Neuropathy Problems Archives

Multiple sclerosis -

• Multiple Sclerosis

Follow Ups:

• Re: Multiple sclerosis - (Archive.) Walt Stoll 08:40:27 6/12/01 (0)
• Re: Multiple sclerosis - JJ 19:46:47 6/10/01 (1)
  • Re: Multiple sclerosis - MAI 22:33:41 6/10/01 (0)
• Re: Multiple sclerosis - Jan 16:23:55 6/10/01 (1)
  • Re: Multiple sclerosis - MAI 16:34:14 6/10/01 (0)

In Reply to: Multiple sclerosis - posted by Some causative factors on June 10, 2001 at 15:58:17:

Systemic yeast/fungus is another cause of M.S. or it can mimic M.S.

Follow Ups:

• Re: Multiple sclerosis - MAI 16:34:14 6/10/01 (0)

In Reply to: Re: Multiple sclerosis - posted by Jan on June 10, 2001 at 16:23:55:

Are you walking on the moon right now?

Have you found some water or it is a communist enterprise? (no condition to support form of live).

In Reply to: Multiple sclerosis - posted by Some causative factors on June 10, 2001 at 15:58:17:

Aspartame poisoning can cause symptoms of multiple sclerosis too.

Follow Ups:

• Re: Multiple sclerosis - MAI 22:33:41 6/10/01 (0)

In Reply to: Re: Multiple sclerosis - posted by JJ on June 10, 2001 at 19:46:47:

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 which determine the individual’s 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 fluids 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.

Multiple Sclerosis

In multiple sclerosis (MS), an autoimmune T-cell attack on the CNS myelin sheath results in demyelinated plaques. The periventricular white matter, medulla oblongata and the optic nerves are most commonly affected, but any part of the CNS can be involved. The plaques commonly surround venules. In active plaques, a disrupted blood-brain barrier and some edema can often be seen. Inflammatory cells, including activated T-cells, plasma cells and macrophages are prominent and accumulate around centrally located vessels, and in the periphery where myelin loss occurs. Microscopical changes include loss of myelin; however, axons are relatively spared.

The demyelinization causes the common symptoms of MS, such as disturbances in vision, coordination, speech, strength, sensation and bladder control, among others. Genetically, MS is linked to HLA-DR2 [2]. The relatively low concordance of monozygotic twins to develop the disease (25-30%) [56] suggests that the myelin basic protein (MBP)-specific T-cell repertoire may be shaped differently even in monozygotic twins [57], and also that other factors may operate in the pathogenesis of the disease. Robinson et al. discuss more recent research that indicates a connection between MS and genes encoded within or closely linked to the TCR (T-cell receptor) beta chain gene complex [58].

Several epidemiological studies link environmental metal exposure to the subsequent development of MS. Ingalls et al describe the outbreak and clustering of MS and other demyelinating diseases as well as myasthenia gravis following pollution of the environment with large concentrations of heavy metal wastes in sewage and river water in one area [59, 60]. Irvine et al. find that areas with soils low in copper, iron and vanadium, but high in lead, nickel and zinc, and with drinking waters low in selenium and sulfate may predispose to MS [61].

Can metals cause demyelinization? Schwyzer et al. discuss how exposure to toxic low- molecular weight substances cause modification of protein or glycoprotein in the myelin sheath [62]. This induces the formation of autoantibodies and phagocytosis of the damaged myelin will lead to the formation of plaques. Simultaneously, MBP-specific lymphocytes are present in the blood of MS patients [63]. In rats, exposure to methylmercury will generate antibodies to neurotypic and gliotypic proteins such as MBP and GFAP (glial fibrillary acidic protein) [64]. Metals are used for the staining of brain and nervous tissue in histopathology [65]. Following a disrupted blood-brain barrier (e.g. after injury), metals can enter the CNS, bind to proteolipid protein (PLP) or MBP in myelin and evoke an autoimmune response. The disruption of the blood-brain barrier is not the only way that metals can enter the CNS. Chang [66] injected radioactively-labeled mercury into rodents and subsequently demonstrated the deposition of radioactivity in the myelin sheath of the brain. Interestingly, several studies show that there is no difference between the amount of heavy metal deposition in autopsies of MS subjects compared to controls [67–69]. Further, investigators found no difference between the number of amalgam fillings between MS patients and controls [70, 71], nor between blood and urine levels of mercury and lead [71].

Siblerud et al. [72] compare laboratory measurements of MS patients with dental metal fillings with MS patients with metal fillings removed. The metalexposed MS patients had significantly lower levels of red blood cells, hemoglobin, hematocrit, thyroxine, total T-cells and CD8+ suppressor cells than the unexposed MS patients. The exposed MS group showed significantly higher blood urea nitrogen and hair content of mercury, than the unexposed group. The metal-exposed MS group also had significantly more (33.7%) exacerbations during the past 12 months compared to the unexposed group.

Another aspect of the role of heavy metals in the development of MS is the interaction between zinc and other divalent cations. It has been shown that zinc stabilizes the association of MBP with brain myelin membranes by promoting its (Zn) binding to proteolipid protein [73]. Another study confirms this finding, and also investigates the potency of other divalent cations to interfere with the binding of zinc to MBP [74]. The ions most effective to interfere with zinc binding were cadmium, mercury and copper. However, MBP aggregation was not inhibited by copper.
Several factors have been studied concerning the induction of autoimmunity. Certain types of major histocompatibility complex (MHC) are associated with an increased risk for autoimmunity in animal models. In man, the human lymphocyte antigen (HLA) linkage to susceptibility has only a relative predictive value, thus indicating that other factors also contribute to the development of autoimmunity. Obvious is the overrepresentation of female patients in certain autoimmune diseases (for example, in SLE, the female predominance ratio is 10–20:1, for MS 10:1 [2]), indicating that sex hormones may play a role in the pathogenesis. It is also common that autoimmune disease debuts in women of child-bearing age, when the levels of estrogen and progesterone peak. The observation that monozygous twins do not always develop the same disease (e.g. the concordance rate of autoimmune diabetes is around 30% [2]) further indicates that there are other factors involved in the pathogenesis of autoimmune disease. In one study [3], the results of HLA typing of metal-sensitive patients showed higher frequencies of certain HLA antigens, among others HLA DR 4 and HLA B27. In another study [4], HLA DR 4 antigen was significantly increased in palladium-sensitive patients.

The effects of metals in biological systems: toxicity and allergy

Available literature clearly demonstrates metal-induced autoimmunity in animal systems [5]. Reports that link metal exposure to the development of autoimmunity in man include epidemiological studies, occupational exposure to metals, and a high prevalence of side-effects following treatment with metal chelators and colloidal gold. Metals in nature occur bound to sulfur groups in metal ores in the ground. When extracted for industrial use, they are purified and thereby lose their chemical stability. Some transition metals such as iron, cobalt, zinc, selenium, molybdenum, magnesium, chromium, manganese and copper are essential for life. Others, such as titanium, chromium, iron, nickel, copper, palladium, silver, platinum, gold and mercury are widely used in industry and in various implants. Except for chromium, iron and copper, those metals have no established function in man.

In living organisms, metals exert their effects in different ways. They avidly bind to sulfhydryl (SH) groups but also to -OH, NH2 and Cl groups in proteins, enzymes, co-enzymes and cell membranes. The metal binding interferes with cellular processes, changing membrane charge, permeability, and the antigenicity of autologous structures. Metals in ionic form reach cell membranes attached to circulating blood proteins, particularly the water-soluble component of lipoproteins. Here, the affinity is strongest for SH-containing molecules such as methionine, cysteine and glutathione. It is this feature that allows ionic metals to exchange freely between lipoprotein and the macromolecules of ligands of cell membranes, including red blood cells. The hemoglobin of red blood cells is particularly rich in SH groups which further explains how ionic metals reach the various cell membranes via blood. Since metals in ionic form are lipophilic, they readily pass the blood brain barrier. For example, mercury vapor readily oxidizes in brain and nervous tissue to its ionic form, where ionic mercury binds with SH groups of cell membranes, protein and brain enzymes [6].

The toxic effects of metals are mediated through free radical formation, cell membrane disturbance or enzyme inhibition, among others. By binding to cell membranes, metals alter the membrane charge, which may result in changed membrane permeability, calcification and cell death. Metals also bind to mitochondria, thereby impairing cellular respiration [7]. Depending on genetically determined detoxification systems, an individual may tolerate more or less exposure to toxic metals before showing adverse effects.

The immunological effects of metals are either non-specific such as immunomodulation or antigen-specific such as allergy and autoimmunity. Metals may act as immunosuppressants (cytostatically) or as immunoadjuvants (non-specific activation of the immune system). One example of immunomodulation is the ability of metals to modify cytokine production in vitro and in vivo. The resulting imbalance between Th1 and Th2 activation can result in immunodysregulations leading to impaired cell-mediated immunity and/or aberrant humoral immunity that may culminate in autoimmune disease. Heo et al. found that lead and mercury enhanced IL-4 production by a Th2 clone (and inhibited Th1 proliferation) in vitro and in vivo. This suggests that these metals may induce an autoimmune response by dysregulating the balance between Th1 and Th2, which could enhance the production of antibodies to self antigens [8]. Another example is the enhancement of the intensity and duration of antigen-specific IgE responses by gold salts [9], mercury, platinum and aluminum [10, 11].

Metals may also induce allergy in genetically susceptible individuals. Most of these are of type 4 (delayed- type hypersensitivity, such as contact dermatitis) but immediate-type reactions are sometimes also observed [12-14]. It can be anticipated that cellular reactions triggered by metals may operate elsewhere in the body where metals are deposited. Traditionally, metal allergy has been diagnosed by patch test. This method has, however, several drawbacks; objective interpretation is difficult, application of allergen onto skin may aggravate an existing allergy and, finally, it harbors the risk of de novo sensitization. Recently, Penz et al. compared the diagnostic efficiency of the expression of CD69 activation markers, cytokine release and lymphocyte stimulation test (LST) in nickel allergy. Of the tests, LST had the highest diagnostic efficiency (87%) for the diagnosis of nickel sensitization [15]. LST has been used in immunology diagnostics for delayed-type hypersensitivity for decades [2]. Memory Lymphocyte Immuno Stimulation Assay (MELISA®) has been found particularly useful for diagnosis of metal allergy in vitro [16–19].

Several mechanisms are proposed for how metals act within the immune system and induce autoimmunity. Metals bind to SH and other groups, thereby modifying self-proteins which via T-cells may activate B-cells and render the altered self-protein target for autoantibodies. Due to cross-reactions, the T-cells may also react to the native protein. Metal-binding directly to MHC II without prior processing by antigen-presenting cells or even directly to the T-cell receptor is also proposed. Another possibility is described in a study of scleroderma where autoantigens possess metal-binding sites, which after binding will generate free radicals. Free radicals will fragment the auto-antigens, thereby exposing cryptic epitopes which may then trigger autoimmunity [20]. In this case, the metal is not a part of the autoimmune epitope.

In his excellent review on metal-induced autoimmunity, Bigazzi [21] provides further evidence that metals may cause aberrant MHC II expression on target cells, inhibit T-suppressor cells, cause alterations in the idiotype-anti-idiotype network and induce heat-shock proteins. These and other factors may play a role in metal-induced autoimmunity.

Autoantibodies

Autoantibodies occur in systemic and organ-specific autoimmune disease. Since autoantibodies sometimes occur before the onset of disease, they can be used as predictive markers. Some are disease-specific markers and used to establish a diagnosis, to record progression and predict outcome of the disease. Both drugs and heavy metals are known to induce autoantibodies [22]. Monestier et al. found that treatment with D-penicillamine (D-pen) or quinidine, two lupus-inducing drugs in humans, resulted in production of autoantibodies against chromatin antigens in genetically susceptible mice [23]. The authors found that the Vh chains of several D-pen or quinidine-induced monoclonal antibodies (mAb) are most similar to those of anti-nucleolar mAb obtained from mercury-injected mice. The authors refer to a study showing that cross-reactive idiotypes are shared by autoantibodies induced by heavy metals, D-pen and in graft-vs.-host reactions.

The potential of heavy metals to induce autoantibodies has been investigated in animal models. Originally described by Druet [24], it has since then been confirmed by other groups. Eneström et al. showed that both mercury and silver induced antinucleolar antibodies (ANoA), targeted against fibrillarin, in genetically susceptible mice [25, 26].While mercury furthermore induced systemic immune complex deposition and polyclonal activation of B- and T-cells, silver did not. Pollard and colleagues, who demonstrated the same results with regards to mercury, ANoA and fibrillamin, propose that mercury binds to the thiols in the cysteine group of fibrillamin, thereby changing its antigenicity and subsequently evoking the production of autoantibodies [27]. In patients with systemic scleroderma, ANoA in about half of the patients reacted with fibrillamin. After exposure to mercury, certain strains of rats produced high levels of antibodies to laminin [21].

In a recent article [28], El-Fawal and co-workers studied the immune status of occupationally metal-exposed workers and in experimental animals. Antibodies to neuronal cytoskeletal proteins, neurofilaments and myelin basic protein (MBP) were frequently present in the sera of male workers exposed to lead and mercury. The titers correlated with blood and urinary concentrations of those metals. Similar results were obtained in animal systems. In rats exposed to metals, histopathology showed central nervous system (CNS) and peripheral nervous system (PNS) changes as well as astrogliosis. The authors conclude that autoantibodies can be used to monitor the neurotoxicity of environmental chemicals and that immune mechanisms may be involved in the progression of neurodegeneration.

In Reply to: Multiple sclerosis - posted by Some causative factors on June 10, 2001 at 15:58:17:

NMI