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differences have been reported between the species
with regard to the exact cells involved. For example,
human (Nordlind and Henze, 1984) but not murine
(Pollard and Landberg, 2001; Reardon and Lucas,
1987) thymocytes proliferate
in vitro
in response to
mercury. Murine T cells show an absolute requirement
for adherent cells (Jiang and Moller, 1995; Pollard and
Landberg, 2001), whereas they are not needed (Caron
et al.,
1970; Nordlind and Henze, 1984), or may even be
dementrial (Shenker
et al.,
1992), for the proliferative
effect of Hg on human lymphocytes. Mercury caused
after injection a signifi cant proliferation of T cells in 22
of 23 mouse strains as assessed by the popliteal lymph
node test (Stiller-Winkler
et al.,
1988), demonstrating
the ability of Hg to cause immune stimulation also
in
vivo
. However, the dependency on MHC class II mol-
ecules (Hu
et al.,
1997) and costimulatory molecules,
especially IL-1 (Pollard and Landberg, 2001), in com-
bination with the oligoclonal murine T-cell response
in
vitro
(Jiang and Moller, 1996) as well as
in vivo
(Heo
et al.,
1997) makes it possible that the Hg-induced T-cell
response is antigen-dependent, although the antigen(s)
is (are) unknown. Secondary effects of a polyclonal
activation of T cells by mercury are B-cell activation
and Ig isotype switching because of cytokines such as
IL-4 and IFN-
autoimmunity nor the number of humans that may
carry such susceptibility is known. Because the genetic
susceptibility to mercury-induced autoimmunity in
rodents is, to a large extent, determined by MHC class
II genes, which are also well known for their association
with spontaneous autoimmune diseases in humans,
there are strong theoretical reasons to assume the exist-
ence of humans genetically susceptible to mercury. Fur-
thermore, genetic factors outside MHC determine the
accumulation of Hg in mice given the same dose of Hg
(Nielsen and Hultman, 1998), and non-MHC genes also
determine the internal dose of Hg required to elicit an
autoimmune response in mice with susceptible MHC
genes (Hultman and Nielsen, 2001).
The largest cohort of humans exposed to inorganic
mercury is dental amalgam bearers. Studies of dental
amalgam implanted in the peritoneal cavity of mice
(Hultman
et al.,
1994) and inserted in the teeth of rats
(Hultman
et al.,
1998), have clearly demonstrated
the potential of dental amalgam to cause systemic
autoimmune diseases in genetically (MHC) suscep-
tible rodents. However, it seems likely that the dose
required for
de novo
induction of autoimmunity is not
met in most humans with dental amalgam fi llings.
However, to what extent some dental amalgam bear-
ers may develop
de novo
autoimmunity or accelera-
tion of spontaneous autoimmune diseases because of a
genotype causing high accumulation of Hg in the body
and/or a low thresholds for induction of autoimmunity
is unknown.
Historically, large cohorts have been exposed to
mercury in environmental disasters (Bakir
et al.,
1973;
Harada, 1995), but autoimmune conditions have not
been reported. This would indicate either that the fre-
quency of such susceptibility genes is low or absent
in the affected populations or that the dose was insuf-
fi cient to elicit a reaction. However, in the Hg dis-
asters, the main exposure was to organic mercury
compounds, especially methylmercury but also ethyl
mercury. Both these compounds are able to induce
systemic autoimmunity in genetically susceptible
mice (Havarinasab
et al.,
2004; Hultman and Hans-
son-Georgiadis, 1999), although probably because of
transformation of the organic compounds to inorganic
mercury (Havarinasab and Hultman, 2005), which is,
however, incomplete and, at least for MeHg, a rather
slow process (Haggqvist
et al.,
2005; Havarinasab
et
al.,
2004). Therefore, the exposure to autoimmuno-
genic inorganic Hg might have been too low in many
cases to induce autoimmunity. Another explanation
for the lack of reports on autoimmune diseases dur-
ing the environmental Hg disasters might have been
a limited attention to autoimmune diseases in those
early years and not least that symptoms of autoim-
.
However, a number of nonantigen-specifi c prolifer-
ative effects of Hg have been reported
in vitro
: increase
in intracellular calcium (Tan
et al.,
1993), aggregation
of transmembrane CD4, CD3, CD45, and Thy-1 recep-
tors on T cells with increased tyrosine kinase p56
lck
(Nakashima
et al.,
1994), and attenuation of lym-
phocyte apoptosis (Whitekus
et al.,
1999) because of
interference with the
Fas-Fas
ligand interaction
in vitro
(McCabe
et al.,
2003).
γ
9
METAL-INDUCED AUTOIMMUNIT
Y
This is a seemingly paradoxical area of metal immu-
notoxicology. Ample evidence from experimental stud-
ies demonstrate that certain metals, most notably Hg
and Au, may cause autoimmune diseases in several
species (Fournie
et al.,
2002; Hultman
et al.,
1995; Pol-
lard
et al.,
2005; Schuhmann
et al.,
1990), but there are
relatively few reports of metal-induced autoimmunity
in humans. Some authors (Descotes, 1999) have, there-
fore, questioned whether metal-induced autoimmunity
is a relevant issue for humans. Some factors must, how-
ever, be taken into consideration when trying to assess
the potential of metals for inducing autoimmunity.
First, induction of autoimmune diseases is heavily
dependent on genetic susceptibility, and neither the
susceptible genotype(s) in humans for metal-induced
