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Allergy and Autoimmunity Caused by Metals: A Unifying Concept

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Metals, such as mercury, aluminum, gold, and nickel, play a role in various allergic and autoimmune diseases. This chapter discusses the factors underlying their immunotoxic properties. Mercury (in the form of thimerosal) and aluminum are both ingredients in vaccines. They can also enter the body through dental restorative materials, cigarette smoke, and environmental pollution. These metals bind to autologous proteins and thus function as immunologocally active haptens. They also possess immunomodulating properties. Metal-specific responses are mediated by sensitized T cells and depend on the genetic makeup of the individual. This means that some individuals are resistant and others are susceptible. A better understanding of the immunopathological role of metals will contribute to improved treatment of immune-mediated diseases and hopefully to the development of safer vaccines.
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5Allergy and Autoimmunity
Caused by Metals: A Unifying
Concept
Vera Stejskal
Department of Immunology, University of Stockholm, Stockholm, Sweden
Introduction
Allergy and autoimmunity are caused by an abnor-
mal immune response and have the same clinical
outcomes, including local and systemic inflam-
mation resembling autoimmune/inflammatory
syndrome induced by adjuvants (ASIA) (Shoenfeld
and Agmon-Levin, 2011; Perricone et al., 2013).
This chapter will give an overview of the lit-
erature on metal-induced pathologies, such as
delayed-type hypersensitivity and autoimmunity.
Because of the vast amount of information avail-
able on this subject, the focus of this review will
be mainly on specific T cell reactivity to mercury,
aluminum, nickel, and gold, all of which are
known to induce immunotoxic effects in human
subjects. Mercury, as a constituent of thimerosal,
and aluminum are both used in vaccines.
The immunological effects of metals include
immunomodulation, allergy, and autoimmunity.
Metals may act as immunosuppressants or as
immune adjuvants. One example of immunomod-
ulation is the ability of metals to modify cytokine
production in vitro and in vivo.
In the body, metal ions may firmly bind to cells
and proteins. This binding results in the modifi-
cation of autologous epitopes (i.e. haptenization).
In susceptible individuals, T cells falsely recognize
the modified proteins as foreign and start an
autoimmune attack (Griem and Gleichmann,
1995; Schiraldi and Monestier, 2009; Wang
and Dai, 2013). In experimental animals, the
recognition of metal haptens is dependent on the
Vaccines and Autoimmunity, First Edition. Edited by Yehuda Shoenfeld, Nancy Agmon-Levin, and Lucija Tomljenovic.
© 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.
genetic makeup: some rodent strains are resistant,
while others are susceptible to the induction of
autoimmunity by metals (Griem and Gleichmann,
1995; Bigazzi, 1999; Fournié et al., 2001; Schiraldi
and Monestier, 2009). Clusters of autoimmunity
have been reported in areas of increased exposure
to heavy metals (Ingalls, 1986). It has been found
that mercury, nickel, cadmium, lead, aluminum,
and arsenic can exert immunotoxic effects through
epigenetic mechanisms, such as DNA methylation
and histone modification (Greer and McCombe,
2012).
In humans, the expression of autoimmune
diseases can differ between genetically identical
twins. This suggests that, in addition to genetics,
environmental factors are involved in the disease
process. The genes controlling susceptibility to
metals are the subject of intensive studies (Wang
et al., 2012; Woods et al., 2013), but no clear
conclusion has yet been reached. Genes that
might predispose for toxic effects of metals are, for
example, those involved in detoxification and syn-
thesis of glutathione. In the case of metal allergy,
only a few genetic studies have been performed,
such as those on workers occupationally sensitized
to beryllium (Wang and Dai, 2013).
Delayed-type hypersensitivity
The type of allergy induced by metals in humans
is cellular-type hypersensitivity, also called type IV
delayed-type hypersensitivity. “Delayed” refers to
57
V. Stejskal
the fact the first symptoms appear 2448 hours
after initial exposure to the allergen, which
makes causal connection difficult. Metals
such as mercury are low-molecular haptens
and only rarely produce antibodies (Wylie
et al., 1992). Hence, immunological responses
induced by metals are mostly T cell-mediated.
The gold standard for diagnosis of delayed-type
hypersensitivity is patch testing. In patch test,
the suspected metal allergens are applied under
occlusion on the skin of the back. A dermatologist
evaluates the reaction after 23 days. Another
diagnostic approach, one that is becoming more
widespread, is the lymphocyte transformation
test (LTT), which allows an objective evaluation
of memory lymphocytes present in the blood
of patients. In this test, blood lymphocytes are
cultivated with metals or other allergens for 5
days in vitro, after which the number of prolifer-
ating lymphocytes is determined by radioisotope
incorporation.
A standardized and validated form of LTT is
LTT-MELISA (Memory Lymphocyte Stimulation
Assay) (Stejskal et al., 1994, 2006; Prochazkova
et al., 2004; Valentine-Thon et al., 2007). In
addition to objective radioisotope evaluation,
morphological confirmation of the presence of
activated lymphocytes (lymphoblasts) is also
performed (Stejskal et al., 2006).
The allergic and autoimmune effects
of metals
Exposure to metals can be external (e.g. through
pollution, occupation, cosmetics, and handling of
metallic items) or internal (e.g. through foods,
dental restorations, orthopaedic implants, and
vaccines). Cigarette smoke contains many metals,
such as mercury, cadmium, lead, arsenic, and
nickel, and increasing evidence is linking it to
autoimmune disorders (Arnson et al., 2010).
Mercury
It has been known for decades that exposure to
mercury through skin-lightening ointments will,
in some individuals, lead to the development of
serious side effects, such as kidney disease (Turk
and Baker, 1968; Barr et al., 1972; Kibukamusoke
et al., 1974), as well as neurological complications
such as peripheral polyneuropathy (Kern et al.,
1991; Adawe and Oberg, 2013). In a more recent
paper, skin-lightening creams induced neuropsy-
chological problems and glomerulonephritis in
a patient with juvenile diabetes (Pelcova et al.,
2002). After mercury chelation, the symptoms
disappeared, confirming a causal relationship.
Mercury-containing ointments are still being used
in some countries (Weldon et al., 2000).
The main source of inorganic mercury in the
general population is mercury released from den-
tal amalgam fillings (Clarkson et al., 1988). Dental
amalgam consists of 50% mercury, 22–32%
silver, 14% tin, 8% copper, and other trace
metals (Ferracane, 2001). Since mercury func-
tions as both adjuvant and allergen, it has no
safe dose level (IPCS, 1991). The most common
source of methyl mercury is ingested polluted
fish. Methyl mercury can also be formed through
the conversion of metallic mercury by oral and
gastrointestinal bacteria, and vice versa (Liang and
Brooks, 1995).
Thimerosal and phenyl mercury are organic
mercury compounds used as antiseptics and
preservatives in eye drops and vaccines (Rietschel
and Fowler, 2001). Like methyl mercury, these
organic mercury compounds are decomposed
to inorganic mercury in the body (WHO, 1990;
Havarinasab and Hultman, 2005).
Inorganic mercury, thimerosal, and nickel are the
most common allergens in children, a fact that is
not widely recognized. Of 1094 children with skin
disease, 10% reacted to thimerosal (ethylmercury
thiosalicylate) and 6% to mercury (Seidenari et al.,
2005) in patch test. A review of PubMed articles
investigating allergens in at least 100 children from
the years 19662010 showed that among the top
five allergens across 49 studies, three were metals:
nickel, gold, and thimerosal (Bonitsis et al., 2011).
Sensitization to thimerosal can be demonstrated
in vitro by LTT-MELISA, as shown previously
(Stejskal et al., 1994, 1999; Stejskal, 2014). In
a large study of over 3000 patients, tested by
LTT-MELISA in three different laboratories, the
prevalence of thimerosal-specific lymphocyte
responses was around 7% (Stejskal et al., 1999).
As shown in Table 5.1, LTT-MELISA can identify
thimerosal-specific responses in patients who
have experienced side effects after exposure to
thimerosal-containing products.
According to one paper (Westphal et al., 2000),
thimerosal sensitization depends on homozygous
gene deletion of the glutathione S-transferases,
indicating the role of genetics in detoxification
capacity.
It is important to note that memory lymphocytes
induced by various mercury compounds do not
crossreact, as shown by Italian dermatologists
(Tosti et al., 1989; Santucci et al., 1998) and by
58
Allergy and Autoimmunity Caused by Metals: A Unifying Concept
Table 5 . 1 Lymphocyte responses in LTT-MELISA to thimerosal and other metals in patients with side effects following
exposure to thimerosal-containing products
Patient
number
Sex Age Health
status
Thimerosal
exposure
Symptoms after
exposure
Positive
thimerosal
responses (SI)
Other positive
responses
1 F 45 CFS Hepatitis-B vaccine,
gamma globulin
Flu-like symptoms
after hepatitis B
vaccine
20 Cadmium, palladium,
phenyl mercury, tin
2 F 52 Skin/eye
irritation,
fatigue
Anti-D globulin ×3,
eye drops, TB
vaccine, patch
test
Worsening of
symptoms after
thimerosal
patch testing
19 Ethyl mercury,
inorganic mercury,
methyl mercury
3 F 58 CFS Vaccines Flu-like symptoms
post-vaccination
5.9 Inorganic mercury,
phenyl mercury
4 F 53 CFS, oral
lichen
planus
Gamma globulin ×
8, cosmetics
Eyelid eczema and
edema from
cosmetics
41 None
5 F 48 CFS Vaccines Not known 7.3 None
6 F 18 Heart
problems
Vaccines Not known 16.3 Cadmium, copper,
inorganic mercury,
lead, methyl mercury,
phenyl mercury
7 F 57 CFS Gamma globulin, TB
vaccine
Not known 65 None
8 F 45 CFS Vaccines Not known 12.4 Ethyl mercury, gold,
inorganic mercury,
lead, methyl mercury,
nickel, phenyl
mercury, tin
9 M 47 CFS Gamma globulin,
eye drops
Not known 4.4 Cadmium, ethyl
mercury, gold,
inorganic mercury,
lead, methyl mercury,
nickel, palladium,
phenyl mercury, tin
10 F 53 CFS Gamma globulin,
eye drops
Not known 4.4 Cadmium, ethyl
mercury, methyl
mercury, nickel
Lymphocytes were isolated from human blood and cultivated for 5 days with a wide range of metal salts, including thimerosal,
inorganic mercury, methyl mercury, phenyl mercury, gold, palladium, tin, lead, nickel, and cadmium (Stejskal et al., 1999).
Metal-specific responses were measured by 3H thymidine uptake. Lymphocyte responses are shown as stimulation index (SI)
=counts per minute (cpm) in metal-treated cultures divided by counts per minute in control cultures. SI 3 is a positive
response and SI 10 is a strongly positive response (shown in bold)
LTT-MELISA testing (Stejskal et al., 1994). How-
ever, sensitization to several mercury compounds,
as well as to other metals, is frequently observed.
Clinical observations accumulated over many
years indicate that exposure to mercury can
induce multiple sclerosis and other autoimmune
diseases. As early as 1966, Baasch suggested that
multiple sclerosis is caused by a neuroallergic
reaction to mercury released from amalgam
fillings, comparing it to an adult form of acro-
dynia (pink disease) (Baasch, 1966). Acrodynia
occurred in some children who were treated with
a mercury-containing teething powder (Warkany
and Hubbard, 1953). The same conclusion – that
dental and environmental exposure to mercury
could be one of the factors leading to multiple
sclerosis was also reached by Ingalls (1983,
1986).
59
V. Stejskal
Recent research supports these early clini-
cal observations. Prochazkova et al. (2004), at
Charles University in Prague, studied the impact
of amalgam replacement on health in patients
with various autoimmune diseases who showed
increased mercury-specific responses in vitro.After
the replacement of mercury-containing amalgam
with metal-free materials, 71% of the patients
showed health improvement by 6 months later. In
the group of patients that did not undergo dental
treatment, no health improvement occurred.
Other studies seemingly contradict the hypoth-
esis that mercury might be one of the causes of
neurodegenerative diseases. Saxe et al. (1999)
measured the concentration of mercury in the
brains of Alzheimer’s patients and controls. Since
there were no statistically significant differences
in brain mercury levels between the two groups,
the authors concluded that mercury does not
appear to be a neurotoxic factor in the patho-
genesis of Alzheimer’s disease. Similar findings
were published by Clausen (1993), who studied
mercury levels in the brains of patients with mul-
tiple sclerosis. The conclusions drawn from these
studies may be questioned. In mercury-sensitized
patients, even mercury concentrations within
the normal range might provoke neuroallergic
reactions in the brain.
The protocol of identification of metal hypersen-
sitivity and removal of sensitizing metals has been
successfully used in patients with fibromyalgia
(Stejskal et al., 2013) and autoimmune thyroid
diseases (Sterzl et al., 1999, 2006; Hybenova
et al., 2010). In the latter group, the removal of
mercury-containing amalgam not only downreg-
ulated mercury-specific responses in vitro, but also
resulted in a significant decrease of antithyroid
peroxidase and antithyreoglobulin antibodies
compared to levels prior to treatment.
Another disease of autoimmune origin is oral
lichen planus. In one study, 72% of patients with
oral lichen planus showed a positive response
to mercury in vitro (Stejskal et al., 1996). In
addition to oral symptoms, the patients suffered
from arthralgia, myalgia, eczema, and chronic ill
health. After removal of amalgams, both local and
systemic symptoms significantly decreased.
Finally, a study was recently published which
showed successful treatment of orofacial granulo-
matosis on removal of amalgam in patients with a
hypersensitivity to mercury (Tomka et al., 2011).
Gold
The autoimmune potential of gold compounds
has been known for many years. Serious side
effects, such as nephropathy, were observed in
some patients after the use of colloidal gold as a
treatment for rheumatoid arthritis (Palosuo et al.,
1976), and the possible mechanisms behind these
side effects have been discussed (Stejskal et al.,
1999). According to some studies, gold allergy is
more common in patients who have developed
autoimmune side effects after treatment with
gold, indicating the existence of both allergy and
autoimmunity induced by gold in the same patient
(Möller et al., 1996). It is important to emphasize
that, as with other metals, gold allergy is not only
expressed on the mucosa or skin, but also inside
the body. For example, the rate of restenosis after
implantation of gold-stented plates is high in
patients suffering from gold allergy (Ekqvist et al.,
2007).
Nickel
Nickel is the most common sensitizer, and also
the most studied (Thyssen and Menné, 2010). In
Swedish patients with chronic fatigue syndrome
(CFS), the frequency of nickel allergy was around
40%, as diagnosed by LTT-MELISA (Stejskal
et al., 1999). The coexistence of both allergic
and autoimmune symptoms, induced by nickel,
has been published, suggesting the autoimmune
potential of nickel compounds (Kosboth et al.,
2007; Niedziela and Bluvshteyn-Walker, 2012).
Direct evidence of nickel-induced autoimmunity
was observed in susceptible rats that developed
scleroderma-related autoantibodies and cutaneous
sclerosis after exposure to nickel (Al-Mogairen
et al., 2010). Since nickel can also induce Toll-like
receptors (TLRs) (Schmidt et al., 2010), the
autoimmune potential of this metal is plausible
and should be studied in the future.
Aluminum
Aluminum is a ubiquitous metal, widely occurring
in the environment and used in many everyday
objects, foods, and pharmaceuticals. Aluminum
is a well-known adjuvant in vaccines, despite its
neurotoxic properties (Shaw and Tomljenovic,
2013). As described by Shoenfeld et al. (Shoen-
feld and Agmon-Levin, 2011; Perricone et al.,
2013), adjuvants can promote ASIA in susceptible
patients. Allergy to aluminum is rare, but has
been described. Delayed-type hypersensitivity
to aluminum and itching nodules were found
in children exposed to aluminum-containing
vaccines (Bergfors et al., 2003). Exley et al. (2009)
described a patient who developed CFS after
multiple vaccinations with aluminum-containing
60
Allergy and Autoimmunity Caused by Metals: A Unifying Concept
vaccines. A muscle biopsy confirmed the pres-
ence of aluminum-containing macrophages; the
aluminum content in the patient’s urine was also
increased. Macrophagic myofasciitis (MMF) has
been described by Gherardi and Authier (2012) as
a systemic disease whose main histopathological
feature is a granulomatous lesion comprising
aluminum-loaded macrophages at the site of pre-
vious intramuscular vaccination. Typical clinical
manifestations in MMF patients include myalgias,
arthralgias, marked asthenia, weakness, cognitive
dysfunction, and CFS. In addition, 1520% of
MMF patients may also have coexistent autoim-
mune diseases, the most frequent of which are
multiple sclerosis, Hashimoto’s thyroiditis, and
diffuse autoimmune neuromuscular diseases,
such as dermatomyositis, necrotizing autoimmune
myopathy, myasthenia gravis, and inclusion body
myositis (Authier et al., 2001; Guis et al., 2002).
Conclusions
Scientific literature and clinical experience show
that metals play a key role in the development
of autoimmune diseases. Whether metals induce
autoimmunity or whether they aggravate existing
disease, the removal of sensitizing metals upon
identification of metal triggers has improved
patient health.
Larger randomized studies in susceptible indi-
viduals, selected on the basis of genotypic or
phenotypic biomarkers, should be pursued in the
future. As suggested by Weiss and Liff (1983),
studies of phenotypic markers may be suitable for
the elucidation of causal pathways and identifica-
tion of specific risk factors. The limited power of
epidemiological studies to detect minor susceptible
populations, such as those susceptible to mercury,
has been discussed by Wallach et al. (2003). The
benefits of this approach for patients can be mon-
itored not only by the decrease in antibody titers
(Sterzl et al., 1999), but also by downregulation
of metal-specific lymphocyte responses in vitro
(Stejskal et al., 1999, 2006, 2013; Yaqob et al.,
2006).
Finally, the identification of sensitized T cells in
human blood can be made use of in future stud-
ies of vaccine-induced side effects. Elucidation of
the possible mechanisms will contribute not only
to successful treatment of affected individuals but
also to the development of safer vaccines. The use
of human blood lymphocytes in vaccine research
has recently been suggested (Brookes et al., 2014).
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63
... Although its use was recently decreased, thimerosal (organic mercury) has been a common ingredient of vaccinees to serve the purposes of antiseptics and preservatives. It was reported that 10.1% of 1094 children with skin disease showed thimerosal-induced delayed-type hypersensitivity [6], fewer than 10% of 3,162 patients who were suspected for metal allergy showed thimerosal-specifi c lymphocyte responses by LTT-MELISA test [7]. Heavy metals such as thimerosal or cadmium caused cellular-type hypersensitivity (or Type IV delayed-type hypersensitivity) [7]. ...
... It was reported that 10.1% of 1094 children with skin disease showed thimerosal-induced delayed-type hypersensitivity [6], fewer than 10% of 3,162 patients who were suspected for metal allergy showed thimerosal-specifi c lymphocyte responses by LTT-MELISA test [7]. Heavy metals such as thimerosal or cadmium caused cellular-type hypersensitivity (or Type IV delayed-type hypersensitivity) [7]. Recently, there are some allegations that quantum dots are being used in COVID-19 vaccinees and cadmium is contained in the quantum dot nanoparticles [8,9]. ...
... Th e "delayed" type of allergy, which occurs in 1-2 days aft er initial exposure to the allergen, is cellular-type hypersensitivity and this type of hypersensitivity or allergy can be induced by metals in humans [7]. Heavy metals such as mercury, aluminum, or cadmium were known to cause hypersensitivity and autoimmunity in humans, because heavy metals modulate some parts of immune system and enhance immune responses to unrelated antigens and activate neoantigen-specifi c T cells [20]. ...
Article
Full-text available
More than 100 persons died within 7 days of infl uenza vaccination by November 2020 (for two months of 2020 fl u vaccination) in the Republic of Korea (South Korea). The current study was conducted to allocate properly any possible causality by examining the presence of heavy metals in a vaccine and metal-induced immunotoxic lesions after fl u vaccinations in the experimental mice. It detected cadmium 0.12 ppb (parts per billion = μg/L) and mercury 1.77 ppb in one of the cost-free infl uenza vaccinees (Lot Number: A14720017) distributed by the Korean government. Lungs of the undiluted-vaccine-injected mice showed signifi cantly more diff use infl ammatory damages than lungs of the 1:4 dilutedvaccine-injected mice which showed no to mild infl ammatory changes (p < 0.027 by the method 1, and p < 0.001 by the method 2). Based on this study, it can be presumed that the metals-induced immunotoxicity of type IV hypersensitivity or of psuedoallergy would have caused death in some of persons who coincidentally died within 7 days of vaccinations. Background : A 17-year-old man died within three days of infl uenza vaccination (Lot Number: A14720007), a 77-year-old woman died within a day (Lot Number: A14720016), and more than 100 persons died within 7 days of infl uenza vaccination by November 2020 (for two months of 2020 fl u vaccination) in the Republic of Korea (South Korea). Singapore authorities halted two of the seven brands of fl u vaccinees even though there was no report of death after fl u vaccinations in Singapore. This raises a possibility that there can be a diff erence between the excipients of the fl u vaccinees used in Singapore and in Korea. Our assumptions were that there would have been immunotoxic metals in the fl u vaccinees, the metals would have induced type IV hypersensitivity or Complement Activation-Related Psuedoallergy (CARPA), and would have caused some deaths of 100 persons who incidentally died within 7 days after fl u vaccinations. Methods: In this study, we analyzed twice for the presence of any metal components of aluminum, indium, cadmium, gallium, and mercury in the infl uenza vaccine. Analysis of the metal contents of the 1:29 diluted fl u vaccine was assessed by the Inductively Coupled Plasma Mass Spectrometry (ICP-MS) method. Simultaneously, total 10 BALB/c mice were used to analyze any pathological changes after 7 days of fl u vaccination. Animals were divided into two groups: one group of 5 mice were injected intraperitoneally with 0.1 ml of 1:4 diluted fl u vaccine with injectable distilled water; and the other group of 5 mice were injected intraperitoneally with 0.1 ml of undiluted fl u vaccine. They were freely reared for 7 days in a Polycarbonate cage (400 x 255 x 180 mm). The mice were sacrifi ced after CO2 short-acting gas anesthesia. Brains, hearts, lungs, livers, and kidneys were harvested, prepared with H & E stain, and observed for any histopathological changes. Findings : In one of the cost-free infl uenza vaccinees (Lot Number: A14720017), which were distributed by the Korean Government, the current study detected cadmium 0.12 ppb (parts per billion = μg/L), and mercury 1.77 ppb. But neither aluminum, gallium, nor indium was detected. Both experimental groups showed no demonstrable infl ammatory changes in the specimens of brains, hearts, livers, and kidneys. However, lungs of the undiluted-vaccine-injected group showed signifi cantly more diff use damages than lungs of the 1:4 diluted-vaccine-injected group which showed no to mild infl ammatory changes. The semiquantitative scores of the diluted-vaccine-injected group and the undiluted-vaccine-injected group were 0.7 ± 0.3 and 1.9 ± 0.3, respectively by method one ([a street-view], mean ± SE, p = 0.027 <0.05); and 9.0 ± 1.1 and 18.6 ± 1.6, respectively by method two ([a sky-view], mean ± SE, p < 0.001). Interpretation: Mercury (1.77 ppb) and cadmium (0.12 ppb) were found in the freely distributed infl uenza vaccine by the Korean Government for the season of 2020-2021. Infl ammatory damages in the lungs of experimental mice, which occurred within 7 days after infl uenza vaccination, could be caused by metal-induced type IV hypersensitivity ( delayed-type, T-cell-mediated hypersensitivity) or metal nanoparticle-induced CARPA. In application, metal-induced delayed-type hypersensitivity or metal nanoparticle-induced CARPA could explain some deaths of the 100 persons who unintentionally died within 7 days of infl uenza vaccination by the November 2020 and of the 1,531 persons who coincidentally died within 7 days after Infl uenza vaccination from the fall of 2019 to the spring of 2020 in South Korea, and of the persons who fortuitously died within one week after infl uenza vaccinations in the United States-23.2persons/100,000 vaccinees of an age of over 75 and 11.3 persons/100,000 vaccinees of an age between 65 and 75. The results may be helpful for the causal identifi cation of some deaths of COVID-19 vaccinees.
... Although its use was recently decreased, thimerosal (organic mercury) has been a common ingredient of vaccinees to serve the purposes of antiseptics and preservatives. It was reported that 10.1% of 1094 children with skin disease showed thimerosal-induced delayed-type hypersensitivity [6], fewer than 10% of 3,162 patients who were suspected for metal allergy showed thimerosal-specifi c lymphocyte responses by LTT-MELISA test [7]. Heavy metals such as thimerosal or cadmium caused cellular-type hypersensitivity (or Type IV delayed-type hypersensitivity) [7]. ...
... It was reported that 10.1% of 1094 children with skin disease showed thimerosal-induced delayed-type hypersensitivity [6], fewer than 10% of 3,162 patients who were suspected for metal allergy showed thimerosal-specifi c lymphocyte responses by LTT-MELISA test [7]. Heavy metals such as thimerosal or cadmium caused cellular-type hypersensitivity (or Type IV delayed-type hypersensitivity) [7]. Recently, there are some allegations that quantum dots are being used in COVID-19 vaccinees and cadmium is contained in the quantum dot nanoparticles [8,9]. ...
... Th e "delayed" type of allergy, which occurs in 1-2 days aft er initial exposure to the allergen, is cellular-type hypersensitivity and this type of hypersensitivity or allergy can be induced by metals in humans [7]. Heavy metals such as mercury, aluminum, or cadmium were known to cause hypersensitivity and autoimmunity in humans, because heavy metals modulate some parts of immune system and enhance immune responses to unrelated antigens and activate neoantigen-specifi c T cells [20]. ...
... All Hg salts analyzed have immunomodulatory potential (Shenker et al., 1992) as well as allergenic properties (Stejskal et al., 1996). Mercury has been revealed to stimulate autoimmunity in genetically susceptible animals (Pelletier et al., 1988;Goldman et al., 1991;Stejskal, 2015a) and can induce or promote the development of autoimmunity in humans Prochazkova et al., 2004). In the other hand, Hg-containing compounds can deeply induce immunostimulation, immunosuppression, immunomodulation, delayed-type hypersensitivity (type 4 allergy), and autoimmunity, through the pathways that involve altering the immune cytokines production (Kern et al., 2014;Berlin et al., 2015). ...
... Moreover, a toxic metal such as Hg could act as a hapten, producing a complex with one or more biological macromolecules, which together act as an antigen (Vas and Monestier, 2008;Kern et al., 2014). Mercury is a low-molecular hapten and only rarely produce antibodies (Stejskal, 2015a). Genetic factors such as major histocompatibility complex genes could influence on these effects that they are widely variable among individuals (Vas and Monestier, 2008). ...
... Another study using murine models reported that the exposure to subtoxic levels of Hg in genetically susceptible strains of mice provoked an autoimmune disease characterized by the production of highly specific anti-nucleolar autoantibodies, hyperglobulinemia, and nephritis (Jha et al., 2014). Moreover, a wide range of clinical observations revealed that Hg exposure could induce multiple sclerosis and other autoimmune diseases (Stejskal, 2015a). Furthermore, in a study, 72% of patients with oral lichen planus, another kind of autoimmune disease, demonstrated a significant response to Hg in vitro (Stejskal et al., 1996). ...
... The usual environmental factors that are implicated in the development of autoimmune diseases include bacteria, viruses, and xenobiotics, such as chemicals, drugs, and metals. Many cases of autoimmunity are reported following an infection, for instance, after Epstein-Barr virus infection (Rachmawati et al., 2015;Stejskal, 2015). However, it seems that despite persistent research efforts, no conclusive evidence has linked particular microorganisms or viruses to the pathogenesis of specific autoimmune diseases. ...
... The immunological effects of metals are either non-specific such as immunomodulation or antigen-specific such as delayed-type hypersensitivity (Stejskal, 2015;Stejskal et al., 2015;Kennon et al., 2019;Kitagawa et al., 2019) and autoimmunity (Aten et al., 1991;Bigazzi, 1999;Guzzi et al., 2008;Zhang and Lawrence, 2016). Metals may act as immunosuppressants (cytostatically) such as gold compounds or as immunoadjuvants (non-specific activation of the immune system) such as aluminum compounds. ...
Article
It has been demonstrated that metals can induce autoimmunity. However, few studies have attempted to assess and elucidate the underlying mechanisms of action. Recent research has tried to evaluate the possible interactions of the immune system with metal ions, particularly with heavy metals. Research indicates that metals have the potential to induce or promote the development of autoimmunity in humans. Metal-induced inflammation may dysregulate the hypothalamic-pituitary-adrenal (HPA) axis and thus contribute to fatigue and other non-specific symptoms characterizing disorders related to autoimmune diseases. The toxic effects of several metals are also mediated through free radical formation, cell membrane disturbance, or enzyme inhibition. There are worldwide increases in environmental metal pollution. It is therefore critical that studies on the role of metals in autoimmunity, and neuroendocrine disorders, including effects on the developing immune system and brain and the genetic susceptibility are performed. These studies can lead to efficient preventive strategies and improved therapeutic approaches. In this review, we have retrieved and commented on studies that evaluated the effects of metal toxicity on immune and endocrine-related pathways. This review aims to increase awareness of metals as factors in the onset and progression of autoimmune and neuroendocrine disorders.
... Immunological effects of metals/metalloids include immunomodulation, autoimmunity and allergy. Immunomodulation consists of the ability of metals/metalloids to modify the production of cytokines in vitro and in vivo [29]. Adequate intake of micronutrients, including trace elements such as selenium, zinc, copper, and iron, supports an effective immune response by cytokines produced by Th1, avoiding a switch to a response mediated by Th2 cells. ...
Article
Full-text available
Trace elements produce double-edged effects on the lives of animals and particularly of humans. On one hand, these elements represent potentially toxic agents; on the other hand, they are essentially needed to support growth and development and confer protection against disease. Certain trace elements and metals are particularly involved in humoral and cellular immune responses, playing the roles of cofactors for essential enzymes and antioxidant molecules. The amount taken up and the accumulation in human tissues decisively control whether the exerted effects are toxic or beneficial. For these reasons, there is an urgent need to re-consider, harmonize and update current legislative regulations regarding the concentrations of trace elements in food and in drinking water. This review aims to provide information on the interrelation of certain trace elements with risk of autoimmune disease, with a particular focus on type 1 diabetes and multiple sclerosis. In addition, an overview of the current regulations and regulatory gaps is provided in order to highlight the importance of this issue for everyday nutrition and human health.
... 6 7 Intake of even lower dose of Hg +2 causes acute damage to kidney and autoimmune diseases in animals and humans. 8 Due to global concern on the high toxicity effects, World Health Organization (WHO) has set the limit of mercury in drinking water as 0.001 mg/L. 9 The permissible limit of mercury set by Indian standards of effluent discharge is 0.01 mg/L. ...
Article
Full-text available
This study reports colorimetric and spectroscopic probing of heavy metal Hg+ ² ion by using water soluble starch capped silver nanoparticle (AgNPs). AgNPs have been prepared through reduction method and characterized by Surface plasmon resonance (SPR) peak from UV-Vis spectroscopy. We have shown that when heavy metal ion like Hg+ ² interact with AgNPs, then AgNPs reduces mercury ions to elemental mercury by forming white colour of Ag-Hg amalgam and hence toxic Hg+ ² ion is detected colorimetrically The formation of white colour due to mixing of AgNPs and Hg+ ² ion at different concentration has been mapped by the shift in the surface Plasmon resonance peak, which confirms that this coloration may be due to the Ag-Hg amalgam formation. We have also checked the antibacterial activity of AgNPs and Ag-Hg amalgam and found that conversion of Ag NPs to Ag-Hg amalgam exhibits a better antibacterial effect on E. coli bacteria. This study provides simple green method for synthesis of AgNPs as well as safe method for detection of heavy toxic metal ions.
... The existing data demonstrate the association between heavy metal exposure and autoimmune response [13], whereas essential trace elements, especially zinc, are also involved in immune system regulation [14]. Consequently, it could be proposed that alteration in trace element status in ASD may at least partially mediate neuroinflammation [15]. ...
Article
The objective of the present study was to estimate the association between brain inflammatory markers and serum trace element levels as assessed by inductively coupled plasma mass spectrometry at NexION 300D. Leukocyte elastase (LE), α1-proteinase inhibitor (α1-PI) activity, anti-nerve growth factor-antibodies (anti-NGF-Ab), and anti-myelin basic protein-antibodies (anti-MBP-Ab) levels were assessed as inflammatory markers. The obtained data demonstrate that the increase in LE and α1-PI activity is associated with higher serum Cr and Cu levels, respectively. The increase in Anti-NGF-Ab levels was associated with a nearly significant 16% increase in serum Mn levels. Autistic children with high MBP-Ab levels were characterized by 28% higher serum Mn and lower Mg concentration. The results of correlation analysis were generally in agreement with the outcome of group comparisons. Regression analysis demonstrated that serum Mg was significantly negatively associated with LE activity, whereas both serum Fe and V concentrations were characterized by a positive influence on the parameter. In turn, serum Cu was a significant predictor of α1-PI, as well as Cr levels. At the same time, the serum concentrations of Cd and Fe were found to be inversely associated with α1-PI levels. Serum Cd and Mn levels were significant positive predictors of anti-MBP-Ab levels, whereas Mg levels had a negative impact on anti-MBP-Ab values. Generally, the obtained data demonstrate the interrelationship between trace element homeostasis and neuroinflammation in autism. Hypothetically, modulation of trace element status may be used for reduction of neuroinflammatory response, although further studies are required to reveal the underlying mechanisms of the observed associations.
Article
Introduction & Objectives Cutaneous and systemic reactions to various metal implants and medical devices have been well documented. The aim of this review was to focus on the probable common mechanisms of allergy and autoimmunity that may lead to similar clinical outcomes following the growing evidence in the literature of metal and nickel-related systemic, autoimmune or autoinflammatory disorders. Materials & Methods Detailed search of the available electronic databases (PubMed-Medline) was conducted for review of the literature on that topic till present. Results Multiple reports on the immunological effects of metals including immunomodulation, allergy, or autoimmunity were identified. It was found that metals may act through immunosuppression, immunotoxicity, or as immune adjuvants thus provoking allergy and autoimmunity in susceptible individuals. Both external or internal exposure to metals was observed. Nickel has been identified as the most common sensitizer, and also the most studied one. The coexistence of both allergic and autoimmune symptoms, induced by nickel, has been published, suggesting the autoimmune potential of nickel compounds. Conclusions Clinical experience and scientific literature together demonstrate that metals may play an important role in the development of autoimmune diseases. While metal implant allergies and complications are on the rise, they remain diagnostic and therapeutic challenge. Elucidation of their possible mechanisms will contribute to more successful and safer treatment of affected individuals.
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Chronis rhinosinusitis is considered as a widespread public health issue with a prevalence of 10%. The disease significantly reduces quality of life and increases the risk of cardiovascular diseases as well as certain forms of cancer. Alteration of mucociliary clearance frequently observed in the patients and plays a significant role in disease pathogenesis. Certain studies have demonstrated that patients with chronic rhinosinusitis are characterized by significant reduction of essential trace elements and toxic metal overload. However, the particular mechanisms of the role of trace element dysbalance in chronic rhinosinusitis are unclear. We hypothesize that exposure to toxic trace elements (arsenic, nickel, cadmium) damages ciliary mucosal epithelium thus affecting mucociliary transport. In turn, altered mucociliary transport results in reduced removal of the inhaled metal-containing particles from nasal mucosa leading to their absorption and further aggravation of toxicity. Essential trace elements (zinc, selenium) play a significant role in regulation of mucociliary transport and immunity, thus their deficiency (either dietary or due to antagonism with toxic metals) may be associated with impaired functions and increased toxic metal toxicity. Therefore, a vicious circle involving metal accumulation and toxicity, essential element deficiency, impairment of mucociliary transport and metal particle removal, resulting in further accumulation of metals and aggravation of toxic effects is formed. The present hypothesis is supported by the findings on the impact of trace elements especially zinc and arsenic on mucociliary clearance, the role of mucociliary transport in heavy metal particles elimination from the airways, trace element dysbalance in chronic rhinosinusitis, as well as toxic and essential metal antagonism. The data from hypothesis testing and its verification may be used for development of therapeutic approach for management of chronic rhinosinusitis. Particularly, the use of essential elements (zinc, selenium) may reduce toxic metal toxicity thus destroying the vicious circle of heavy metal exposure, toxicity, alteration of mucociliary clearance, and aggravation of chronic rhinosinusitis. Essential element supplementation may be considered as a tool for management of chronic refractory rhinosinusitis. In addition, analysis of essential and toxic trace element status may provide an additional diagnostic approach to risk assessment of chronic rhinosinusitis in highly polluted environments.
Article
Аim of the present study is to set up a procedure for interdisciplinary interaction in complicated orthopaedic cases with the analysis of causes of complications after dental implantation and prosthetic treatment. Material and Methods. Digital panoramic radiography (J.Morita Veraviewepocs), cone-beam computed tomography (J.Morita Accuitomo 100), results of MELISA (Memory Lymphocyte Immuno-Stimulation Assay)-tests from InVitaLab (Neuss Germany), histological examination of bone tissue in sections, painted hematoxylin-eosin for I. Van Gieson (x 250/400), metallographic examination of the implant from the ВТ-6 (Ti-6AI-4V) alloy on oblique samples in scanning microscope Epiquant (х250). Results and Discussion. According to clinical studies of biocompatibility of dental materials, the most difficult for diagnosis and treatment are adverse reactions of patients in the form of allergies or intoxication against the background of the so-called "somaticized state", related to the use of dental prostheses. Typical "manifestations of psychosomatic disorders in the oral cavity" include chronic pain or occlusal discomfort, burning mouth syndrome, atypical odontangiography, phantom bite syndrome, senestopathy, and halitophobia. Specialists, distant from the problems of psychosomatic medicine, point out suspected diseases and non-specified conditions (Z.03.89), person with feared health complaint in whom no diagnosis is made (Z.71.1) conditions of unclear etiology (K29.7, K59 .9, D50.9, E03.2, F48.0/ G90.8) or unspecified (K29.9, T78.8 / T88.7). According to the European Academy of Allergy and Clinical Immunology data, the resources for diagnosing hypersensitivity reactions to metals (most often IV type) are still limited, and incidence of allergy upon the use of the titanium alloy Ti-4Al-6V, is one of the causes for the failure of dental implantation. In most patients, elimination of "incompatible" dentures yields a long-lasting positive result. However, in some patients, replacement of fillings, repeated endodontic treatment or even tooth extraction only exacerbate psychosocial distress. Patient H. (43 years old) suddenly felt significantly worse 7 years ago after prosthetic treatment for a partial loss of teeth on the upper and lower jaw (K08.432) . Complaints of malaise increased after completion of subsequent dental restorative treatment with use of dental implants. The dental and periodontal tissues status, orthopantomography and computed tomography data, as well as complete contact osteogenesis of the alveolar bone adjacent to the dental implant, without signs of fibrotisation and cellular inflammatory reaction on histological sections, as well as the absence of relief cracks, fractures, or other signs of destruction on oblique slices of the implant from the alloy ВT-6 (Ti-6AI-4V), did not confirm the hypothesis of postosteointegrational failure of dental implantation and prosthetics. In the process of differential diagnosis with the assistance of specialists of various medical specialties, taking into account the positive reaction to salt / compounds of titanium cadmium, weakly positive - nickel and iron, according to the results of the MELISA test, the clinical diagnosis: main condition-somatoform disorder (F45.2) after accomplished dental prosthetics (Z98.8); other condition-allergy, unspecified (Т78.40) - was clarified. Conclusions. Experience of interdisciplinary collaboration in the process of differential diagnostics and treatment of psychosomatic and allergic disorders and other adverse reactions related to dental practice, is the key element of evidence base for the founding of adapted medical guidelines and unified clinical protocols. Complications in the patient H. occurred due to insufficiently careful analysis of her history of life and disease during arrangement of prosthetic treatment, which should be considered a medical error. In the further treatment of patient H., an individual selection of materials for prosthetics, control of the applicability of dentures, and exact adherence of the patient to all medical orders are necessary.
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Background: The multiple symptoms of chronic fatigue syndrome (CFS) and fibromyalgia resemble those described in patients suffering from autoimmune/inflammatory syndrome induced by adjuvants (ASIA). It has been suggested that chronic metal-induced inflammation might play a role both in CFS and fibromyalgia as well as in ASIA. Humans are exposed to metals mainly through the release of metal ions from corroding dental restorations and orthopedic implants, food, vaccines and jewelry. Metals readily bind to sulphur and other groups in the mitochondria, enzymes and cell proteins. Metal-bound proteins are recognized by the immune system of susceptible subjects and might trigger an abnormal immune response, including allergy and autoimmunity. Objectives: To study three subjects with CFS and two with fibromyalgia, all of whom suspected metal exposure as a trigger for their ill health. Methods: We measured delayed-type hypersensitivity to metals (metal allergy) using a validated lymphocyte transformation test, LTT-MELISA. All patients except one were sensitized to metals present in their dental restorations. The remaining patient reacted to metals in his skull implant. The removal of sensitizing metals resulted in long-term health improvement. Nine healthy controls matched for gender and age showed only marginal reactivity to the metals tested. Conclusions: Patients with CFS and fibromyalgia are frequently sensitized to metals found in the environment or used in dentistry and surgery. This allergy to metals might initiate or aggravate non-specific symptoms in metal-sensitized patients.
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Fibromyalgia (FM) is a disease of unknown etiology. Inflammation could be one of the mechanisms behind this disease. We studied the frequency and clinical relevance of metal allergy in FM patients. Fifteen female FM patients were included in the study. Metal allergy was measured by a lymphocyte transformation test, MELISA®. Ten healthy age-matched women were used as controls for in vitro studies. Reduction of metal exposure in the FM patients was achieved by replacement of dental metal restorations and by the avoidance of known sources of metal exposure. Objective health assessment was performed 5 years after treatment. Subjective health assessment was established by a questionnaire, completed 2, 5 and in some cases 10 years after the start of the study. Follow-up MELISA was also performed. All FM patients tested positive to at least one of the metals tested. The most frequent reactions were to nickel, followed by inorganic mercury, cadmium and lead. Some healthy controls responded to inorganic mercury in vitro but most of the tests were negative. Objective examination 5 years later showed that half of the patients no longer fulfilled the FM diagnosis, 20% had improved and the remaining 30% still had FM. All patients reported subjective health improvement. This correlated with the normalisation of metal-specific responses in vitro. Metal allergy is frequent in FM patients. The reduction of metal exposure resulted in improved health in the majority of metal-sensitized patients. This suggests that metal-induced inflammation might be an important risk factor in a subset of patients with FM.
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Understanding the relevant biological activity of any pharmaceutical formulation destined for human use is crucial. For vaccine-based formulations, activity must reflect the expected immune response, while for non-vaccine therapeutic agents, such as monoclonal antibodies, a lack of immune response to the formulation is desired. During early formulation development, various biochemical and biophysical characteristics can be monitored in a high-throughput screening (HTS) format. However, it remains impractical and arguably unethical to screen samples in this way for immunological functionality in animal models. Furthermore, data for immunological functionality lag formulation design by months, making it cumbersome to relate back to formulations in real-time. It is also likely that animal testing may not accurately reflect the response in humans. For a more effective formulation screen, a human whole blood (hWB) approach can be used to assess immunological functionality. The functional activity relates directly to the human immune response to a complete formulation (adjuvant/antigen) and includes adjuvant response, antigen response, adjuvant-modulated antigen response, stability, and potentially safety. The following commentary discusses the hWB approach as a valuable new tool to de-risk manufacture, formulation design, and clinical progression.
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This document is the result of a conference on "Biological Monitoring of Metals" held in Rochester, June 2-6, 1986, organized jointly by the Environmental Health Sciences Center of the School of Medicine and Dentistry of the University of Rochester, NY, and the Scientific Committee on the Toxicology of Metals within the International Commission on Occupational Health (ICOH) at the Karolinska Institute and the National (Swedish) Institute of Environmental Medicine and the University of Umea, Sweden. The aim of the Conference was to define and evaluate the scientific basis for the biological monitoring of metals. The conference was co-sponsored by the World Health Organization through its International Program on Chemical Safety and received substantial encouragement and support from the Swedish Work Environmental Fund and the United States Environmental Protection Agency. This was the second conference organized jointly by the Scientific Committee on the Toxicology of Metals and The Toxicology Division of the University of Rochester. The previous joint conference was held in 1982 on the Reproductive and Developmental Toxicity of Metals. In addition, conferences have been organized by each group (see Appendices A and B). Several of these conferences are specially relevant to the topic of the current conference. These include the joint conference mentioned above and the conferences on dose-effect and dose-response relationship held in Tokyo in 1974 and on accumulation of metals held in Buenos Aires in 1972.
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Macrophagic myofasciitis (MMF), a condition newly recognized in France, is manifested by diffuse myalgias and characterized by highly specific myopathological alterations which have recently been shown to represent an unusually persistent local reaction to intramuscular injections of aluminium-containing vaccines. Among 92 MMF patients recognized so far, eight of them, which included the seven patients reported here, had a symptomatic demyelinating CNS disorder. CNS manifestations included hemisensory or sensorimotor symptoms (four out of seven), bilateral pyramidal signs (six out of seven), cerebellar signs (four out of seven), visual loss (two out of seven), cognitive and behavioural disorders (one out of seven) and bladder dysfunction (one out of seven). Brain T2-weighted MRI showed single (two out of seven) or multiple (four out of seven) supratentorial white matter hyperintense signals and corpus callosum atrophy (one out of seven). Evoked potentials were abnormal in four out of six patients and CSF in four out of seven. According to Poser's criteria for multiple sclerosis, the diagnosis was clinically definite (five out of seven) or clinically probable multiple sclerosis (two out of seven). Six out of seven patients had diffuse myalgias. Deltoid muscle biopsy showed stereotypical accumulations of PAS (periodic acid–Schiff)-positive macrophages, sparse CD8+ T cells and minimal myofibre damage. Aluminium-containing vaccines had been administered 3–78 months (median = 33 months) before muscle biopsy (hepatitis B virus: four out of seven, tetanus toxoid: one out of seven, both hepatitis B virus and tetanus toxoid: two out of seven). The association between MMF and multiple sclerosis-like disorders may give new insights into the controversial issues surrounding vaccinations and demyelinating CNS disorders. Deltoid muscle biopsy searching for myopathological alterations of MMF should be performed in multiple sclerosis patients with diffuse myalgias.
Article
Objectives To describe demographic characteristics, patterns of use, and symptoms associated with mercury poisoning among persons who used aMexican beauty cream containing mercurous chloride and to estimate the prevalence of cream use in Texas near the Mexico border. Design Case series and cross-sectional survey. Setting Border communities ofArizona, California, New Mexico, and Texas. Participants Persons who used the cream and contacted a health department in response to announcements about the cream and households that participated in the Survey of Health andEnvironmental Conditions in Texas Border Counties and Colonias, 1997. Mainoutcome measures Urine mercury concentrations, self-reported symptoms, and prevalence of cream use among households. Results Of 330 cream users who contacted their health department, 96% were women, and 95% were Hispanic.The mean urine mercury concentration was 146.7 μg/L (reference range : 0-20μg/L). In 5% of 2,194 randomly selected Texas households near the Mexico border, at least 1 person had used “Crema de Belleza-Manning”(Laboratorios Vida Natural, S.A., Tampico, Tamaulipas, Mexico) in the previous year. Conclusions Most cream users had increased urine mercury concentrations. Cream use was common in Texas near the Mexico border.Physicians should consider toxicity in patients with neurologic symptoms of unclear cause and use public health departments when investigating unusual illnesses.
Article
In 2011 a new syndrome termed 'ASIA Autoimmune/Inflammatory Syndrome Induced by Adjuvants' was defined pointing to summarize for the first time the spectrum of immune-mediated diseases triggered by an adjuvant stimulus such as chronic exposure to silicone, tetramethylpentadecane, pristane, aluminum and other adjuvants, as well as infectious components, that also may have an adjuvant effect. All these environmental factors have been found to induce autoimmunity by themselves both in animal models and in humans: for instance, silicone was associated with siliconosis, aluminum hydroxide with post-vaccination phenomena and macrophagic myofasciitis syndrome. Several mechanisms have been hypothesized to be involved in the onset of adjuvant-induced autoimmunity; a genetic favorable background plays a key role in the appearance on such vaccine-related diseases and also justifies the rarity of these phenomena. This paper will focus on protean facets which are part of ASIA, focusing on the roles and mechanisms of action of different adjuvants which lead to the autoimmune/inflammatory response. The data herein illustrate the critical role of environmental factors in the induction of autoimmunity. Indeed, it is the interplay of genetic susceptibility and environment that is the major player for the initiation of breach of tolerance.
Article
Somali women often use creams and soaps to lighten skin tone, fade freckles or get rid of age spots. Use of these products raises a health concern, as some have been found to contain mercury. This article describes an investigation that involved interviewing Somali women about skin-lightening practices and the products they use and then testing those products for mercury. Twenty-seven samples of products purchased at markets in Minneapolis and St. Paul were analyzed bythe Minnesota Department of Health for specific mercury levels. Eleven of the 27 (47%) were found to contain mercury. Some exceeded the current FDA threshold of 1 part per million. This has prompted both state and federal health officials to issue warnings about the use of these products.