Chemistry Reference
In-Depth Information
HLA-DR52c
-chain and probably two other coordi-
nation sites on a limited selection of DR52c-associated
peptides.
In some studies, the exact way the metal interacts
with the peptide-MHC structure to inhibit the reaction
has not been explained. For example, Pb inhibits pres-
entation of ovalbumin to the T-cell hybridoma DO11.10,
allowing for an effect on either the ovalbumin peptide
or the class II molecule (Smith and Lawrence, 1988).
Although these observations have increased the
understanding of interactions between T cells and pep-
tides-MHC, they fail to explain why, for example, Ni
hypersensitivity is not linked to certain HLA class I or
class II alleles (Emtestam
et al.,
1993). T-cell receptor
(TCR) families have, therefore, been intensely studied.
In Ni
2+
sensitization, the phenotype TCRV
β
These mechanisms have been studied for Au and Hg.
Murine T-cell hybridomas specifi c for bovine RNase
A treated with Au(III) recognize cryptic epitopes of
non-Au-treated RNase. These T-cell hybridomas also
reacted with RNase A pretreated with Pd(II), Pd(IV),
Pt(IV), or Ni(IV), whereas metal ions such as Cu(II),
Fe(II), F(III), or Zn(II) failed to elicit any cross-reactiv-
ity. The sensitizing potential of Au(III), Pd (II), Pd(IV),
Pt(IV), and Ni(IV) may, therefore, be due to their ability
to induce presentation of cryptic self-peptides (Griem
et al.,
1996).
Mercury has been shown to interact with the major
autoantigen in Hg-induced experimental systemic
autoimmunity, the nucleolar 34-kDa protein fi brillarin.
First, by binding to sulfhydryl groups, fi brillarin is
physically altered (Pollard
et al.,
1997). Second, nonap-
optotic (necrotic) cell death caused by Hg modifi es the
proteolytic cleavage pattern for fi brillarin, resulting in
neopeptides of fi brillarin (Pollard
et al.,
2000). Because
exposure to Hg creates a 19-kDa immunogenic frag-
ment of fi brillarin even without physical modifi cation
of fi brillarin, a new cleavage pattern of fi brillarin seems
to be of prime importance for induction of autoim-
munity development (Pollard
et al.,
2000). In another
experiment, T-cell clones obtained from genetically
Hg-susceptible mice that had been given repeated
injections of Hg for 1 week reacted with Hg-carrying
self-proteins, including Hg(II)-complexed fi brillarin
(Kubicka-Muranyi
et al.,
1993; 1995). After 8 weeks Hg
treatment, the T-cell clones preferentially reacted with
untreated fi brillarin, suggesting a shift of the T-cell spe-
cifi city from self-proteins modifi ed by Hg to unaltered
self-proteins. This process is known as a determinant
spreading (McCluskey
et al.,
1998) and makes tracing
of the original insult-inducing autoimmunity diffi cult.
17 domi-
nates the T-cell response
in vitro
(Budinger
et al.,
2001),
and this TCR type is associated with the clinical sever-
ity of the Ni
2+
-induced contact dermatitis (Vollmer
et al.,
1997). It has been proposed that Ni might enhance
short-lived, nonproductive contacts between the TCR
and the MHC-peptide complex, sometimes resulting
in a suffi ciently high avidity for activation of the T cell,
a process that may also be facilitated by carriers of Ni
such as serum albumin (Thierse
et al.,
2004). A similar
observation has been made for Be, because V
β
3 seems
to be required in combination with HLA-DPB1Glu69 to
elicit Be-responding CD4
+
clones (Fontenot
et al.,
2001).
β
7 OTHER INTERACTIONS BETWEEN
METALS AND PROTEINS—IMPLICATIONS
FOR AUTOIMMUNITY
Apart from the possibility of a direct, but chemically
promiscuous, interaction between TCR and metal-pep-
tide-MHC complexes, metals may interact with pro-
teins in other ways to alter presentation of the peptide
to T cells. First, metals that possess a high redox poten-
tial (oxidizing capacity), such as Au (III), Pd(IV), and
Pt(IV), may oxidize and denaturate sulfur-containing
amino acid side chains of proteins. Second, metals such
as Hg(II), Pt(II), and Au(I) make strong bindings with
side chains in proteins, forming stable metal-protein
complexes that may alter the protein unfolding taking
place in antigen-processing. Third, metals may induce
a change in the specifi city of the proteolytic profi le of
APC. The effect of one or more of these mechanisms
might be to display a hitherto unrecognized part of
peptides, so called cryptic epitopes, which are pre-
sented to the T cells instead of the usual immunodomi-
nant epitopes. Because the T cells have not been made
tolerant to the cryptic epitopes, this might lead to self-
reactivity (Griem
et al.,
1998).
8 NONSPECIFIC IMMUNOSTIMULATION
INDUCED BY METALS: THE EXAMPLES
OF PB AND HG
Stimulation of cells in the immune system by metals
that do not primarily induce antigen-specifi c reactions
or generate metal-specifi c lymphocytes is considered
nonspecifi c immunostimulation. An example of this
is the lead-induced increase of plaque-forming (B-)
(Stiller-Winkler
et al.,
1988) cells and increased expres-
sion of class II molecules on B cells (McCabe
et al.,
1991).
Mercury stimulates proliferation of T cells in guinea
pigs, rats, and rabbits (Pauly
et al.,
1969); humans
(Carron
et al.,
1970); and mice (Jiang and Moller, 1995;
Pollard and Landberg, 2001; Reardon and Lucas,
1987), although the stimulatory concentration range is
very narrow in humans and mice. However, distinct
