2017 study: Pathogenic implications of Fe & Zn in MS lesions

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2017 study: Pathogenic implications of Fe & Zn in MS lesions

Postby jimmylegs » Thu Dec 07, 2017 7:08 am

"Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions (2017)
https://link.springer.com/article/10.10 ... 017-1696-8
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage."

thinking back to forum chats going back close to a decade ago now...:

Zinc deficiency-induced iron accumulation, a consequence of alterations in iron regulatory protein-binding activity, iron transporters, and iron storage proteins (2008)
https://www.ncbi.nlm.nih.gov/pubmed/18073202
Abstract
"One consequence of zinc deficiency is an elevation in cell and tissue iron concentrations. To examine the mechanism(s) underlying this phenomenon, Swiss 3T3 cells were cultured in zinc-deficient (D, 0.5 microM zinc), zinc-supplemented (S, 50 microM zinc), or control (C, 4 microM zinc) media. After 24 h of culture, cells in the D group were characterized by a 50% decrease in intracellular zinc and a 35% increase in intracellular iron relative to cells in the S and C groups. The increase in cellular iron was associated with increased transferrin receptor 1 protein and mRNA levels and increased ferritin light chain expression. The divalent metal transporter 1(+)iron-responsive element isoform mRNA was decreased during zinc deficiency-induced iron accumulation. Examination of zinc-deficient cells revealed increased binding of iron regulatory protein 2 (IRP2) and decreased binding of IRP1 to a consensus iron-responsive element. The increased IRP2-binding activity in zinc-deficient cells coincided with an increased level of IRP2 protein. The accumulation of IRP2 protein was independent of zinc deficiency-induced intracellular nitric oxide production but was attenuated by the addition of the antioxidant N-acetylcysteine or ascorbate to the D medium. These data support the concept that zinc deficiency can result in alterations in iron transporter, storage, and regulatory proteins, which facilitate iron accumulation."

next a small study, and i'd rather see serum ferritin than serum iron (or both, anyway), but still interesting:

Serum level of iron, zinc and copper in patients with multiple sclerosis (2013)
http://jmj.jums.ac.ir/article-1-22-en.pdf
"Introduction:
Multiple sclerosis (MS) is one of the most common neurologic disorders. It appears that in addition to the common risk factors, there may be other factors, such as serum level of trace elements, which affect the development or course of the disease. The aim of this study was to evaluate the serum levels of iron, zinc and copper in patients with MS and compare them with the control group.
Materials and Methods:
In this study, serum levels of iron, zinc and copper were determined in 25 patients with MS and compared with those of 25 healthy individuals matched with age and sex. Data were analyzed in SPSS, version17 using statistical descriptive methods (mean- percentage, SD) and t-test
Results:
In this study, there were 9 males in the case and control groups and the rest were female. The mean age of the patients was 28 ± 3.44 years for men and 24 ± 2.55 years for women. Mean serum iron levels were significantly elevated in MS patients (127.04 ± 34.67) compared to these levels in the control group (103.95 ± 33.81). Mean serum zinc levels were significantly decreased in MS patients (10.92 ± 2.114) as compared to these levels in the control group (14.05 ± 3.2). Also, mean serum copper levels were significantly decreased in MS patients (88.58 ± 19.56) compared to the levels in the control group (110.37 ± 37.1).
Conclusion:
The findings of this study show that serum levels of Iron, Zinc and Copper in patients with MS are different from those in normal population."

i found that when i fixed my zinc deficiency, copper did at first jump up as well. was nervous originally, but ended up okay with it increasing, as long as the level stays ideally just below the target zinc level in serum
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Re: 2017 study: Pathogenic implications of Fe & Zn in MS les

Postby frodo » Thu Dec 14, 2017 2:13 am

i found that when i fixed my zinc deficiency, copper did at first jump up as well. was nervous originally, but ended up okay with it increasing, as long as the level stays ideally just below the target zinc level in serum


There are too much reports about iron and zinc to be a coincidence. Thanks for the summary.
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Re: 2017 study: Pathogenic implications of Fe & Zn in MS les

Postby jimmylegs » Thu Dec 14, 2017 4:56 pm

no probs :)
i had to be careful in the beginning bc i was also very low iron status for a long time.
needed to carefully bring things up into their respective sweet spots.
i like serum zinc near 18 umol/l, copper near 17 umol/l and ferritin around 80 ng/ml
(i almost just wrote ferretin lol - NO THANKS)
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Re: 2017 study: Pathogenic implications of Fe & Zn in MS les

Postby jimmylegs » Fri Dec 22, 2017 5:37 pm

Iron Homeostasis in Tissues Is Affected during Persistent Chlamydia pneumoniae Infection in Mice (2017)
https://www.hindawi.com/journals/bmri/2017/3642301/abs/

Abstract
"Chlamydia pneumoniae (C. pneumoniae) may be a mediator in the pathogenesis of atherosclerosis. For its growth C. pneumoniae depends on iron (Fe), but how Fe changes in tissues during persistent infection or affects bacterial replication in tissues is unknown. C. pneumoniae-infected C57BL/6J mice were sacrificed on days 4, 8, 20, and 40. Mice had bacteria in the lungs and liver on all days. Inflammatory markers, chemokine Cxcl2 and interferon-gamma, were not affected in the liver on day 40. The copper (Cu)/zinc (Zn) ratio in serum, another marker of infection/inflammation, increased on day 4 and tended to increase again on day 40. The Fe markers, transferrin receptor (TfR), Hepcidin (Hamp1), and ferroportin 1 (Fpn1), increased in the liver on day 4 and then normalized except for TfR that tended to decrease. TfR responses were similar to Fe in serum that increased on day 4 but tended to decrease thereafter. In the liver, Fe was increased on day 4 and also on day 40. The reappearing increases in Cu/Zn on day 40 concomitant with the increase in liver Fe on day 40, even though TfR tended to decrease, and the fact that viable C. pneumoniae was present in the lungs and liver may indicate the early phase of activation of recurrent infection."

fascinating and consistent with observations elsewhere. zinc demand goes up while fighting infection, copper zinc ratio is increased as zinc is consumed and copper is not. i'll be curious to see whether i can determine if that ratio change actually occurred because of a zinc drop, copper increase, or both. for iron homeostasis to be affected would be logical in this circumstance. (checked the full text; no detail on the guilty party where the cu/zn ratio increase is concerned)
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Re: 2017 study: Pathogenic implications of Fe & Zn in MS les

Postby jimmylegs » Fri Dec 22, 2017 5:47 pm

more fascinating stuff

A Molecular Mechanism for Bacterial Susceptibility to Zinc (2011)
http://journals.plos.org/plospathogens/ ... at.1002357
"Dietary zinc deficiency is a global health problem affecting almost two billion people. Infectious diseases associated with zinc deficiency include respiratory infections caused by bacteria, and notably, Streptococcus pneumoniae, which is responsible for more than 1 million deaths annually. The association between zinc and immunity is well known, but the mechanism by which zinc provides protection against infectious diseases has remained a mystery. Previously, we found that manganese was essential for S. pneumoniae growth and its ability to cause disease. Intriguingly, we also observed that zinc could bind to the manganese transport protein. Therefore, we sought to determine if zinc could inhibit manganese transport, and to observe what the effects would be on S. pneumoniae. We found that zinc prevented manganese uptake. This slowed bacterial growth and rendered it hypersensitive to immune cell killing. We also observed that, during S. pneumoniae infection in mice, zinc released by the host increased to concentrations that could compete for manganese uptake. Our study provides direct evidence for how zinc is toxic to bacteria by preventing manganese uptake. Furthermore, we show how this could be harnessed by the immune system, thereby providing a scientific basis for the protective effect of zinc against infectious diseases."
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Re: 2017 study: Pathogenic implications of Fe & Zn in MS les

Postby jimmylegs » Sun Dec 24, 2017 10:34 am

gonna take a while to get my head around this stuff

Nutritional immunity beyond iron: a role for manganese and zinc (2010)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847644/

"...The struggle for zinc
Zinc is the second most abundant transition metal within the vertebrate host and has been suggested to interact with as many as 10% of host proteins [7]. Tissue levels of zinc range from 0.8 μg/g in serum, to between 100 and 200 μg/g in spleen, liver, and kidney [8,9]. In vertebrates, zinc functions as a protein cofactor and can have both catalytic and structural roles. Zinc is critically important for proper immune function as even a mild zinc insufficiency results in widespread defects in both innate and adaptive immunity [4]. Despite the fact that chronic zinc deficiency results in pleiotropic effects on the immune system, there is increasing evidence suggesting that the host actively sequesters zinc during infection to hinder microbial growth.

An appreciation that zinc sequestration occurs upon microbial infection resulted from technical advances that permit imaging of metal distribution within vertebrate tissue sections. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) produces a two-dimensional image of metal distribution within tissue sections, and can be used to monitor the impact of infection on elemental localization. LA-ICP-MS revealed that tissue abscesses caused by Staphylococcus aureus are virtually devoid of detectable zinc. This is in contrast to the high levels of zinc in surrounding healthy tissue (Figure 1) [10]. Although the factors responsible for sequestering zinc within abscesses are unknown, the lack of nutrient zinc within the abscess appears to represent an immune strategy to control infection.

https://www.ncbi.nlm.nih.gov/pmc/articl ... figure/F1/
Figure 1
Zinc and manganese are found at reduced levels at localized sites of infection as compared to surrounding healthy tissues

In addition to extracellular zinc sequestration, infected vertebrates can also decrease cellular zinc concentrations to protect against intracellular pathogens. Phagocytic and antigen presenting cells of the immune system engulf bacteria into phagosomes, which subsequently merge with lysosomes subjecting engulfed bacteria to an onslaught of antimicrobial factors. ZIP8, which belongs to the Zrt Irt protein family of zinc transporters, is expressed by macrophages and IFN-γ stimulated T cells [11,12]. In stimulated T cells ZIP8 associates with the lysosomal protein Lamp1 suggesting an association with the lysosome [12]. In transfected human embryonic kidney cells ZIP8 also associated with lysosomes [11]. Initial studies have suggested that ZIP8 transports zinc, consistent with its assignment as a Zrt Irt family member [11]. In support of this, T cells decrease lysosomal zinc levels upon activation and cells over-expressing ZIP8 have increased cytosolic zinc levels [11,12]. Taken together, these results are consistent with a model whereby ZIP8 is oriented to transport zinc from the lysosome into the cytoplasm as a mechanism to disrupt zinc-dependent bacterial processes.

In addition to decreasing lysosomal zinc levels, vertebrates also reduce cytoplasmic zinc levels in response to bacterial infection. Stimulation of dendritic cells with lipopolysacharide results in decreased expression of ZIP importers and increased expression of ZnT zinc exporters, resulting in reduced cytosolic zinc levels [13,14]. While it is clear that vertebrates alter lysosomal and cytoplasmic zinc levels in response to bacterial pathogens, it is unclear if this response directly impacts the offending organisms. Alterations in zinc concentrations impacts T-cell development as well as dendritic cell activation and maturation, [4,12-14] making it difficult to determine the impact of reduced zinc levels on microbial growth and virulence. Additional studies are needed to untangle the multiple effects of altered zinc levels during bacterial infection.

While the mechanisms and function of zinc sequestration by the host are unclear, shortages in available zinc clearly have the potential to disrupt a number of bacterial processes that are critical to infection. ...

... Unlike zinc, there is little information regarding the effects of manganese deficiency on immune development and function. There are, however, limited data suggesting that toxic levels of manganese may impair immune function [31]. Further, emerging data have revealed that vertebrates resist bacterial infections through manganese sequestration.

As is the case with zinc, LA-ICP-MS analysis of staphylococcal infection found that abscesses are devoid of detectable manganese, while the surrounding healthy tissues are replete with the metal [10]. Subsequent studies revealed that the host protein calprotectin is necessary for sequestration of manganese within abscesses (Figure 1) [10]. Calprotectin is a member of the S100 family of proteins whose contribution to nutritional immunity is discussed below. In addition to localized sequestration of manganese within tissues during infection, there is growing evidence that vertebrates limit manganese availability as a mechanism to protect against intracellular pathogens.

... these data suggest a broad role for extracellular manganese chelation and intracellular manganese transport in protecting against bacterial infection. Manganese sequestration by the host may be particularly important to the control of pathogens that have evolved to substitute manganese for iron in metalloproteins, as is the case with Borrelia burgdorferi, the causative agent of lyme disease [37]. Additional investigations are needed to fully define the extent that manganese chelation inhibits pathogenesis and to identify the host factors responsible for this arm of nutritional immunity.

Given the fact that a number of bacterial proteins are manganese dependent, it is clear that host-mediated manganese sequestration also has the potential to disrupt bacterial pathogenesis. ..."

dunno if it's just coz of reading this stuff or bc i was out three nights in a row eating random pot luck foods with random ppl BUT, throat has just served notice that an infection is making a move. battle stations!
take control of your own health
pursue optimal self care at least as actively as a diagnosis
ask for referrals to preventive health care specialists eg dietitians
don't let suboptimal self care muddy any underlying diagnostic picture!
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