Autoimmunity has been for decades considered the result of a breakdown in self-tolerance. At the present, it is known that autoimmunity is a physiological process [44]. This phenomenon becomes pathological when the number of autoreactive cells, and particularly the avidity of their receptors for autoantigens, increases [44]. Triggering of the disease usually depends both on the increase in immunogenicity of the target cell, which may be secondary to a viral infection (Chediak-Higashi syndrome and Griscelli syndrome by EBV), and on the individual's own capacity to recognize the autoantigens (HLA, or T cell repertoire in Familial hemophagocytic lymphohistiocytosis [FHL]) [45]. Moreover, apart from the genetic defects that may predispose to autoimmune diseases, one must take into account the environmental factors that are implicated in the development of such pathologies. Among them, an important role is played by xenobiotics such as chemicals, drugs and metals [46]. Iron, aluminum, and manganese readily cross the blood brain barrier via specific or non-specific carriers, and contribute to the nervous tissue damage [47,48]. The toxic effects of metals are mediated through free radical formation, or enzyme inhibition [49-53]. In addition, metals may act as immunosuppressants (cytostatically), or as immunoadjuvants (through non-specific activation of the immune response) [54,55]. Several mechanisms are proposed on how metals may act within the immune system to induce autoimmunity. Patients suffering from scleroderma develop autoantigens with metal-binding sites. After metal binding, free radical species are generated which fragment auto-antigens thereby exposing cryptic epitopes, which may then trigger autoimmunity [56,57]. Taken together, these findings underlie the importance of exogenous factors in the pathogenesis of autoimmunity. Nevertheless, all these elements do not appear sufficient to provoke chronic autoimmune diseases such as Multiple Slerosis (MS), myasthenia gravis, Insulin Dependent Diabetes Mellitus (IDDM) or Hashimoto's thyroiditis, and the passage to chronic disease is usually secondary to a defect in immunoregulation.

Several classes of regulatory T cells, such as Th2, CD25+ and natural killer (NK) T cells, are implied in autoimmune pathologies. In an animal model of a Th2-dominated autoimmune syndrome, the administration of the antioxidant N-acetyl-cysteine (NAC) induced a decrease in mast-cell expression of both IgE and IL-4 [58]. Of major interest is the discovery of the therapeutic potential of a new benzoquinone-containing product derived from wheat germ fermentation. This latter has been shown to have immune restorative properties because it affects the Th1/Th2 network by inhibiting the Th2 response [59]. Another beneficial effect of this molecule is its anti-metastatic activity, shown in various human malignancies and Jurkat leukemia cell line [60]. Intriguingly, the combined treatment with wheat germ and vitamin C profoundly inhibited metastasis formation in various tumor models of different origin (Lewis lung carcinoma, B16 melanoma and human colon carcinoma xenografts [HCR25]) [61]. On the contrary, wheat germ had no toxicity on peripheral blood leukocytes (PBLs) at doses that affected tumor cells. The crude powder extract of fermented wheat germ inhibits nucleic acid ribose synthesis primarily through the non-oxidative steps of the pentose cycle [60]. Curiously, another quinone compound, carnosic acid quinone, like wheat germ, recovers potent antioxidant activity upon standing [62].