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Review

Zinc Status and Autoimmunity: A Systematic Review and Meta-Analysis

by
Alessandro Sanna
1,
Davide Firinu
2,
Patrizia Zavattari
3,* and
Paolo Valera
1,*
1
Department of Civil, Environmental Engineering and Architecture, University of Cagliari, 09123 Cagliari, Italy
2
Department of Medical Sciences and Public Health, Monserrato Campus, University of Cagliari, 09042 Monserrato, Italy
3
Unit of Biology and Genetics, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
*
Authors to whom correspondence should be addressed.
Nutrients 2018, 10(1), 68; https://doi.org/10.3390/nu10010068
Submission received: 6 December 2017 / Revised: 4 January 2018 / Accepted: 8 January 2018 / Published: 11 January 2018
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Abstract

:
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.

1. Introduction

Zinc is an essential trace element for living organisms and their biological processes [1,2]. The body cannot accumulate zinc and it is, therefore, essential to take this element consistently in the diet. Although dietary zinc levels vary substantially, eukaryotic cells need to maintain intracellular zinc homeostasis to ensure its proper function. This homeostasis is regulated in mammals by import and export processes, vesicle retaining zinc (zincosomes) and association to metallothioneins (MTs) [3,4]. Zinc plays a key structural or catalytic role in more than 300 enzymes and is involved at all levels of cellular signal transduction. Zinc is involved in cell communication, cell proliferation, differentiation and survival. Therefore, zinc also plays a key role in regulating the immune system, both innate and adaptive, with consequent implications in pathologies where zinc deficiency and inflammation are observed.
The understanding of zinc’s importance in human health unfortunately begun only in the 1960s. Zinc deficiency is associated with a decline in the immune system, with inflammation leading to chronicity [5]. In addition, dietary zinc deficiency was considered to be very rare, although it affects 20–25% of the world’s population [6,7]. Data from the World Health Organization [8] report that zinc deficiency is the fifth largest health risk factor in developing countries and the eleventh in the world [9]. Rarely is zinc deficiency seen as a serious deficit; more frequently it is seen as a less accentuated deficit. Patients with severe deficits present: lymphopenia, decreased ratio between T helper (Th) to cytotoxic T cells, reduced natural killer (NK) cell activity, and increased monocytes cytotoxicity. This condition characterizes the malabsorption autosomal recessive syndrome, Acrodermatitis enteropathica, due to a mutation of a zinc-importing protein, ZIP4 [10].
Less accentuated zinc deficiency states can be caused by nutritional deficits due, for example, to a diet high in lignin and phytates, in vegetarians and vegans, chelating zinc, so preventing its proper absorption [11,12]. This state is characterized by slight weight loss, rough skin, oligospermia and hyperammoniaemia [13].
Several clinical trials of zinc supplementation have been conducted in patients with zinc deficit suffering from various pathologies (viral, bacterial and parasitic infections or autoimmune diseases) [14], or as vaccine supplements [15]. Although there is countless evidence supporting the fact that controlled zinc supplementation can prevent chronic inflammation and other zinc deficiency-related illnesses, or even improve symptoms (as seen in both humans and animal models), to date zinc supplementation does not fall into commonly used medical practices in risk subjects/populations. The purpose of this study was to examine the experimental evidence reported in the literature over the last 40 years regarding zinc levels in the body of patients with autoimmune disorders compared to control individuals. The biological matrices for which it was possible to collect enough bibliographic material to perform a meta-analysis were predominantly serum and plasma; to a lesser extent data were collected on urine, hair and spinal fluid.

2. Materials and Methods

2.1. Search Strategy

In order to select the included studies, a literature search was undertaken of PubMed, Cochrane Central Register of Controlled Trials, Web of Science and Science Direct databases from inception to 23 January 2017 and without any limitation of on year of publication. Keywords used were zinc and ((dietary or supplement) or (serum or plasma)) and (autoimmune disease or autoimmunity). Typing, in the search window, the keywords in the databases chosen, without any restrictions, the result was a list of publications for which only the title, authors and abstracts were available. After eliminating the duplicates the titles and abstracts of the remaining articles were read and those not relevant for the purpose of this meta-analysis were excluded. After this step, the entire manuscript of each remaining paper, defined as eligible, was read, thus excluding those that did not fall within the criteria defined in the “study eligibility criteria” (Section 2.3, below). Finally, the papers that satisfied all selection criteria have been included in the meta-analysis.
Full search details for all databases are presented in Table S1 (Supplemental Material). This study was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) requirements [16,17]. The standard flowchart, which describes the process selection, is reported in Figure 1.

2.2. Study Selection

All reference lists were downloaded for elimination of duplicates. Furthermore, title and abstract of each reference were screened by two independent reviewers to perform the eligibility assessment of full text for this review. Study eligibility was restricted to human studies and English language.

2.3. Study Eligibility Criteria

Observational studies, prospective and retrospective studies, case-control studies or randomized controlled trials (RCTs) investigating the relationship between zinc status and autoimmune diseases were eligible for inclusion. In particular, only diseases for which the autoimmunity was a franc condition were included in this study. The American Autoimmune Related Diseases Association (AARDA) [18] was consulted to verify that the diseases considered in this study were really autoimmune diseases.
The studies were selected if zinc concentration in biological samples or dietary/supplemental zinc were an index of zinc status.
Moreover, the presence of both number of subject involved (≥5) and the statistical parameters were taken into account for the meta-analysis process. On the other hand, letters, conference proceedings, reviews, duplicated data, data of both animal and cellular studies, and studies that did not indicate data of interest were excluded. Although studies on animals are not considered eligible for the meta-analysis process, a discussion on them was performed separately. Also, thirteen studies were excluded because we did not have access to the full text, maybe the most of these studies were published more than 20 years ago.

2.4. Study Quality Assessment and Data Extraction

The Newcastle-Ottawa Scale (NOS) for case-control studies was used to assess the quality of the included studies [19]. Ten full-text studies were excluded because control data was not complete in reference to both number of controls and their relationship with cases. Two independent reviewers extracted data from each eligible study. The data extracted included the type of study (observational studies, prospective and retrospective studies, case-control studies, randomized controlled trials), country, year of publication, sample size, age and sex of patients, autoimmune disease, zinc status in biological samples, type of samples, method of samples analysis, statistical method, standard deviation and statistical significance.
Table 1 reports the general characteristics of selected studies included in meta-analysis in reference to serum samples whereas Table 2 indicates the baseline characteristics for meta-analysis related to plasma samples. Furthermore, Table 3 reports the general information about the studies that are related to hair, urine and Cerebral Spinal Fluid (CSF) samples.
In most of the included studies, the measurement unit of the zinc concentration data were different for the same biological media. For this reason, all data of zinc in both serum and plasma samples were converted in μg/mL, whereas zinc data in hair samples were converted in μg/g.

2.5. Statistical Analysis

Data were processed by MetaEasy Excel add-in (Microsoft Corporation, Redmond, WA, USA), which used seven different methods. In particular, three methods refer to dichotomous data and four methods refer to continuous data. In order to improve their heterogeneity, data were grouped depending on different biological media: serum, plasma, hair, urine and cerebrospinal fluid. Means of zinc status in both patients and controls, standard deviations of zinc status in both patients and controls, number of subjects involved and p-value were used. p-value < 0.05 was considered as statistically significant.
Also, overall estimates of effect were performed with seven models: Fixed Effects (FE), DerSimonial-Laird (DL), Q method (Q), Maximum-Likelihood (ML), Profile—Likelihood (PL), t-Test (T) and Permutations method (PE). Heterogeneity was assessed by different measures: Cochrane’s Q, τ2 test, I2 test and H2M test. Publication bias was evaluated using funnel plot 3 considering the estimate of effects and their standard errors as a precision indicator (1/SE) [82].

3. Results

From 26,095 articles identified by literature search, 21,766 duplicates were deleted. After the screening of 4329 remaining articles, 4150 of them were excluded because they were irrelevant for our study. Afterwards, 179 papers were considered potentially relevant for our study but only 62 of them satisfied the inclusion criteria (see Section 2.4). Therefore, 117 articles were excluded and the reasons for their exclusion is shown in PRISMA diagram (Figure 1). In particular, 13 of the 117 papers were excluded because, with the means available to the Italian library system, it was not possible to retrieve them. However, the 13 papers are listed in Table S2 (Supplemental Material).

3.1. Zn Status and Autoimmune Diseases

The relationship between Zn status and autoimmune diseases has been investigated by many authors since the 1970s. The 62 studies included in the meta-analysis were case-control studies. Also, all of them were published between 1975 and 2017 and they are related to different autoimmune diseases. Indeed, 22 studies describe the zinc status in Type 1 Diabetes (T1D), 18 full-text are related to Rheumatoid Arthritis (RA), 7 articles investigated zinc status in Multiple Sclerosis (MS) patients while 15 papers are related to other diseases among which Alopecia Areata (AA), Systemic Lupus Erythematosus (SLE), Pemphigus Vulgaris (PV), Autoimmune Hepatitis (AH), Celiac Disease (CD), Hashimoto Thyroiditis (HT), Sjogren’s syndrome (SS), Juvenile Idiopathic Arthritis (JIA).

3.2. Zn Status in Serum Samples

The meta-analysis results show that, for all models, Zn concentration in serum of autoimmune disease patients was significantly lower than controls (FE: mean effect = −1.19 and confidence interval: −1.26 to −1.11; DL: mean effect = −1.29 and confidence interval: −1.91 to −0.67; Q: mean effect = −1.29 and confidence interval: −1.91 to −0.67; ML: mean effect = −1.29 and confidence interval: −1.96 to −0.63; PL: mean effect = −1.29 and confidence interval: −1.97 to −0.61; T: mean effect = −1.29 and confidence interval: −1.99 to −0.60; PE: mean effect = −1.29 and confidence interval: −2.95 to −0.49). Indeed, 70% of the articles considered show that patients have a zinc deficiency compared to the control group.
Regarding the heterogeneity of data, the elaboration shows the following results: Cochrane Q = 2589.53; τ2 = 3.88 (for DL model); τ2 = 4.52 (for ML and PL models); I2 = 98.49%; H2M = 65.39. Forest plot in Figure 2 shows the study effects for each study and the overall estimates effects. Despite high heterogeneity, overall estimates effects were positive for all models. Moreover, overall effects that were calculated with FE models were more efficient than effects calculated with the other models.

3.3. Zn Status in Plasma Samples

As already seen for serum, also in plasma samples the meta-analysis results show that, for all models, Zn concentration in the serum of autoimmune disease patients was significantly lower than controls. Indeed, for 62% of the articles included in the meta-analysis process, patients had lower zinc concentrations than controls.
As shown in Figure 3, only FE model overall estimates effects could be considered favorable (FE: mean effect = −3.97 and confidence interval: −4.08 to −3.87). Even in this case, as in the previous one, data was highly heterogeneous.

3.4. Zn Status in Hair, Urine and Cerebrospinal Fluid Samples

In reference to Zn hair concentration, only FE model overall estimates effects could be considered favorable (FE: mean effect = −2.49 and confidence interval: −2.72 to −2.28). However, heterogeneity was considerable and the number of studies was limited. On the other hand, no significant variations in urinary and CSF zinc were observed between patients and controls.

3.5. Publication Bias

To evaluate the presence of publication bias, Funnel Plots were calculated. As shown in Figure 4, in both meta-analysis related to serum Zn and plasma Zn, it is possible to observe the presence of bias in the selected literature.

4. Discussion

This review of the literature on the possible linkage between zinc levels (especially in serum and plasma) and autoimmune diseases has revealed a huge amount of studies on this subject, although the selection due to meta-analysis methods has narrowed the final analysis to 62 publications, temporally distributed as shown in Figure S1 (Supplemental Material).
As expected, the data presented in this review, although very heterogeneous in the manner of collecting and investigating samples, etc., have proved to be extremely consistent in witnessing a deficiency of zinc in serum and plasma of patients compared to controls. A recurring question found in many studies was whether alterations in the homeostasis of this element represent the basis of the inflammatory status or consequences thereof.
As is well known, there are populations such as Finnish or Sardinian with polygenic predisposition to autoimmune diseases, in whom there has been a natural selection in favor of certain genetic loci, playing a role in the immune response. In particular, certain HLA (Humane Leucocyte Antigens) haplotypes, such as HLA-DR3-B18 in Sardinia and HLA-DR4 in Finland, are particularly frequent in those populations, terribly increasing the relative risk of developing multiple sclerosis [83], type 1 diabetes [84] and even comorbidity of these two and other autoimmune pathologies [85]. In addition, recent works have also shown that DNA genetic variations largely drive the development and function of specific leukocyte subsets [86], in particular those who may have key pro-inflammatory or regulatory roles in autoimmune diseases [87].
Of note, there is the repeated observation of a sex-related bias in different autoimmune diseases, but often not attributable to known genetic causes [88,89], and that environmental influences at various timepoints contribute to a shift towards unbalanced immune responses [90,91].
Zinc has been recognized as one of these factors, as its homeostasis is essential against inflammatory diseases to regulate different aspects of the immune system, both for innate and adaptive immune response, cell cycle progression, cell maturation and differentiation [92]. Zinc deficiency is therefore associated with an incorrect maturation and function of T and B cells, an unbalanced ratio between Th1 and Th2 [93], and between regulatory and pro-inflammatory T cells, and a weakening of NK cell function. Zinc can inhibit Th17 lymphocytes, which confer susceptibility to autoimmune diseases owing to their strong inflammatory properties, as well as a variety of other proinflammatory responses on T-cells and B-cells [94,95].
These unbalanced states can, however, be restored by zinc integration [96,97,98]. As demonstrated in several studies analyzed in this meta-analysis, patients with multiple sclerosis exhibit low levels of zinc in the plasma [99,100,101]. This is also observed in the mouse model, affected by experimental autoimmune encephalomyelitis (EAE), in which the symptoms decrease in severity and even regress after zinc treatment, inducing proliferation of regulatory T cells and decreasing pro-inflammatory cells [102,103,104,105]. Even in type 1 diabetes, the autoimmune diabetes, zinc homeostasis plays a key role by acting on various molecular mechanisms [106,107]. The protagonist in beta-pancreatic cells is definitely the ZnT8 zinc importer, essential for the transport of insulin secretory vesicles, and for the formation of insulin granules [108,109,110]. Even in this case, the benefits of zinc supplementation are known. Chronic zinc deficiency increases inflammation potentially leading to its chronic perpetuation [5].
Alternatively, hypozincemia could represent a common result of inflammation during the autoimmune disorders here discussed. It has been shown that induction of acute-phase response upregulates Zip14 via IL-6 and IL-1 signaling [111], inducing liver sequestration and redistribution in the cellular compartment [112]. Furthermore, the experiments conducted by Bonaventura and colleagues on synovial cells isolated from joints of patients affected by rheumatoid arthritis are illuminating. The authors have shown that exposure of cells to pro-inflammatory cytokines such as interleukin-17 and tumor necrosis factor alpha, increases the expression of zinc importer carriers, resulting in enhanced intracellular Zn uptake and further increasing inflammation and interleukin-6 production. These experiments have clarified the existence of a feedback loop between inflammation and cellular zinc uptake [113].
Indeed, in pathologies such as multiple sclerosis, serum levels of zinc decrease mainly during relapses; in pathologies characterized by chronic inflammation, such as rheumatoid arthritis, a continuous recruitment of zinc within the cells would be established, hence a continuous depletion of zinc in serum. Probably, in the induction of autoimmunity, there is a role for either a primary zinc deficiency and for its secondary reduction due to inflammation, that warrant further focused studies for a thorough determination of timing (preclinical phase of disease vs. overt disease or during pregnancy, childhood, and elderly), cause/pathophysiology, degree of reduction and span/duration (over time) of hypozincemia. Finally, zinc also acts as a co-factor for many proteins implicated in the epigenome establishment. This means that the development of a new organism may be conditioned, from the earliest stages, by possible imbalance in zinc homeostasis [114]. Therefore, interventions to correct any nutritional imbalances should be anticipated during the stages of pregnancy and lactation. In fact, zinc deficiencies during pregnancy are associated with fetal or adult illness, also due to the improper development of the immune system [115,116,117].
One aspect not to be overlooked is the bioaccessibility and then the bioavailability of this and other elements. In this regard, environmental studies [118,119] are also desirable for helping to clarify the potential environmental impact of exposures/deficiencies to particular elements, essential for/toxic to human health, including any corrective measures to improve the conditions in which man lives and works and therefore having a strong impact on human health. In fact, in the mining exploration field, it is well known that the abundance of some elements is typically linked to some lithologies and/or metallogenic contexts. This relative abundance (or deficiency) affects any media linked to these environments such as water [119,120,121,122,123,124,125,126], soil [89,118,119,124,127,128,129,130,131,132] and so also the biological sphere. However, it should be considered that the complexity and dynamism of the environment could complicate the interpretations [133].
Given the importance of zinc in regulating the functioning of the immune system, it is, therefore, logical to associate an imbalance in the homeostasis of this element with the state of autoimmunity. It would therefore be desirable to mount a screening campaign for the evaluation of zinc levels in neonatal, preschool and school-age children, and hence a relevant campaign for the integration of essential elements for man, including zinc. In populations at higher genetic risk of autoimmunity it would be therefore interesting to have a clinical trial investigate personalized zinc supplementation for preventing and/or treating autoimmune diseases.

Supplementary Materials

The following are available online at https://www.mdpi.com/2072-6643/10/1/68/s1. Table S1, Full search details for all databases; Table S2, List of the 13 papers excluded because not possible to retrieve with the means available to the Italian library system; Figure S1, (a) Temporal distribution of the 62 publications included in the meta-analysis; (b) Temporal distribution of publications related to the most frequent pathologies.

Acknowledgments

We wish to thank the very kind staff of the Biomedical-Scientific District Library of the University of Cagliari for having worked hard to find publications to which we had no direct access. We thank Silvia Cosentino for kindly reviewing the grammar and syntax of the manuscript.

Author Contributions

A.S.: search strategy, study quality assessment and data extraction, meta-analysis, statistical analysis, interpretation of data, drafting of the manuscript, figures and tables preparation. D.F.: interpretation of the immunological aspects, participation in writing the discussion. P.Z.: design and supervision of the study, search strategy supervision, interpretation of data, extrapolation of the biological rational of the results found, manuscript writing. P.V.: search strategy supervision, study quality assessment and data extraction, environmental assessment and interpretation of data, supervision of figures and tables drafting, manuscript writing. All Authors discussed the results and commented on the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Raulin, J. Etude chimique sur la vegetation. Ann. Sci. Nat. Bot. Biol. Veg. 1869, 11, 293–299. [Google Scholar]
  2. Wessels, I.; Maywald, M.; Rink, L. Zinc as a Gatekeeper of Immune Function. Nutrients 2017, 9, 1286. [Google Scholar] [CrossRef] [PubMed]
  3. Beyersmann, D.; Haase, H. Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals 2001, 14, 331–341. [Google Scholar] [CrossRef] [PubMed]
  4. Harris, E.D. Cellular transporter for zinc. Nutr. Rev. 2002, 60, 121–124. [Google Scholar] [PubMed]
  5. Foster, M.; Samman, S. Zinc and Regulation of inflammatory cytokines: Implications for cardiometabolic disease. Nutrients 2012, 4, 676–694. [Google Scholar] [CrossRef] [PubMed]
  6. Maret, W.; Sandstead, H.H. Zinc requirements and the risks and benefits of zinc supplementation. J. Trace Elem. Med. Biol. 2006, 20, 3–18. [Google Scholar] [CrossRef] [PubMed]
  7. Wuehler, S.E.; Peerson, J.M.; Brown, K.H. Use of national food balance data to estimate the adequacy of zinc in national food supplies: Methodology and regional estimates. Public Health Nutr. 2005, 8, 812–819. [Google Scholar] [CrossRef] [PubMed]
  8. World Health Organization. Available online: http://www.who.int/whr/2002 (accessed on 3 July 2017).
  9. Chandel, G.; Datta, K.; Datta, S.K. Detection of genomic changes in transgenic Bt rice populations through genetic fingerprinting using amplified fragment length polymorphism (AFLP). GM Crops 2010, 1, 327–336. [Google Scholar] [CrossRef] [PubMed]
  10. Küry, S.; Dréno, B.; Bézieau, S.; Giraudet, S.; Kharfi, M.; Kamoun, R.; Moisan, J.P. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat. Genet. 2002, 31, 239–240. [Google Scholar] [CrossRef] [PubMed]
  11. Wapnir, R.A. Zinc deficiency, malnutrition and the gastrointestinal tract. J. Nutr. 2000, 130, 1388–1392. [Google Scholar]
  12. Miller, L.V.; Krebs, N.F.; Hambidge, K.M. A mathematical model of zinc absorption in humans as a function of dietary zinc and phytate. J. Nutr. 2007, 137, 135–141. [Google Scholar] [PubMed]
  13. Prasad, A.S. Clinical manifestations of zinc deficiency. Annu. Rev. Nutr. 1985, 5, 341–363. [Google Scholar] [CrossRef] [PubMed]
  14. Prasad, A.S. Zinc: Role in immunity, oxidative stress and chronic inflammation. Curr. Opin. Clin. Nutr. Metab. Care 2009, 12, 646–652. [Google Scholar] [CrossRef] [PubMed]
  15. De Pasquale-Jardieu, P.; Fraker, P.J. Interference in the development of a secondary immune response in mice by zinc deprivation: Persistence of effects. J. Nutr. 1984, 114, 1762–1769. [Google Scholar] [CrossRef]
  16. Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gøtzsche, P.C.; Ioannidis, J.P.A.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. BMJ 2009, 6, 354–391. [Google Scholar]
  17. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Int. J. Surg. 2010, 8, 336–341. [Google Scholar] [CrossRef] [PubMed]
  18. American Autoimmune Related Diseases Association. Available online: https://www.aarda.org/diseaselist/ (accessed on 3 July 2017).
  19. Egger, M.; Smith, G.D.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315, 629–634. [Google Scholar] [CrossRef] [PubMed]
  20. Aaseth, J.; Munthe, E.; Forre, O.; Steinnes, E. Trace elements in serum and urine of patients with rheumatoid arthritis. Scand. J. Rheumatol. 1978, 7, 237–240. [Google Scholar] [CrossRef] [PubMed]
  21. Abdel Fattah, N.S.A.; Atef, M.M.; Al-Qaradaghi, S.M.Q. Evaluation of serum zinc level in patients with newly diagnosed and resistant alopecia areata. Int. J. Dermatol. 2016, 55, 24–29. [Google Scholar] [CrossRef] [PubMed]
  22. Arreola, F.; Paniagua, R.; Díaz-Bensussen, S.; Urquieta, B.; López-Montaño, E.; Partida-Hernández, G.; Villalpando, S. Bone mineral content, 25-hydroxycalciferol and zinc serum levels in insulin-dependent (type I) diabetic patients. Arch. Investig. Med. 1990, 21, 195–199. [Google Scholar]
  23. Banford, J.C.; Brown, D.H.; Hazelton, R.A.; McNeil, C.J.; Sturrock, R.D.; Smith, W.E. Serum copper and erythrocyte superoxide dismutase in rheumatoid arthritis. Ann. Rheum. Dis. 1982, 41, 458–462. [Google Scholar] [CrossRef] [PubMed]
  24. Bhat, Y.J.; Manzoor, S.; Khan, A.R.; Qayoom, S. Trace element levels in alopecia areata. Indian J. Dermatol. Venereol. Leprol. 2009, 75, 29–31. [Google Scholar] [CrossRef] [PubMed]
  25. Bideci, A.; Camurdan, M.O.; Cinaz, P.; Dursun, H.; Demirel, F. Serum zinc, insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels in children with type 1 diabetes mellitus. J. Pediatr. Endocrinol. Metab. 2005, 18, 1007–1011. [Google Scholar] [CrossRef] [PubMed]
  26. Brandão-Neto, J.; da Silva, C.A.; Figueiredo, N.B.; Shuhama, T.; da Cunha, N.F.; Dourado, F.B.; Naves, L.A. Lack of acute zinc effects in glucose metabolism in healthy and insulin-dependent diabetes mellitus patients. Biometals 1999, 12, 161–165. [Google Scholar] [CrossRef] [PubMed]
  27. Car, N.; Car, A.; Granić, M.; Skrabalo, Z.; Momcilović, B. Zinc and copper in the serum of diabetic patients. Biol. Trace Elem. Res. 1992, 32, 325–329. [Google Scholar] [CrossRef] [PubMed]
  28. Dijkmans, B.A.; van der Voet, G.B.; Cats, A.; de Wolff, F.A. Serum aluminium concentrations in patients with rheumatoid arthritis. Scand. J. Rheumatol. 1987, 16, 361–364. [Google Scholar] [CrossRef] [PubMed]
  29. Dore-Duffy, P.; Peterson, M.; Catalanotto, F.; Marlow, S.; Ho, S.Y.; Ostrom, M.; Weinstein, A. Zinc profiles in rheumatoid arthritis. Clin. Exp. Rheumatol. 1990, 8, 541–546. [Google Scholar] [PubMed]
  30. Dore-Duffy, P.; Catalanotto, F.; Donaldson, J.O.; Ostrom, K.M.; Testa, M.A. Zinc in multiple sclerosis. Ann. Neurol. 1983, 14, 450–454. [Google Scholar] [CrossRef] [PubMed]
  31. Erdal, M.; Sahin, M.; Hasimi, A.; Uckaya, G.; Kutlu, M.; Saglam, K. Trace element levels in hashimoto thyroiditis patients with subclinical hypothyroidism. Biol. Trace Elem. Res. 2008, 123, 1–7. [Google Scholar] [CrossRef] [PubMed]
  32. Ghazavi, A.; Kianbakht, S.; Ghasami, K.; Mosayebi, G. High copper and low zinc serum levels in Iranian patients with multiple sclerosis: A case control study. Clin. Lab. 2012, 58, 161–164. [Google Scholar] [PubMed]
  33. Hägglöf, B.; Hallmans, G.; Holmgren, G.; Ludvigsson, J.; Falkmer, S. Prospective and retrospective studies of zinc concentrations in serum, blood clots, hair and urine in young patients with insulin-dependent diabetes mellitus. Acta Endocrinol. 1983, 102, 88–95. [Google Scholar] [PubMed]
  34. Hansson, L.; Huunan-Seppälä, A.; Mattila, A. The content of calcium, magnesium, copper, zinc, lead and chromium in the blood of patients with rheumatoid arthritis. Scand. J. Rheumatol. 1975, 4, 33–38. [Google Scholar] [CrossRef] [PubMed]
  35. Haugen, M.A.; Høyeraal, H.M.; Larsen, S.; Gilboe, I.M.; Trygg, K. Nutrient intake and nutritional status in children with juvenile chronic arthritis. Scand. J. Rheumatol. 1992, 21, 165–170. [Google Scholar] [CrossRef] [PubMed]
  36. Helgeland, M.; Svendsen, E.; Førre, O.; Haugen, M. Dietary intake and serum concentrations of antioxidants in children with juvenile arthritis. Clin. Exp. Rheumatol. 2000, 18, 637–641. [Google Scholar] [PubMed]
  37. Helliwell, M.; Coombes, E.J.; Moody, B.J.; Batstone, G.F.; Robertson, J.C. Nutritional status in patients with rheumatoid arthritis. Ann. Rheum. Dis. 1984, 43, 386–390. [Google Scholar] [CrossRef] [PubMed]
  38. Isbir, T.; Tamer, L.; Taylor, A.; Isbir, M. Zinc, copper and magnesium status in insulin-dependent diabetes. Diabetes Res. 1994, 26, 41–45. [Google Scholar] [PubMed]
  39. Jansen, J.; Rosenkranz, E.; Overbeck, S.; Warmuth, S.; Mocchegiani, E.; Giacconi, R.; Weiskirchen, R.; Karges, W.; Rink, L. Disturbed zinc homeostasis in diabetic patients by in vitro and in vivo analysis of insulinomimetic activity of zinc. J. Nutr. Biochem. 2012, 23, 1458–1466. [Google Scholar] [CrossRef] [PubMed]
  40. Javanbakht, M.; Daneshpazhooh, M.; Chams-Davatchi, C.; Eshraghian, M.; Zarei, M.; Chamari, M. Serum selenium, zinc, and copper in early diagnosed patients with pemphigus vulgaris. Iran J. Public Health 2012, 41, 105–109. [Google Scholar] [PubMed]
  41. Kapaki, E.; Segditsa, J.; Papageorgiou, C. Zinc, copper and magnesium concentration in serum and CSF of patients with neurological disorders. Acta Neurol. Scand. 1989, 79, 373–378. [Google Scholar] [CrossRef] [PubMed]
  42. Kiilerich, S.; Hvid-Jacobsen, K.; Vaag, A.; Sørensen, S.S. 65 Zinc absorption in patients with insulin-dependent diabetes mellitus assessed by whole-body counting technique. Clin. Chim. Acta 1990, 189, 13–18. [Google Scholar] [CrossRef]
  43. Kiilerich, S.; Christiansen, C. Distribution of serum zinc between albumin and alpha 2-macroglobulin in patients with different zinc metabolic disorders. Clin. Chim. Acta 1986, 154, 1–6. [Google Scholar] [CrossRef]
  44. Kobbah, A.M.; Hellsing, K.; Tuvemo, T. Early changes of some serum proteins and metals in diabetic children. Acta Paediatr. Scand. 1988, 77, 734–740. [Google Scholar] [CrossRef] [PubMed]
  45. Lin, C.C.; Tsweng, G.J.; Lee, C.F.; Chen, B.H.; Huang, Y.L. Magnesium, zinc, and chromium levels in children, adolescents, and young adults with type 1 diabetes. Clin. Nutr. 2016, 35, 880–884. [Google Scholar] [CrossRef] [PubMed]
  46. Iyanda, A.A.; Anetor, J.I.; Oparinde, P. Serum levels of minerals and vitamins in two categories of female alopecia subjects using hair relaxer. DSI 2011, 29, 121–124. [Google Scholar] [CrossRef]
  47. Maldonado, M.A.; Gil Extremera, B.; Fernández Soto, M.; Ruiz Martínez, M.; González Jiménez, A.; Guijarro Morales, A.; de Dios Luna del Castillo, J. Zinc levels after intravenous administration of zinc sulphate in insulin-dependent diabetes mellitus patients. Klin. Wochenschr. 1991, 69, 640–644. [Google Scholar]
  48. Mierzecki, A.; Strecker, D.; Radomska, K. A pilot study on zinc levels in patients with rheumatoid arthritis. Biol. Trace Elem. Res. 2011, 143, 854–862. [Google Scholar] [CrossRef] [PubMed]
  49. Negoro, A.; Umemoto, M.; Fujii, M.; Kakibuchi, M.; Terada, T.; Hashimoto, N.; Sakagami, M. Taste function in Sjögren’s syndrome patients with special reference to clinical tests. Auris Nasus Larynx 2004, 31, 141–147. [Google Scholar] [CrossRef] [PubMed]
  50. Nicoloff, G.; Angelova, M.; Nikolov, A. Serum fibrillin-antifibrillin immune complexes among diabetic children. Vascul. Pharmacol. 2005, 43, 171–175. [Google Scholar] [CrossRef] [PubMed]
  51. Önal, S.; Nazıroğlu, M.; Çolakm, M.; Bulut, V.; Flores-Arce, M.F. Effects of different medical treatments on serum copper, selenium and zinc levels in patients with rheumatoid arthritis. Biol. Trace Elem. Res. 2011, 142, 447–455. [Google Scholar] [CrossRef] [PubMed]
  52. Palm, R.; Hallmans, G. Zinc and copper in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 1982, 45, 691–698. [Google Scholar] [CrossRef] [PubMed]
  53. Raz, I.; Havivi, E. Trace elements in blood cells of diabetic subjects. Diabetes Res. 1989, 10, 21–24. [Google Scholar] [PubMed]
  54. Sahebari, M.; Abrishami-Moghaddam, M.; Moezzi, A.; Ghayour-Mobarhan, M.; Mirfeizi, Z.; Esmaily, H.; Ferns, G. Association between serum trace element concentrations and the disease activity of systemic lupus erythematosus. Lupus 2014, 23, 793–801. [Google Scholar] [CrossRef] [PubMed]
  55. Silverio Amancio, O.M.; Alves Chaud, D.M.; Yanaguibashi, G.; Esteves Hilário, M.O. Copper and zinc intake and serum levels in patients with juvenile rheumatoid arthritis. Eur. J. Clin. Nutr. 2003, 57, 706–712. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Ullah, Z.; Ullah, M.I.; Hussain, S.; Kaul, H.; Lone, K.P. Determination of Serum Trace Elements (Zn, Cu, and Fe) in Pakistani Patients with Rheumatoid Arthritis. Biol. Trace Elem. Res. 2017, 175, 10–16. [Google Scholar] [CrossRef] [PubMed]
  57. Yazdanpanah, M.P.; Ghayour-Mobarhan, M.; Taji, A.; Javidi, Z.; Pezeshkpoor, F.; Tavallaie, S.; Momenzadeh, A.; Esmaili, H.; Shojaie-Noori, S.; Khoddami, M.; et al. Serum zinc and copper status in Iranian patients with pemphigus vulgaris. Int. J. Dermatol. 2011, 50, 1343–1346. [Google Scholar] [CrossRef] [PubMed]
  58. Yilmaz, A.; Sari, R.A.; Gundogdu, M.; Kose, N.; Dag, E. Trace elements and some extracellular antioxidant proteins levels in serum of patients with systemic lupus erythematosus. Clin. Rheumatol. 2005, 24, 331–335. [Google Scholar] [CrossRef] [PubMed]
  59. Zoli, A.; Altomonte, L.; Caricchio, R.; Galossi, A.; Mirone, L.; Ruffini, M.P.; Magaró, M. Serum zinc and copper in active rheumatoid arthritis: Correlation with interleukin 1 beta and tumour necrosis factor alpha. Clin. Rheumatol. 1998, 17, 378–382. [Google Scholar] [CrossRef] [PubMed]
  60. Arreola, F.; Paniagua, R.; Herrera, J.; Díaz-Bensussen, S.; Mondragón, L.; Bermúdez, J.A.; Pérez Pastén, E.; Villalpando, S. Low plasma zinc and androgen in insulin-dependent diabetes mellitus. Arch. Androl. 1986, 16, 151–154. [Google Scholar] [CrossRef] [PubMed]
  61. Bacon, M.C.; White, P.H.; Raiten, D.J.; Craft, N.; Margolis, S.; Levanderh, O.A.; Taylor, M.L.; Lipnick, R.N.; Sami, S. Nutritional status and growth in juvenile heumatoid arthritis. Semin. Arthritis Rheum. 1990, 20, 97–106. [Google Scholar] [CrossRef]
  62. Balogh, Z.; El-Ghobarey, A.F.; Fell, G.S.; Brown, D.H.; Dunlop, J.; Dick, W.C. Plasma zinc and its relationship to clinical symptoms and drug treatment in rheumatoid arthritis. Ann. Rheum. Dis. 1980, 39, 329–332. [Google Scholar] [CrossRef] [PubMed]
  63. Crofton, R.W.; Glover, S.C.; Ewen, S.W.; Aggett, P.J.; Mowat, N.A.; Mills, C.F. Zinc absorption in celiac disease and dermatitis herpetiformis: A test of small intestinal function. Am. J. Clin. Nutr. 1983, 38, 706–712. [Google Scholar] [CrossRef] [PubMed]
  64. Cunningham, J.J.; Fu, A.; Mearkle, P.L.; Brown, G. Hyperzincuria in individuals with insulin-dependent diabetes mellitus: Concurrent zinc status and the effect of high-dose zinc supplementation. Metabolism 1994, 43, 1558–1562. [Google Scholar] [CrossRef]
  65. Ho, S.Y.; Catalanotto, F.A.; Lisak, R.P.; Dore-Duffy, P. Zinc in multiple sclerosis. II: Correlation with disease activity and elevated plasma membrane-bound zinc in erythrocytes from patients with multiple sclerosis. Ann. Neurol. 1986, 20, 712–715. [Google Scholar] [CrossRef] [PubMed]
  66. Kennedy, A.C.; Fell, G.S.; Rooney, P.J.; Stevens, W.H.; Dick, W.C.; Buchanan, W.W. Zinc: Its relationship to osteoporosis in rheumatoid arthritis. Scand. J. Rheumatol. 1975, 4, 243–245. [Google Scholar] [CrossRef] [PubMed]
  67. Melchior, T.; Wiese Simonsen, A.; Johannessen, C.; Binder, C. Plasma zinc concentrations during the first 2 years after diagnosis of insulin-dependent diabetes mellitus: A prospective study. J. Intern. Med. 1989, 226, 53–58. [Google Scholar] [CrossRef] [PubMed]
  68. Milanino, R.; Frigo, A.; Bambara, L.M.; Marrella, M.; Moretti, U.; Pasqualicchio, M.; Biasi, D.; Gasperini, R.; Mainenti, L.; Velo, G.P. Copper and zinc status in rheumatoid arthritis: Studies of plasma, erythrocytes, and urine, and their relationship to disease activity markers and pharmacological treatment. Clin. Exp. Rheumatol. 1993, 11, 271–281. [Google Scholar] [PubMed]
  69. Mocchegiani, E.; Boemi, M.; Fumelli, P.; Fabris, N. Zinc-dependent low thymic hormone level in type I diabetes. Diabetes 1989, 38, 932–937. [Google Scholar] [CrossRef] [PubMed]
  70. Naveh, Y.; Schapira, D.; Ravel, Y.; Geller, E.; Scharf, Y. Zinc metabolism in rheumatoid arthritis: Plasma and urinary zinc and relationship to disease activity. J. Rheumatol. 1997, 24, 643–646. [Google Scholar] [PubMed]
  71. Pereira, T.C.; Saron, M.L.; Carvalho, W.A.; Vilela, M.M.; Hoehr, N.F.; Hessel, G. Research on zinc blood levels and nutritional status in adolescents with autoimmune hepatitis. Arq. Gastroenterol. 2011, 48, 62–65. [Google Scholar] [CrossRef] [PubMed]
  72. Quilliot, D.; Dousset, B.; Guerci, B.; Dubois, F.; Drouin, P.; Ziegler, O. Evidence that diabetes mellitus favors impaired metabolism of zinc, copper, and selenium in chronic pancreatitis. Pancreas 2001, 22, 299–306. [Google Scholar] [CrossRef] [PubMed]
  73. Rohn, R.D.; Pleban, P.; Jenkins, L.L. Magnesium, zinc and copper in plasma and blood cellular components in children with IDDM. Clin. Chim. Acta 1993, 215, 21–28. [Google Scholar] [CrossRef]
  74. Ruíz, C.; Alegría, A.; Barberá, R.; Farré, R.; Lagarda, M.J. Selenium, Zinc and Copper in Plasma of patients with Type 1 Diabetes Mellitus in Different Metabolic Control States. J. Trace Elem. Med. Biol. 1998, 12, 91–95. [Google Scholar] [CrossRef]
  75. Smith, D.K.; Feldman, E.B.; Feldman, D.S. Trace element status in multiple sclerosis. Am. J. Clin. Nutr. 1989, 50, 136–140. [Google Scholar] [CrossRef] [PubMed]
  76. Tuncer, S.; Kamanli, A.; Akçil, E.; Kavas, G.O.; Seçkin, B.; Atay, M.B. Trace element and magnesium levels and superoxide dismutase activity in rheumatoid arthritis. Biol. Trace Elem. Res. 1999, 68, 137–142. [Google Scholar] [CrossRef] [PubMed]
  77. Viktorínová, A.; Toserová, E.; Krizko, M.; Duracková, Z. Altered metabolism of copper, zinc, and magnesium is associated with increased levels of glycated hemoglobin in patients with diabetes mellitus. Metabolism 2009, 58, 1477–1482. [Google Scholar] [CrossRef] [PubMed]
  78. Yazar, M.; Sarban, S.; Kocyigit, A.; Isikan, E. Synovial fluid and plasma selenium, copper, zinc, and iron concentrations in patients with rheumatoid arthritis and osteoarthritis. Biol. Trace Elem. Res. 2005, 106, 123–132. [Google Scholar] [CrossRef]
  79. Afridi, H.I.; Kazi, T.G.; Brabazon, D.; Naher, S. Interaction between zinc, cadmium, and lead in scalp hair samples of Pakistani and Irish smokers rheumatoid arthritis subjects in relation to controls. Biol. Trace Elem. Res. 2012, 148, 139–147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Afridi, H.I.; Talpur, F.N.; Kazi, T.G.; Brabazon, D. Estimation of toxic elements in the samples of different cigarettes and their effect on the essential elemental status in the biological samples of Irish smoker rheumatoid arthritis consumers. Environ. Monit. Assess. 2015, 187, 157. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Melø, T.M.; Larsen, C.; White, L.R.; Aasly, J.; Sjøbakk, T.E.; Flaten, T.P.; Sonnewald, U.; Syversen, T. Manganese, copper, and zinc in cerebrospinal fluid from patients with multiple sclerosis. Biol. Trace Elem. Res. 2003, 93, 1–8. [Google Scholar] [CrossRef]
  82. Peters, J.L.; Sutton, A.J.; Jones, D.R.; Abrams, K.R.; Rushton, L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J. Clin. Epidemiol. 2008, 61, 991–996. [Google Scholar] [CrossRef] [PubMed]
  83. Marrosu, M.G.; Murru, R.; Murru, M.R.; Costa, G.; Zavattari, P.; Whalen, M.; Cocco, E.; Mancosu, C.; Schirru, L.; Solla, E.; et al. Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Hum. Mol. Genet. 2001, 10, 2907–2916. [Google Scholar] [CrossRef] [PubMed]
  84. Zavattari, P.; Lampis, R.; Mulargia, A.; Loddo, M.; Angius, E.; Todd, J.A.; Cucca, F. Confirmation of the DRB1-DQB1 loci as the major component of IDDM1 in the isolated founder population of Sardinia. Hum. Mol. Genet. 2000, 9, 2967–2972. [Google Scholar] [CrossRef] [PubMed]
  85. Pitzalis, M.; Zavattari, P.; Murru, R.; Deidda, E.; Zoledziewska, M.; Murru, D.; Moi, L.; Motzo, C.; Orrù, V.; Costa, G.; et al. Genetic loci linked to Type 1 Diabetes and Multiple Sclerosis families in Sardinia. BMC Med. Genet. 2008, 9, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Orrù, V.; Steri, M.; Sole, G.; Sidore, C.; Virdis, F.; Dei, M.; Lai, S.; Zoledziewska, M.; Busonero, F.; Mulas, A.; et al. Genetic variants regulating immune cell levels in health and disease. Cell 2013, 155, 242–256. [Google Scholar] [CrossRef] [PubMed]
  87. Steri, M.; Orru, V.; Idda, M.L.; Pitzalis, M.; Pala, M.; Zara, I.; Sidore, C.; Faa, V.; Floris, M.; Deiana, M.; et al. Overexpression of the cytokine BAFF and autoimmunity risk. N. Engl. J. Med. 2017, 376, 1615–1626. [Google Scholar] [CrossRef] [PubMed]
  88. Contu, D.; Morelli, L.; Zavattari, P.; Lampis, R.; Angius, E.; Frongia, P.; Murru, D.; Maioli, M.; Francalacci, P.; Todd, J.A.; et al. Sex-related bias and exclusion mapping of the nonrecombinant portion of chromosome Y in human type 1 diabetes in the isolated founder population of Sardinia. Diabetes 2002, 51, 3573–3576. [Google Scholar] [CrossRef] [PubMed]
  89. Monti, M.C.; Guido, D.; Montomoli, C.; Sardu, C.; Sanna, A.; Pretti, S.; Lorefice, L.; Marrosu, M.G.; Valera, P.; Cocco, E. Is Geo-Environmental Exposure a Risk Factor for Multiple Sclerosis? A Population-Based Cross-Sectional Studyin South-Western Sardinia. PLoS ONE 2016, 11, e0163313. [Google Scholar] [CrossRef] [PubMed]
  90. Brodin, P.; Jojic, V.; Gao, T.; Bhattacharya, S.; Angel, C.J.L.; Furman, D.; Shen-Orr, S.; Dekker, C.L.; Swan, G.E.; Butte, A.J.; et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 2015, 160, 37–47. [Google Scholar] [CrossRef] [PubMed]
  91. Wu, C.; Yosef, N.; Thalhamer, T.; Zhu, C.; Xiao, S.; Kishi, Y.; Regev, A.; Kuchroo, V.K. Induction of pathogenic TH 17 cells by inducible salt-sensing kinase SGK1. Nature 2013, 496, 513–517. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Haase, H.; Rink, L. Multiple impacts of zinc on immune function. Metallomics 2014, 6, 1175–1180. [Google Scholar] [CrossRef] [PubMed]
  93. Prasad, A.S. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J. Infect. Dis. 2000, 182, 62–68. [Google Scholar] [CrossRef] [PubMed]
  94. Lee, H.; Kim, B.; Choi, Y.H.; Hwang, Y.; Kim, D.H.; Cho, S.; Hong, S.J.; Lee, W. Inhibition of interleukin-1β-mediated interleukin-1 receptor-associated kinase 4 phosphorylation by zinc leads to repression of memory T helper type 17 response in humans. Immunology 2015, 146, 645–656. [Google Scholar] [CrossRef] [PubMed]
  95. Hojyo, S.; Miyai, T.; Fujishiro, H.; Kawamura, M.; Yasuda, T.; Hijikata, A.; Bin, B.; Irié, T.; Tanaka, J.; Atsumi, T.; et al. Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. Proc. Natl. Acad. Sci. USA 2014, 111, 11786–11791. [Google Scholar] [CrossRef] [PubMed]
  96. Rosenkranz, E.; Metz, C.H.; Maywald, M.; Hilgers, R.D.; Wessels, I.; Senff, T.; Haase, H.; Jager, M.; Ott, M.; Aspinall, R.; et al. Zinc supplementation induces regulatory T cells by inhibition of Sirt-1 deacetylase in mixed lymphocyte cultures. Mol. Nutr. Food Res. 2016, 60, 661–667. [Google Scholar] [CrossRef] [PubMed]
  97. Rosenkranz, E.; Maywald, M.; Hilgers, R.D.; Brieger, A.; Clarner, T.; Kipp, M.; Plumakers, B.; Meyer, S.; Schwerdtle, T.; Rink, L. Induction of regulatory T cells in Th1-/Th17-driven experimental autoimmune encephalomyelitis by zinc administration. J. Nutr. Biochem. 2016, 29, 116–123. [Google Scholar] [CrossRef] [PubMed]
  98. Kitabayashi, C.; Fukada, T.; Kanamoto, M.; Ohashi, W.; Hojyo, S.; Atsumi, T.; Ueda, N.; Azuma, I.; Hirota, H.; Murakami, M.; et al. Zinc suppresses Th17 development via inhibition of STAT3 activation. Int. Immunol. 2010, 22, 375–386. [Google Scholar] [CrossRef] [PubMed]
  99. Bredholt, M.; Frederiksen, J.L. Zinc in multiple sclerosis: A systematic review and meta-analysis. ASN Neuro 2016, 8. [Google Scholar] [CrossRef] [PubMed]
  100. Socha, K.; Karpinska, E.; Kochanowicz, J.; Soroczynska, J.; Jakoniuk, M.; Wilkiel, M.; Mariak, Z.D.; Borawska, M.H. Dietary habits; concentration of copper, zinc, and Cu-to-Zn ratio in serum and ability status of patients with relapsing-remitting multiple sclerosis. Nutrition 2017, 39, 76–81. [Google Scholar] [CrossRef] [PubMed]
  101. Popescu, B.F.; Frischer, J.M.; Webb, S.M.; Tham, M.; Adiele, R.C.; Robinson, C.A.; Fitz-Gibbon, P.D.; Weigand, S.D.; Metz, I.; Nehzati, S.; et al. Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions. Acta Neuropathol. 2017, 134, 45–64. [Google Scholar] [CrossRef] [PubMed]
  102. Campo, C.A.; Wellinghausen, N.; Faber, C.; Fischer, A.; Rink, L. Zinc inhibits the mixed lymphocyte culture. Biol. Trace Elem. Res. 2001, 79, 15–22. [Google Scholar] [PubMed]
  103. Faber, C.; Gabriel, P.; Ibs, K.H.; Rink, L. Zinc in pharmacological doses suppresses allogeneic reaction without affecting the antigenic response. Bone Marrow Transpl. 2004, 33, 1241–1246. [Google Scholar] [CrossRef] [PubMed]
  104. Kown, M.H.; van der Steenhoven, T.J.; Jahncke, C.L.; Mari, C.; Lijkwan, M.A.; Koransky, M.L.; Blankenberg, F.G.; Strauss, H.W.; Robbins, R.C. Zinc chloride-mediated reduction of apoptosis as an adjunct immunosuppressive modality in cardiac transplantation. J. Heart Lung Transplant. 2002, 21, 360–365. [Google Scholar] [CrossRef]
  105. Schubert, C.; Guttek, K.; Grungreiff, K.; Thielitz, A.; Buhling, F.; Reinhold, A.; Brocke, S.; Reinhold, D. Oral zinc aspartate treats experimental autoimmune encephalomyelitis. Biometals 2014, 27, 1249–1262. [Google Scholar] [CrossRef] [PubMed]
  106. Rungby, J. Zinc, zinc transporters and diabetes. Diabetologia 2010, 53, 1549–1551. [Google Scholar] [CrossRef] [PubMed]
  107. Jansen, J.; Karges, W.; Rink, L. Zinc and diabetes—Clinical links and molecular mechanisms. J. Nutr. Biochem. 2009, 20, 399–417. [Google Scholar] [CrossRef] [PubMed]
  108. Nicolson, T.J.; Bellomo, E.A.; Wijesekara, N.; Loder, M.K.; Baldwin, J.M.; Gyulkhandanyan, A.V.; Koshkin, V.; Tarasov, A.I.; Carzaniga, R.; Kronenberger, K. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes–associated variants. Diabetes 2009, 58, 2070–2083. [Google Scholar] [CrossRef] [PubMed]
  109. Lemaire, K.; Ravier, M.A.; Schraenen, A.; Creemers, J.W.; Van de Plas, R.; Granvik, M.; Van Lommel, L.; Waelkens, E.; Chimienti, F.; Rutter, G. Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc. Natl. Acad. Sci. USA 2009, 106, 14872–14877. [Google Scholar] [CrossRef] [PubMed]
  110. Wijesekara, N.; Dai, F.; Hardy, A.; Giglou, P.; Bhattacharjee, A.; Koshkin, V.; Chimienti, F.; Gaisano, H.; Rutter, G.; Wheeler, M. Beta cell-specific ZnT8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 2010, 53, 1656–1668. [Google Scholar] [CrossRef] [PubMed]
  111. Liuzzi, J.P.; Lichten, L.A.; Rivera, S.; Blanchard, R.K.; Aydemir, T.B.; Knutson, M.D.; Ganz, T.; Cousins, R.J. Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Proc. Natl. Acad. Sci. USA 2005, 102, 6843–6848. [Google Scholar] [CrossRef] [PubMed]
  112. Aburto-Luna, V.; Treviño, S.; Santos-López, G.; Moroni-González, D.; Calva-Cruz, O.; Aguilar-Alonso, P.; León-Chávez, B.A.; Brambila, E. Hepatic mobilization of zinc after an experimental surgery, and its relationship with inflammatory cytokines release, and expression of metallothionein and Zip14 transporter. Inflamm. Res. 2017, 66, 167–175. [Google Scholar] [CrossRef] [PubMed]
  113. Bonaventura, P.; Lamboux, A.; Albarède, F.; Miossec, P. A Feedback Loop between Inflammation and Zn Uptake. PLoS ONE 2016, 11, e0147146. [Google Scholar] [CrossRef] [PubMed]
  114. Davis, C.D.; Uthus, E.O. DNA methylation, cancer susceptibility, and nutrient interactions. Exp. Biol. Med. 2004, 229, 988–995. [Google Scholar] [CrossRef]
  115. Uriu-Adams, J.Y.; Keen, C.L. Zinc and reproduction: Effects of zinc deficiency on prenatal and early postnatal development. Birth Defects Res. B Dev. Reprod. Toxicol. 2010, 89, 313–325. [Google Scholar] [CrossRef] [PubMed]
  116. Beach, R.S.; Gershwin, M.E.; Hurley, L.S. Gestational zinc deprivation in mice: Persistence of immunodeficiency for three generations. Science 1982, 218, 469–471. [Google Scholar] [CrossRef] [PubMed]
  117. Tomat, A.L.; Inserra, F.; Veiras, L.; Vallone, M.C.; Balaszczuk, A.M.; Costa, M.A.; Arranz, C. Moderate zinc restriction during fetal and postnatal growth of rats: Effects on adult arterial blood pressure and kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 295, 543–549. [Google Scholar] [CrossRef] [PubMed]
  118. Valera, P.; Zavattari, P.; Albanese, S.; Cicchella, D.; Dinelli, E.; Lima, A.; De Vivo, B. A correlation study between multiple sclerosis and type 1 diabetes incidences and geochemical data in Europe. Environ. Geochem. Health 2014, 36, 79–98. [Google Scholar] [CrossRef] [PubMed]
  119. Valera, P.; Zavattari, P.; Sanna, A.; Pretti, S.; Marcello, A.; Mannu, C.; Targhetta, C.; Bruno, G.; Songini, M. Zinc and Other Metals Deficiencies and Risk of Type 1 Diabetes: An Ecological Study in the High Risk Sardinia Island. PLoS ONE 2015, 10, e0141262. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Dinelli, E.; Lima, A.; De Vivo, B.; Albanese, S.; Cicchella, D.; Valera, P. Hydrogeochemical analysis on Italian bottled mineral waters: Effects of geology. J. Geochem. Explor. 2010, 107, 317–335. [Google Scholar] [CrossRef]
  121. Cicchella, D.; Albanese, S.; De Vivo, B.; Dinelli, E.; Giaccio, L.; Lima, A.; Valera, P. Trace elements and ions in Italian bottled mineral waters: Identification of anomalous values and human health related effects. J. Geochem. Explor. 2010, 107, 336–349. [Google Scholar] [CrossRef]
  122. Dinelli, E.; Lima, A.; Albanese, S.; Birke, M.; Cicchella, D.; Giaccio, L.; Valera, P.; De Vivo, B. Comparative study between bottled mineral and tap water in Italy. J. Geochem. Explor. 2012, 112, 368–389. [Google Scholar] [CrossRef]
  123. Dinelli, E.; Lima, A.; Albanese, S.; Birke, M.; Cicchella, D.; Giaccio, L.; Valera, P.; De Vivo, B. Major and trace elements in tap water from Italy. J. Geochem. Explor. 2012, 112, 54–75. [Google Scholar] [CrossRef]
  124. El Amari, K.; Valera, P.; Hibti, M.; Pretti, S.; Marcello, A.; Essarraj, S. Impact of mine tailings on surrounding soils and ground water: Case of Kettara old mine, Morocco. J. Afr. Earth Sci. 2014, 100, 437–449. [Google Scholar] [CrossRef]
  125. Pompili, M.; Vichi, M.; Dinelli, E.; Pycha, R.; Valera, P.; Albanese, S.; Lima, A.; De Vivo, B.; Cicchella, D.; Fiorillo, A.; et al. Relationships of local lithium concentrations in drinking water to regional suicide rates in Italy. World J. Biol. Psychiatry 2015, 16, 567–574. [Google Scholar] [CrossRef] [PubMed]
  126. Pompili, M.; Vichi, M.; Dinelli, E.; Erbuto, D.; Pycha, R.; Serafini, G.; Giordano, G.; Valera, P.; Albanese, S.; Lima, A.; et al. Arsenic: Association of regional concentrations in drinking water with suicide and natural causes of death in Italy. Psychiatry Res. 2017, 249, 311–317. [Google Scholar] [CrossRef] [PubMed]
  127. Scheib, A.J.; Flight, D.M.A.; Birke, M.; Tarvainen, T.; Locutura, J.; Albanese, S.; Andersson, M.; Arnoldussen, A.; Baritz, R.; Batista, M.J.; et al. The geochemistry of niobium and its distribution and relative mobility in agricultural soils of Europe. Geochem. Explor. Environ. A 2012, 12, 293–302. [Google Scholar] [CrossRef]
  128. Mann, A.; Reimann, C.; De Caritat, P.; Turner, N.; Birke, M.; Albanese, S.; Andersson, M.; Baritz, R.; Batista, M.J.; Bel-Lan, A.; et al. Mobile metal ion® analysis of european agricultural soils: Bioavailability, weathering, Geogenic patterns and anthropogenic anomalies. Geochem. Explor. Environ. A 2015, 15, 99–112. [Google Scholar] [CrossRef]
  129. Négrel, P.; Sadeghi, M.; Ladenberger, A.; Reimann, C.; Birke, M.; Albanese, S.; Andersson, M.; Baritz, R.; Batista, M.J.; Bel-Lan, A.; et al. Geochemical fingerprinting and source discrimination of agricultural soils at continental scale. Chem. Geol. 2015, 396, 1–15. [Google Scholar] [CrossRef]
  130. Ladenberger, A.; Demetriades, A.; Reimann, C.; Birke, M.; Sadeghi, M.; Uhlbäck, J.; Andersson, M.; Jonsson, E.; Albanese, S.; Baritz, R.; et al. GEMAS: Indium in agricultural and grazing land soil of Europe—Its source and geochemical distribution patterns. J. Geochem. Explor. 2015, 154, 61–80. [Google Scholar] [CrossRef]
  131. Birke, M.; Reimann, C.; Oorts, K.; Rauch, U.; Demetriades, A.; Dinelli, E.; Ladenberger, A.; Halamić, J.; Gosar, M.; Jähne-Klingberg, F. The GEMAS Project Team. Use of GEMAS data for risk assessment of cadmium in European agricultural and grazing land soil under the REACH Regulation. Appl. Geochem. 2016, 74, 109–121. [Google Scholar] [CrossRef]
  132. Birke, M.; Reimann, C.; Rauch, U.; Ladenberger, A.; Demetriades, A.; Jähne-Klingberg, F.; Oorts, K.; Gosar, M.; Dinelli, E.; Halamić, J. GEMAS: Cadmium distribution and its sources in agricultural and grazing land soil of Europe—Original data versus clr-transformed data. J. Geochem. Explor. 2017, 173, 13–30. [Google Scholar] [CrossRef]
  133. Scheib, A.J.; Birke, M.; Dinelli, E.; Albanese, S.; Andersson, M.; Baritz, R.; Batista, M.J.; Bel-Lan, A.; Cicchella, D.; Demetriades, A.; et al. Geochemical evidence of aeolian deposits in European soils. Boreas 2014, 43, 175–192. [Google Scholar] [CrossRef]
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Figure 1. PRISMA flowchart diagram describing the systematic reviews process. PRISMA = Preferred Reporting Items for Systematic reviews and Meta-Analyses.
Figure 1. PRISMA flowchart diagram describing the systematic reviews process. PRISMA = Preferred Reporting Items for Systematic reviews and Meta-Analyses.
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Figure 2. Forest plot of zinc status in serum samples. FE: Fixed Effects; DL: DerSimonial-Laird; ML: Maximum-Likelihood; PL: Profile—Likelihood; T: t-Test.
Figure 2. Forest plot of zinc status in serum samples. FE: Fixed Effects; DL: DerSimonial-Laird; ML: Maximum-Likelihood; PL: Profile—Likelihood; T: t-Test.
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Figure 3. Forest plot of zinc status in plasma samples.
Figure 3. Forest plot of zinc status in plasma samples.
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Figure 4. (a) Funnel plot for meta-analysis related to serum Zn; (b) Funnel plot for meta-analysis related to plasma Zn.
Figure 4. (a) Funnel plot for meta-analysis related to serum Zn; (b) Funnel plot for meta-analysis related to plasma Zn.
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Table
Table 1. Characteristics of selected studies included in meta-analysis in reference to serum samples.
Table 1. Characteristics of selected studies included in meta-analysis in reference to serum samples.
AuthorsYearDiseaseNo.Zn Status (μg/mL)Direction
PatientsControlsPatientsControls
Aaseth et al. [20]1978RA22120.6540.850low zinc in patients
Abdel Fattah et al. [21]2016AA50500.7550.857low zinc in patients
Arreola et al. [22]1990T1D22110.7341.114low zinc in patients
Banford et al. [23]1982RA854912.10012.100no difference
Bhat et al. [24]2009AA505078.00088.000low zinc in patients
Bideci et al. [25]2005T1D28150.9611.231low zinc in patients
Brandao-Neto et al. [26]1999T1D10101.0401.020no difference
Car et al. [27]1992T1D15150.5620.772low zinc in patients
Dijkmans et al. [28]1987RA25180.6670.942low zinc in patients
Dore-Duffy et al. [29]1983MS6362831.000817.000no difference
Dore-Duffyet al. [30]1990RA57180.8500.997low zinc in patients
Erdal et al. [31]2008HT43491.0931.015no difference
Ghazavi et al. [32]2012MS60600.4021.278low zinc in patients
Hagglof et al. [33]1983T1D66790.9151.000low zinc in patients
Hansson et al. [34]1975RA37701.0661.055low zinc in patients
42261.0520.965low zinc in patients
Haugen et al. [35]1992JIA8170.9090.981low zinc in patients
Helgeland et al. [36]2000JIA14220.8300.870low zinc in patients
Helliwell et al. [37]1984RA50500.8040.883low zinc in patients
Isbir et al. [38]1994T1D20200.5650.696low zinc in patients
Jansen et al. [39]2012T1D880.7680.883low zinc in patients
Javanbakht et al. [40]2012PV43580.9060.988no difference
Kapaki et al. [41]1989MS15281.0301.100no difference
Kiilerich et al. [42]1986T1D7120.7980.948low zinc in patients
Kiilerich et al. [43]1990T1D101041.0070.948no difference
Kobbah et al. [44]1988T1D30440.7850.909low zinc in patients
Lin et al. [45]2016T1D88760.9100.940no difference
Iyanda et al. [46]2011AA20200.7920.933low zinc in patients
20200.7820.933low zinc in patients
Maldonado et al. [47]1991T1D22221.1111.197no difference
Mierzecki et al. [48]2011RA74300.8010.720low zinc in patients
Negoro et al. [49]2004SS31150.7060.866low zinc in patients
Nicoloff et al. [50]2005T1D35200.6751.268low zinc in patients
Onal et al. [51]2011RA32520.4300.748low zinc in patients
Palm et al. [52]1982MS21210.8500.968low zinc in patients
29290.7910.863low zinc in patients
Raz et al. [53]1989T1D23220.9280.170low zinc in patients
Sahebari et al. [54]2014SLE1231000.7010.860low zinc in patients
Silverio Amancio et al. [55]2003JIA20100.8970.900no difference
21130.9760.950no difference
Ullah et al. [56]2017RA61610.8560.959low zinc in patients
Yazdanpanah et al. [57]2011PV25250.7701.207low zinc in patients
Yilmaz et al. [58]2005SLE27200.8750.990low zinc in patients
Zoli et al. [59]1998RA572085.600108.100low zinc in patients
Abbreviations: AA, Alopecia Areata; HT, Hashimoto Thyroiditis; JIA, Juvenile Idiopathic Arthritis; MS, Multiple Sclerosis; PV, Pemphigus Vulgaris; RA, Rheumatoid Arthritis; SLE, Systemic Lupus Erythematosus; SS, Sjogren’s Syndrome; T1D, Type 1 Diabetes.
Table
Table 2. Characteristics of selected studies included in meta-analysis in reference to plasma samples.
Table 2. Characteristics of selected studies included in meta-analysis in reference to plasma samples.
AuthorsYearDiseaseNo.Zn Status (μg/mL)Direction
PatientsControlsPatientsControls
Arreola et al. [60]1986T1D91273.490112.460low zinc in patients
Bacon et al. [61]1990JIA890.8050.983low zinc in patients
JIA1490.8590.983low zinc in patients
JIA1290.8750.983low zinc in patients
Balogh et al. [62]1980RA14010011.74015.100low zinc in patients
Crofton et al. [63]1983CD12150.5820.974low zinc in patients
CD10150.6280.974low zinc in patients
Cunningham et al. [64]1994T1D14150.9500.910no difference
Dore-Duffy et al. [29]1983MS6860845.000788.000low zinc in patients
Dore-Duffy et al. [30]1990RA57170.7950.890low zinc in patients
Ho et al. [65]1986MS45230.8900.880high zinc in patients
Kennedy et al. [66]1975RA1131000.8570.990low zinc in patients
Melchior et al. [67]1989T1D14360.9470.943no difference
T1D12360.8790.817no difference
Milanino et al. [68]1993RA120700.8951.019low zinc in patients
RA10 0.5260.106low zinc in patients
Mocchegiani et al. [69]1989T1D15160.7931.064low zinc in patients
Naveh et al. [70]1997RA1380.5901.110low zinc in patients
RA1680.6001.110low zinc in patients
Pereira et al. [71]2011AH23250.7190.807low zinc in patients
Quilliot et al. [72]2001T1D25200.9400.970low zinc in patients
Rohn et al. [73]1993T1D45120.9420.981no difference
Ruiz et al. [74]1998T1D1691.0201.079no difference
T1D1371.0461.059no difference
T1D31191.0201.040no difference
T1D34241.0461.040no difference
T1D31171.0331.046no difference
T1D25141.0131.059no difference
Smith et al. [75]1989MS27330.9871.000no difference
Tuncer et al. [76]1999RA38201.0871.253low zinc in patients
Viktorinova et al. [77]2009T1D11340.8850.942no difference
Yazar et al. [78]2005RA25250.6630.658no difference
Abbreviations: AH, Autoimmune Hepatitis; Cd, Celiac Disease; JIA, Juvenile Idiopathic Arthritis; MS, Multiple Sclerosis; RA, Rheumatoid Arthritis; T1D, Type 1 Diabetes.
Table
Table 3. Characteristics of selected studies included in meta-analysis in reference to hair, urine and CSF samples.
Table 3. Characteristics of selected studies included in meta-analysis in reference to hair, urine and CSF samples.
AuthorsYearDiseaseNo.Biological SampleZn Status (μg/g)Direction
PatientsControlsPatientsControls
Afridi et al. [79]2015RA1514Hair122.00178.00low zinc in patients
1512117.00167.00low zinc in patients
1213135.00203.00low zinc in patients
1113126.00203.00low zinc in patients
Afridi et al. [80]2012RA3947Hair112.00225.00low zinc in patients
3452138.00250.00low zinc in patients
2322122.00178.00low zinc in patients
2019135.00203.00low zinc in patients
Hagglof et al. [33]1983T1D7430Hair160.90190.80low zinc in patients
Mierzecki et al. [48]2011RA7175Hair150.37150.37no difference
Kiilerich et al. [43]1990T1D1028Urine1006.85509.96high zinc in patients
Milanino et al. [68]1993RA7550Urine437.9457.50no difference
Maldonado et al. [47]1991T1D138Urine353984.00low zinc in patients
Naveh et al. [70]1997RA168Urine538984.00low zinc in patients
2222Urine1396611.00high zinc in patients
Kapaki et al. [41]1989MS1528CSF34.7334.70no difference
Melo et al. [81]2003MS1819CSF19.0023.50no difference
Abbreviations: MS, Multiple Sclerosis; RA, Rheumatoid Arthritis, T1D, Type 1 Diabetes.

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Sanna, A.; Firinu, D.; Zavattari, P.; Valera, P. Zinc Status and Autoimmunity: A Systematic Review and Meta-Analysis. Nutrients 2018, 10, 68. https://doi.org/10.3390/nu10010068

AMA Style

Sanna A, Firinu D, Zavattari P, Valera P. Zinc Status and Autoimmunity: A Systematic Review and Meta-Analysis. Nutrients. 2018; 10(1):68. https://doi.org/10.3390/nu10010068

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Sanna, Alessandro, Davide Firinu, Patrizia Zavattari, and Paolo Valera. 2018. "Zinc Status and Autoimmunity: A Systematic Review and Meta-Analysis" Nutrients 10, no. 1: 68. https://doi.org/10.3390/nu10010068

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