immune function. A two-phase pilot study including a cross-sectional study to determine plasma zinc levels and a prospective, randomized, placebo-controlled trial to determine immunological responses after zinc supplementation was conducted in HIV-infected patients with immunological discordance in a medical school hospital. Immunological discordance was defined in patients who received antiretroviral therapy, had HIV RNA < 40 copies/mL, and a CD4(+) cell count < 200 cells/mm(3) that increased <30% from baseline after receiving ART with undetectable HIV RNA for 12 months. Of 31 patients, 12 (39%) had low plasma zinc levels (<75 μg/dL). Five of 12 patients with low plasma zinc levels and 8 of 19 patients with normal plasma zinc levels were randomized to receive zinc supplementation. The median changes in plasma zinc levels after supplementation versus placebo in patients with low plasma zinc levels were 29 versus 4.5 μg/dL, respectively. The CD4(+) cell count significantly increased (176 versus 250 cells/mm(3), P = 0.042) after zinc supplementation in patients with low plasma zinc levels. Further large-scale studies to determine long-term benefits of zinc supplementation in patients with immunological discordance are required.

Zinc (Zn) is essential for normal cell structure and physiology. Its deficiency causes growth retardation, neuronal degeneration, and immunodeficiency. Zn homeostasis is tightly controlled through Zn transporters and metallothioneins, which regulate Zn concentration and Zn distribution in individual cells, and contributes to Zn-binding protein in cells. Although many molecules involved in these processes have Zn-binding motifs, the molecular mechanisms underlying the role of Zn in the immune system have not been clarified. Recently, we and other groups have demonstrated that Zn plays diverse and specific roles in vivo and in vitro, in studies on the genetic knockout of Zn transporter functions. In this review, we discuss the impact of Zn on mast cell-mediated allergy and T cell-mediated immune responses. We also describe Zn dysregulation as a leading health problem in allergy and immune responses.