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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 24–48 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 2–3 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 1966–2010 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, 15–20% 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).
References
Adawe, A. and Oberg, C. (2013). Skin-lightening prac-
tices and mercury exposure in the Somali community.
Minn Med,96(7): 48–9.
Al-Mogairen, S.M., Meo, S.A., Al-Arfaj, A.S., et al.
(2010). Nickel-induced allergy and contact dermatitis:
does it induce autoimmunity and cutaneous sclero-
sis? An experimental study in Brown Norway rats.
Rheumatol Int,30(9): 1159–64.
Arnson, Y., Shoenfeld, Y., and Amital, H. (2010). Effects
of tobacco smoke on immunity, inflammation and
autoimmunity. J Autoimmun,34(3): J258–65.
Authier, F.J., Cherin, P., Creange, A., et al. (2001). Central
nervous system disease in patients with macrophagic
myofasciitis. Brain,124(Pt 5): 974– 83.
Baasch, E. (1966). Theoretical considerations on the etiol-
ogy of multiple sclerosis. Is multiple sclerosis a mercury
allergy? Schweiz Arch Neurol Neurochir Psychiatr,98(1):
1– 19.
Barr, R.D., Rees, P.H., Cordy, P.E., et al. (1972). Nephrotic
syndrome in adult Africans in Nairobi. BMJ,2(806):
131–4.
Bergfors, E., Trollfors, B., and Inerot, A. (2003). Unex-
pectedly high incidence of persistent itching nodules
and delayed type hypersensitivity to aluminum in chil-
dren after the use of adsorbed vaccines from a single
manufacturer. Vaccine,22:64–9.
Bigazzi, P.E. (1999). Metals and kidney autoimmunity.
Environ Health Perspect,107(Suppl. 5): 753–65.
Bonitsis, N.G., Tatsioni, A., Bassioukas, K., and Ioannidis,
J.P. (2011). Allergens responsible for allergic contact
dermatitis among children: a systematic review and
meta-analysis. Contact Dermatitis,64(5): 245– 57.
Brookes, R.H., Hakimi, J., Ha, Y., et al. (2014). Screening
vaccine formulations for biological activity using fresh
human whole blood. Hum Vaccin Immunother,8: 10(4).
Clarkson, T.W., Friberg, L., Nordberg, G.F., and Sager,
P. (1988). Biological Monitoring of Metals. New York:
Plenum Press.
Clausen, J. (1993). Mercury and multiple sclerosis. Acta
Neurol Scand,87(6): 461–4.
Ekqvist, S., Svedman, C., Möller, H., et al. (2007). High
frequency of contact allergy to gold in patients with
endovascular coronary stents. Br J Dermatol,157(4):
730–8.
Exley, C., Swarbrick, K., Gherardi, R.K., and Authier,
F.J. (2009). Medical A role for the body burden of Al
in vaccine-associated macrophagic myofasciitis and
chronic fatigue syndrome. Med Hypotheses,72: 135–9.
Ferracane, J.L. (2001). Materials in Dentistry: Principles
and Applications. Philadelphia: Lippincott Williams &
Wilkin.
Fournié, G.J., Mas, M., Cautain, B., et al. (2001).
Induction of autoimmunity through bystander effects.
Lessons from immunological disorders induced by
heavy metals. J Autoimmun,16(3): 319– 26.
61
V. Stejskal
Gherardi, R.K. and Authier, F.J. (2012). Macrophagic
myofasciitis: characterization and pathophysiology.
Lupus,21(2): 184– 9.
Greer, J.M. and McCombe, P.A. (2012). The role of epige-
netic mechanisms and processes in autoimmune disor-
ders. Biologics,6: 307– 27.
Griem, P. and Gleichmann, E. (1995). Metal ion induced
autoimmunity. Curr Opin Immunol,7(6): 831–8.
Guis, S., Pellissier, J.F., Nicoli, F., et al. (2002). HLA-DRB1
01 and macrophagic myofasciitis. Arthritis Rheum,46:
2535– 2537.
Havarinasab, S. and Hultman, P. (2005). Organic mercury
compounds and autoimmunity. Autoimmun Rev,4(5):
270– 5.
Hybenova, M., Hrda, P., Procházková, J., et al. (2010). The
role of environmental factors in autoimmune thyroidi-
tis. Neuro Endocrinol Lett,31(3): 283–9.
Ingalls, T.H. (1983). Epidemiology, etiology, and preven-
tion of multiple sclerosis. Hypothesis and fact. Am J
Forensic Med Pathol,4(1): 55–61.
Ingalls, T.H. (1986). Endemic clustering of multiple scle-
rosis in time and place, 1934– 1984. Confirmation of a
hypothesis. Am J Forensic Med Pathol,7(1): 3–8.
IPCS (International Programme on Chemical Safety).
(1991). Environmental Health Criteria 118: Inorganic
Mercury. Geneva: World Health Organization.
Kern, F., Roberts, L., Osterle, L., et al. (1991). Ammoni-
ated mercury ointment as a cause of peripheral neu-
ropathy. Dermatologica,183: 280–2.
Kibukamusoke, J.W., Davies, D.R., and Hutt, M.S.R.
(1974). Membranous nephropathy due to skin
lightening cream. BMJ,2(920): 646 –7.
Kosboth, M., Chin-Loy, A., Lyons, R., et al. (2007). Malar
rash caused by metal allergy in a patient with systemic
lupus erythematosus. Nat Clin Pract Rheumatol,3(4):
240– 5.
Liang, L. and Brooks, R.J. (1995). Mercury reactions in
the human mouth with dental amalgams. Water, Ai r
and Soil Poll,80: 103–7.
Möller, H., Larsson, A., and Björkner, B. (1996). Flare-up
at contact allergy sites in a gold-treated rheumatic
patient. Acta Derm Venereol (Stockh),76:55–8.
Niedziela, M. and Bluvshteyn-Walker, S. (2012). Autoim-
mune thyroid disease and allergic contact dermatitis:
two immune-related pathologies in the same patient.
J Pediatr Endocrinol Metab,25(1–2): 31–2.
Palosuo, T., Provost, T.T., and Milgrom, F. (1976). Gold
nephropathy: serologic data suggesting an immune
complex disease. Clin Exp Immunol,25(2): 311–18.
Pelcova, D., Lukas, E., Urban, P., et al. (2002). Mercury
intoxication from skin ointment containing mercuric
ammonium chloride. Int Arch Occup Environ Health,
75(Suppl.): 54– 9.
Perricone, C., Colafrancesco, S., Mazor, R.D., et al. (2013).
Autoimmune/inflammatory syndrome induced by
adjuvants (ASIA): unveiling the pathogenic, clinical
and diagnostic aspects. J Autoimmun,47: 1– 16.
Prochazkova, J., Sterzl, I., Kucerova, H., et al. (2004). The
beneficial effect of amalgam replacement on health in
patients with autoimmunity. Neuro Endocrinol Lett,25:
211–18.
Rietschel, R.L. and Fowler, J.F. (2001). Fisher’s Contact Der-
matitis, 5th edn. Philadelphia: Lippincott, Williams &
Wilkins.
Santucci, B., Cannistraci, C., Cristaudo, A., et al. (1998).
Thimerosal sensitivities: the role of organo mercury
alkyl compounds. Contact Derm,38: 325– 8.
Saxe, S.R., Wekstein, M.W., Kryscio, R.J., et al. (1999).
Alzheimer’s disease, dental amalgam and mercury. J
Am Dent Assoc,130(2): 191–9.
Schiraldi, M. and Monestier, M. (2009). How can a
chemical element elicit complex immunopathology?
Lessons from mercury-induced autoimmunity. Trends
Immunol,30(10): 502–9.
Schmidt, M., Raghavan, B., Müller, V., et al. (2010). Cru-
cial role for human Toll-like receptor 4 in the develop-
ment of contact allergy to nickel. Nat Immunol,11(9):
814–19.
Seidenari, S., Giusti, F., Pepe, P., and Mantovani,
L. (2005). Contact sensitization in 1094 children
undergoing patch testing over a 7-year period. Pediatr
Dermatol,22:1–5.
Shaw, C.A. and Tomljenovic, L. (2013). Aluminum in
the central nervous system (CNS): toxicity in humans
and animals, vaccine adjuvants, and autoimmunity.
Immunol Res,56(2–3): 304–16.
Shoenfeld, Y. and Agmon-Levin, N. (2011). “ASIA” –
autoimmune/inflammatory syndrome induced by
adjuvants. J Autoimmun,36(1): 4– 8.
Stejskal, V.D., Cederbrant, K., Lindvall, A., and Forsbeck,
M. (1994). MELISA – an in vitro tool for the study of
metal allergy. Toxicol In Vitro,8: 991–1000.
Stejskal, V.D., Forsbeck, M., Cederbrant, K.E., and Aste-
man, O. (1996). Mercury-specific lymphocytes: an
indication of mercury allergy in man. J Clin Immunol,
16(1): 31– 40.
Stejskal, V.D., Danersund, A., Lindvall, A., et al. (1999).
Metal-specific lymphocytes: biomarkers of sensitivity
in man. Neuro Endocrinol Lett,20(5): 289–98.
Stejskal, V., Hudecek, R., Stejskal, J., and Sterzl, I. (2006).
Diagnosis and treatment of metal-induced side-effects.
Neuro Endocrinol Lett,27(Suppl. 1): 7–16.
Stejskal, V., Ockert, K., and Bjørklund, G. (2013).
Metal-induced inflammation triggers fibromyalgia in
metal-allergic patients. Neuro Endocrinol Lett,34(6):
559–65.
Stejskal V. (2014). Metals as a common trigger of inflam-
mation resulting in non-specific symptoms: diagnosis
and treatment. IMAJ,16:2–7.
Sterzl, I., Procházková, J., Hrdá, P., et al. (1999). Mercury
and nickel allergy: risk factors in fatigue and autoim-
munity. Neuro Endocrinol Lett,20(3– 4): 221–8.
Sterzl, I., Prochazkova, J., Hrda, P., et al. (2006).
Removal of dental amalgam decreases anti-TPO
and anti-Tg autoantibodies in patients with
62
Allergy and Autoimmunity Caused by Metals: A Unifying Concept
autoimmune thyroiditis. Neuro Endocrinol Lett,27:
25– 30.
Thyssen, J.P. and Menné, T. (2010). Metal allergy – a
review on exposures, penetration, genetics, preva-
lence, and clinical implications. Chem Res Toxicol,23(2):
309– 18.
Tomka, M., Machovcová, A., Pelclová, D., et al. (2011).
Orofacial granulomatosis associated with hypersensi-
tivity to dental amalgam. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod,112(3): 335–41.
Tosti, A., Guerra, L., and Bardazzi, F. (1989). Hyposen-
sitizing therapy with standard antigenic extracts: an
important source of thimerosal sensitization. Contact
Dermat,20:173–6.
Turk, J.L. and Baker, H. (1968). Nephrotic syndrome due
to ammoniated mercury. Br J Dermatol,80: 623–4.
Valentine-Thon, E., Ilsemann, K., and Sandkamp, M.
(2007). A novel lymphocyte transformation test
(LTT-MELISA) for Lyme borreliosis. Diagn Microbiol
Infect Dis,57(1): 27– 34.
Wallach, H., Nauman, J., Mutter, J., and Daschner,
F. (2003). No difference between self reported
amalgam sensitivities and non-sensitivities? Listen
carefully to the data. Int J Hyg Environ Health,206:
139– 41.
Wang, Y. and Dai, S. (2013). Structural basis of metal
hypersensitivity. Immunol Res,55(1–3): 83– 90.
Wang, Y., Goodrich, J.M., Gillespie, B., et al. (2012). An
investigation of modifying effects of metallothionein
single-nucleotide polymorphisms on the association
between mercury exposure and biomarker levels.
Environ Health Perspect,120(4): 530–4.
Warkany, J. and Hubbard, D.M. (1953). Acrodynia and
mercury. J Pediatr,42: 365–86.
Weiss, N.S. and Liff, J.M. (1983). Accounting for the mul-
ticausal nature in disease in the design and analysis of
epidemiological studies. Am Epidemiol,117: 14–18.
Weldon, M.M., Smolinski, M.S., Maroufi, A., et al. (2000).
Mercury poisoning associated with a Mexican beauty
cream. West J Med,173(1): 15– 18
Westphal, G.A., Schnuch, A., Schulz, T.G., et al. (2000).
Homozygous gene deletions of the glutathione
S-transferases M1 and T1 are associated with
thimerosal sensitization. Int Arch Occup Environ Health,
73(6): 384– 8.
WHO (World Health Organization). (1990). Methylmer-
cury, Environmental Health Criteria 61, 1–197.
Geneva: World Health Organization.
Woods, J.S., Heyer, N.J., Russo, J.E., et al. (2013). Modifi-
cation of neurobehavioral effects of mercury by genetic
polymorphisms of metallothionein in children. Neuro-
toxicol Teratol,39: 36–44.
Wylie, D.E., Lu, L., Carlson, S.D., et al. (1992). Mono-
clonal antibodies specific for mercuric ions. Proc Nat
Acad Sci USA,89: 4104–8.
Yaqob, A., Danersund, A., Stejskal, V.D., et al. (2006).
Metal-specific lymphocyte reactivity is downregulated
after dental metal replacement. Neuro Endocrinol Lett,
27(1–2): 189–97.
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