Metal hypersensitivity is an immunological reaction that may contribute to chronic inflammatory conditions and a wide range of systemic symptoms. Affecting approximately 10–15% of the population, it involves a type IV hypersensitivity response, also known as delayed-type hypersensitivity. This reaction is mediated by T-lymphocytes which, upon contact with specific metals, release proinflammatory cytokines, leading to an immune response.
A precise method for diagnosing metal hypersensitivity is the MELISA® (Memory Lymphocyte Immunostimulation Assay). This validated in vitro lymphocyte transformation test (LTT) measures T-cell-mediated immune reactivity to metals. MELISA is used to identify sensitization to metals commonly present in dental materials, medical implants, and environmental exposures.
Symptoms of Metal Hypersensitivity
Clinical manifestations vary and may include:
- Allergic contact dermatitis – localized inflammatory skin reactions
- Chronic inflammation – low-grade, systemic inflammation with nonspecific symptoms
- Joint and muscle pain – symptoms may resemble autoimmune disorders such as rheumatoid arthritis
- Cognitive difficulties (“brain fog”) – issues with concentration and mental fatigue
- Headache and fatigue – often associated with prolonged exposure
- Autoimmune diseases and multiple chemical sensitivities – immune dysregulation may contribute to chronic conditions
Diagnostic Assessment with the MELISA Test
The MELISA test is a modified lymphocyte transformation assay that evaluates T-cell proliferation in response to specific metals. It involves isolating peripheral blood mononuclear cells (PBMCs) from a blood sample, which are then exposed to relevant metal antigens in a controlled in vitro setting. After incubation, T-cell proliferation is assessed using radiolabeled thymidine or a colorimetric method.
Compared to standard LTT, MELISA offers enhanced sensitivity and specificity through several methodological improvements:
- Increased lymphocyte count per assay to improve response reliability
- Carefully adjusted metal concentrations to avoid toxicity or mitogenic effects
- Partial depletion of macrophages to restore a physiologically relevant lymphocyte-to-monocyte ratio
- Combined assessment of lymphocyte proliferation and morphological evaluation, providing a more comprehensive immune profile
The MELISA test has been validated in multiple independent studies. A 2003 study involving 250 patients found the test to be reproducible, sensitive, and specific. A larger validation in 2016 confirmed these findings, and a 2021 university-led investigation highlighted MELISA as a significantly improved diagnostic tool for metal hypersensitivity.
Clinical Application of MELISA
MELISA is widely used by healthcare professionals to detect immune reactivity to metals. The test is clinically relevant for patients with chronic inflammatory conditions of unknown origin, especially when there is suspected exposure to metals through medical implants, dental materials, or occupational environments.
Selected Literature
Stejskal V, Ockert K, Bjørklund G. Metal-induced inflammation triggers fibromyalgia in metal-allergic patients. Neuro Endocrinol Lett. 2013;34(6):559–565.
Stejskal V, Reynolds T, Bjørklund G. Increased frequency of delayed type hypersensitivity to metals in patients with connective tissue disease. J Trace Elem Med Biol. 2015;31:230–236. doi:10.1016/j.jtemb.2015.01.001
Manousek J, et al. Delayed-type Hypersensitivity to Metals in Newly Diagnosed Patients with Nonischemic Dilated Cardiomyopathy. Cardiovasc Toxicol. 2020;20(6):571–580. doi:10.1007/s12012-020-09582-6
Podzimek S, et al. Metal hypersensitivity and pro-inflammatory cytokine production in patients with failed orthopedic implants: A case-control study. Clin Immunol. 2022;245:109152. doi:10.1016/j.clim.2022.109152
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