Neuroendocrinology Letters, 1999
The role of metals in autoimmunity and the link to neuroendocrinology
Jenny Stejskal, Vera DM Stejskal
Current available literature indicates a risk for metal-induced autoimmunity in man. Metal pathology may be due to toxic or allergic mechanisms where both may play a role. The main factors decisive for disease induced by metals are exposure and genetics which determine the individual detoxifying capacity and sensitivity to metals. This paper reviews the possible mechanisms which may play a role in metal-induced autoimmunity with the emphasis on multiple sclerosis (MS), rheumatoid arthritis (RA) and amyotrophic lateral sclerosis (ALS). We also discuss the role of inflammation induced changes in the hypothalamus-pituitary-adrenal (HPA) axis as a possible explanation of fatigue, depression and other psychosomatic symptoms observed in these diseases. The increased knowledge about individual sensitivity based on genotype and phenotype variability together with the use of biomarkers for the diagnosis of this individual susceptibility seems to be the key in elucidation of the operating mechanisms. Since metal-induced sensitization may be induced by chronic low-dose exposure, the conventional toxicological approach comparing concentrations of metals in brain autopsies, organ biopsies and body fl uids in patients and controls may not provide answers regarding the metal-pathology connection. To address this issue, longitudinal studies of metal-sensitive patients are preferable to the traditional case-control studies.
In the light of current knowledge, it seems plausible that metals are directly or indirectly involved in the induction or promotion of autoimmunity.
At least four different mechanisms could be involved in the induction or promotion of metal-induced pathology:
- free radical formation
- local toxic effects
Current available literature indicates a potential risk for the induction of autoimmunity by metals in man. Based on animal studies, this risk seems to be regulated by genetic factors, among others. For example, certain strains of mice develop ANA antibodies to metals while others do not. In man, the susceptibility to the effects of xenobiotics may be due to the genetically determined detoxifi cation systems, including the acetylator-, sulfoxidizer-, aromatic hydrocarbon receptor-, P450- and MT-phenotypes . Certain MHC structures may present antigens to helper T-cells more efficiently then others and thus facilitate the development of autoimmunity . Thus the ability to detoxify xenobiotics together with the individual susceptibility to the metal are probably the most important factors in the outcome of metal exposure.
Although animal systems may be important for clarifi cation of several autoimmune mechanisms, they only partly reproduce the clinical disease in man. In man, both organ and systemic autoimmune diseases persist for years, while in experimental animal systems, autoimmunity is a transitional phenomenon. To explain this discrepancy, the differences in biochemistry between man and experimental animals must be taken in account. Animals used in experimental studies produce their own vitamin C , which might neutralize the pathologic effects of metals.
Animals produce under non-stress condition between 5-40 grams of vitamin C per day. Under stress, the production of vitamin C rises proportionately. The lack of the critical enzyme L-gulonolactone oxidase (GLO) which catalyzes the last step in the synthesis of L-ascorbic acid from D-glucose, prevents several species, including guinea pigs, monkeys, apes and man, to synthesize the vitamin. This may be one factor which makes man more vulnerable not only to the effects of metals, but to other free radical generating substances as well. Possibly, animals not synthesizing vitamin C and thus with a biochemistry more similar to man in this respect might be more suitable for study of autoimmunity.
In a recent study, Saxe et al.  measured the concentration of mercury in the brains of Alzheimer and MS patients and compared them with the data of controls. The authors concluded that since there was no difference in the mercury deposition in the brains of patients vs. controls, mercury cannot be a factor in the development of those diseases.
Please read our dissection of the Saxe study and its fraudulent, manipulated data.
Similar findings were published by Fung et al.  and Clausen . If allergic rather than toxicologic mechanisms operate in Alzheimer's and MS disease, the interpretation of these studies may be questioned.
In contrast to the toxic effects of metals, the concentration of the metal in a sensitized individual is of minor importance. Minute concentrations of an allergen can induce systemic reactions in sensitized individuals. In such a situation, metal induced inflammatory reactions in the brain or elsewhere could be triggered despite low concentrations detected in body fluids or locally.
The role of immunologically mediated inflammation in the above mentioned diseases is well established.
This is the reason why Saxe's and Fung's studies cannot be used as evidence of the absence of metal-induced pathology in MS and Alzheimer's disease.
Considering the complexity of the immune system and its interaction with the nervous and endocrine systems , it is obvious that a combination of mechanisms is responsible for the induction of autoimmunity. One of the most decisive factors seems to be individual sensitivity based on the genetic constitution. Other factors include nutrition or may be psychological, such as stress. Infectious agents may through immunomodulation compromise the immune system and thus render the individual more sensitive to the effects of environmental agents. The synergistic effects of these factors may play a role in the precipitation of autoimmune disease.
This review can be summed up in a few crucial points. The data indicates that metals have the potential to induce or promote the development of autoimmunity in man. Chronic metal-induced inflammation may dysregulate the HPA-axis and contribute to fatigue and other non-specifi c symptoms characterizing autoimmune diseases. The majority of studies until now are designed from a toxicological approach, including epidemiological studies and measurements of concentrations of metals in tissue and body fl uids. Although these studies establish exposure, they show no significant differences in metal load between patient and control groups. The increased knowledge about individual sensitivity based on genotype and phenotype variability together with the use of biomarkers for the diagnosis of this individual sensitivity seems to be the key in elucidation of the operating mechanisms. In the case of metal pathology in autoimmunity, future studies should be longitudinal studies of metal-sensitive patients rather than traditional case-control studies.