Present State of Scientific Knowledge

Nickel sensitization is not a new concern and has been studied by many groups. While there are still many questions on this issue to be answered, below is a summary of the current information.

  • It is difficult to use animals to study nickel sensitization because animals display different immune responses than do humans. For ethical reasons, it is difficult to expose human subjects to a substance that may compromise their health. Scientists therefore have a dilemma. They would like to understand the mechanisms involved in human nickel sensitization, but they are not confident that the animals available for experimentation are good surrogates.
  • The current thinking is that nickel by itself is not antigenic, but rather that nickel complexes involving histidines or proteins are bound to Langerhans' cells. These cells, located in the basal layer of the epidermis, actively participate in cutaneous immune regulation and surveillance and are responsible for antigen processing and presenting the anti-gen to T-lymphocyte cells. The bound Langerhans' cells migrate to regional lymph nodes where further processing of the antigen occurs and ultimately a population of altered nickel-specific T-lymphocytes are created and recirculated where they may enter peripheral tissue (including the skin). At this point the individual is “sensitized.”
  • In the sensitized individual, when antigen-specific T-lymphocytes encounter the antigen (i.e., nickel ions), they release lymphokines, which are proteins that cause a wide variety of actions on other cells including stimulation of macrophages and natural killer cells and other responses. With a sufficient amount of stimulation, tissue inflammation and other allergic responses occur in an attempt to rid the body of the foreign entity. This integrated response is what causes the allergic contact dermatitis reaction.
  • The condition of the skin is very important in nickel sensitization and nickel ACD. Intact skin with normal barriers is less susceptible (i.e., less permeable to nickel ions) to developing nickel sensitization and nickel ACD than skin that is broken or otherwise abnormal regarding permeability of the skin. Heat, humidity, and increased sweat pro-mote the likelihood and speed with which nickel ions are presented to the skin.(21)
  • There is no known means of reversing immuno-activation (the sensitized condition). However, because the precise mechanism by which nickel ions and Langerhans' cells and T-lymphocytes interact is not understood, dermatologists are reluctant to conclude that such a reversal is biologically impossible. Knowledge about the mechanism may result in awareness of how to "turn off" the immune system to nickel.
  • There is evidence that immunotolerance is possible. First, it is noteworthy that the nickel-producing and nickel-using industries very rarely have workers presenting symptoms of nickel ACD. It would be expected that a group of workers routinely coming into direct skin contact with various forms of nickel metal and salts would display nickel ACD. The fact that it is not seen may be due to a tolerance that the workers acquire over time via an alternate route of exposure (inhalation or ingestion) that causes no allergic reaction by the immune system, even when higher nickel exposures are received later. Second, literature(22) indicates that dental braces made from high-nickel alloys (e.g., nickel-chromium with 60-80% nickel) resulted in nickel-tolerance in girls subsequently having their ears pierced compared to a higher prevalence of nickel sensitization in girls who had their ears pierced, but did not wear such dental braces prior to ear-piercing. This tolerance may be caused by a mechanism involving low nickel exposure orally over time. Third, immunotolerance in animals (mice) has been shown by nickel exposure either intravenously or orally, with T-lymphocytes in nickel-tolerant mice being transferable to other mice to make them nickel-tolerant.

 Orthodontic braces may result in immunotolerance to nickel ACD.
  • Diagnosis of nickel-sensitivity is done via the patch test, which establishes contact of soluble nickel against a small portion of occluded skin. This is done under a specified procedure(23) to limit misinterpretation due to irritation rather than allergic response. An appropriate concentration of a solution of nickel sulfate is placed on a metallic or filter paper disc backed by aluminum foil (impermeable to water) and attached to the subject's upper back or upper arms by adhesive tape so that the skin area under test is completely covered. The patch is left in place for two days and then removed; the skin is evaluated for the severity of inflammation. Patch testing is capable of giving both false negative and false positive results. Nevertheless, it is by far the most routine diagnostic test for determining whether a person is nickel-sensitive along with history of reaction to nickel-releasing materials.
  • In the 1960s another test, called the lymphocyte proliferation test (LPT), or the lymphocyte transformation test (LTT), was developed. Its advantage is that it uses a blood sample from a suspected nickel-sensitized individual and is performed in vitro, thus avoiding the risk of having nickel in contact with the skin and potentially sensitizing a non-nickel-sensitized person. The LPT (or LTT) is based on the fact that nickel-sensitized individuals have T-lymphocytes primed and ready for the nickel antigen being presented. The test pretreats the blood sample to concentrate the T-lymphocytes and then incubates them with a concentration of Ni. In the nickel-sensitive person, the presence of nickel will cause the primed T-lymphocytes to "turn-on" and elicit an immune response. They "turn-on" by doing several things, one of which is to divide rapidly (proliferate). If a radioactively labeled DNA precursor iododeoxyuridine is also present in the culture, the new T-lymphocytes will use this to synthesize new DNA for their daughter cells. Following separation of the T-lymphocytes, an increase in radioactivity above a measured control (to account for normal cell division) is indicative of high cell proliferation, which means the original T-lymphocytes reacted to the nickel present. This test is only now becoming a clinical tool but more work is required to correlate it with patch test results and to make it reliable.

21. Hemingway, J.D.; Molokhia, M.M. 1987. The dissolution of metallic nickel in artificial sweat. Contact Dermatitis 16: 99-105.

22. van Hoogstraten, I.M.W.; Andersen, K.E.; Von Blomberg, B.M.E.; Boden, D.; Bruynzeel, D.P.; Burrows, D.; Camarasa, J.G.; Dooms-Goossens, A.; Kraal, G.; Lahti, A.; Menné, T.; Rycroft, R.J.G.; Shaw, S.; Todd, D.; Vreeburg, K.J.J.; Wilkinson, J.D.; Scheper, R.J. 1991. Reduced frequency of nickel allergy upon oral nickel contact at an early age. Clin. Exp. Immunol. 85: 441-445.

23. Cronin, E. 1980. Contact Dermatitis. Churchill-Livingstone: London.

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