Number: 1999-047-1-700
Title: Immunochemistry of metal
sensitization
Task Group
Chairman: D.M.
Templeton
Members: R.
Klein and M. Schwenk
Objective:
New immunological methods are developing for clinical evaluation
of immune sensitization by a number of occupationally and iatrogenically
important metals. Our goals are to evaluate and systematize the
application of these methods, and to produce a critical examination
of the molecular structural foundations of the sensitizing response.
Description:
A number of metals are immunological sensitizers in humans. Examples
include occupational exposures to Ni, Co, and Cr, inhalation of
Pt compounds and the possibility of sensitization to chloroplatinic
catalysts in silicone implants, beryllium-related lung disease,
and components of alloys used in joint replacements and skeletal
stabilization. In general, activation of the immune system occurs
when the metal ion (hapten) binds to an endogenous protein carrier,
altering its structure and causing it to become antigenic. T-cells
may recognize metal-modified peptides or the T-cell's MHC class
II-peptide complex may itself be modified by a metal ion. The nature
of the metal hapten-carrier complex has not been systematically
reviewed for metals that are important occupational or iatrogenic
immunosensitizers.
While immunochallenges such as patch testing are widely used in
assessing sensitivity to a given metal, they are of variable specificity
and involve potentially exacerbating exposure for the subject. A
number of newer in vitro immunological tests are developing as useful
clinical correlates and biomarkers of metal sensitization, such
as the Be-lymphocyte proliferation test and Ni-, Co-, Cr-lymphocyte
proliferation test. Cytokine (IL-4, IL-5) production after specific
Ni stimulation of the lymphocytes seems to be a very sensitive marker
of Ni sensitization. These tests are not yet applied systematically
or in a standardized manner.
We propose to review the structural aspects of metal-protein interactions
that lead to sensitization, and present recommendations for state-of-the-art
immunological tests for sensitization to specific metals.
Progress:
The development of methodology in clinical immunology is moving
at a rapid pace. The Task Group initially planned a paper to survey
and recommend methods that would include cytokine profiling, the
lymphocyte proliferation test, lymphocyte subtyping, etc. It became
clear that each topic warranted a paper in itself::
- 'Diagnostic relevance of the lymphocyte transformation test for
sensitization to beryllium and other metals', Pure
Appl. Chem.
76(6), 1269-1281, 2004
- 'Cytokine profiles in human exposure to metals', Pure
Appl. Chem.
78(11), 2155-2168, 2006
- 'Lymphocyte subpopulations in human exposure to metals', Pure
Appl. Chem.
80(6), 1349-1364, 2008
Another aspect of the original project was to survey mechanisms
by which metals cause immune reactions. This has published: 'Mechanisms
of immunosensitization to metals', Pure
Appl. Chem.
76(6), 1255-1268, 2004. However, developments in Hg sensitization
(and issues surrounding dental amalgams and Hg chelation) demand
that this be given a very careful appraisal that should be done
in a separate manuscript; a draft is being completed.