Gold causes genetically determined autoimmune and immunostimulatory responses in mice

Havarinasab, Said; Johansson, Uno; Pollard, K. Michael; Hultman, Per

doi:10.1111/j.1365-2249.2007.03469.x

Cited by 27 publications

(25 citation statements)

References 56 publications

(62 reference statements)

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“…5 In mice, gold-induced autoimmunity is probably T cell dependent, but the underlying mechanism has not been established. 8,9 The most common problems encountered in humans subjected to chrysotherapy are contact urticaria and glomerulonephritis, which are mediated via type I and type III hypersensitivity, respectively. 23 Furthermore, exposure to metallic gold in diverse alloys represents a risk of inducing immunopathology.…”

Section: Discussionmentioning

confidence: 99%

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Inflammatory Response to Therapeutic Gold Bead Implantation in Canine Hip Joint Osteoarthritis

et al. 2010

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Inflammatory changes associated with periarticular pure gold bead implants were studied in dogs involved in a clinical trial investigating motor dysfunction and chronic pain owing to hip joint dysplasia and osteoarthritis. Gold beads were percutaneously implanted via a needle into different locations surrounding the greater trochanter of the femur. Nine dogs with implants were necropsied. In all examined animals, characteristic histologic lesions were observed in the tissue surrounding the gold implants-namely, a fibrous capsule composed of concentric fibroblasts intermixed with a variable number of inflammatory cells and a paucicellular innermost layer of collagen with a few fibrocyte-like cells in empty lacunae. Lymphocytes dominated the inflammatory infiltrate, with rarely observed macrophages present in close proximity to the implant site. No giant cells were observed. Immunohistochemistry showed mixed populations of lymphocytes, both CD3 positive (T cells) and CD79a positive (B cells), which in some cases formed lymphoid follicles. Diffuse inflammatory changes were present to a minor extent in the perimysium and surrounding fascia. The inflammation observed in dogs is similar to that observed with gold implants in humans. It is possible that the clinically beneficial effect of gold beads for chronic osteoarthritis depends on sustained localized inflammation with localized release of soluble mediators. The encapsulation of the implant by a paucicellular and poorly vascularized fibrous capsule may help prevent an exaggerated inflammatory reaction by sequestering the gold bead from the surrounding tissue. Keywords B cells, dogs, gold implants, immunohistochemistry, inflammation, osteoarthritis, T cellsThe parenteral therapeutic use of gold salts (chrysotherapy) is well known in human medicine and has been used in cases of rheumatoid arthritis. 23 The mechanisms behind the anti-inflammatory effect of monovalent gold salts and its metabolites, such as Au 3þ , Au(CN) 2 -, and metallic gold, is incompletely understood.5 One proposed mechanism of action for Au þ is due to binding with thiolate and thioether ligands on proteins.5 This is thought to inhibit presentation of complexed antigen to T cells, activity of certain transcription factors, and enzymes such as protein tyrosine phosphatase in T cells, protein kinase C in neutrophils and T cells, and proteins important for B cell differentiation. Au(CN) 2 -is an effective inhibitor of the respiratory burst of neutrophils and monocytes; it also inhibits the proliferation of lymphocytes. 5A more recent therapeutic application of gold is the implantation of gold beads directly into a painful anatomic region, such as the periarticular tissue of arthritic joints. This technique is derived from acupuncture and has been used in veterinary medicine for the past decade, largely as a treatment in canine hip dysplasia.10 A recent double-blind, placebocontrolled clinical trial performed by Jaeger et al showed that the performance of dogs with hip joint osteoarthritis s...

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Section: Discussionmentioning

confidence: 99%

“…1-4, 6, 7) or insufficient pain-relieving effect (dog Nos. 5,8,9). Twenty-nine of the treated dogs and all 42 of the control dogs from the clinical trial were unavailable for postmortem examination.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

Inflammatory Response to Therapeutic Gold Bead Implantation in Canine Hip Joint Osteoarthritis

et al. 2010

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“…However, recent studies point out that antiarthritic gold drugs directly interfere with the functioning of the immune system, at various levels [4,5]. In addition, a number of biochemical studies revealed that gold drugs behave as potent ''thiol reactive species'' and act as effective inhibitors of a number of proteases (mostly cysteine proteases) [6,7], involved in the progression of rheumatoid arthritis (RA).…”

Section: Introductionmentioning

confidence: 99%

New uses for old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhibits potent antimalarial effects in vitro: Mechanistic and pharmacological implications

et al. 2008

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The clinically established gold-based antiarthritic drug auranofin (AF) manifests a pronounced reactivity toward thiol and selenol groups of proteins. In particular, AF behaves as a potent inhibitor of mammalian thioredoxin reductases causing severe intracellular oxidative stress. Given the high sensitivity of Plasmodium falciparum to oxidative stress, we thought that auranofin might act as an effective antimalarial agent. Thus, we report here new experimental results showing that auranofin and a few related gold complexes strongly inhibit P. falciparum growth in vitro. The observed antiplasmodial effects probably arise from direct inhibition of P. falciparum thioredoxin reductase. The above findings and the safe toxicity profile of auranofin warrant rapid evaluation of AF for malaria treatment in animal models.

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“…As with mercury, the humoral responses in rats are transient, peaking within the first few weeks [20, 22, 23]. Immunological responses induced by gold in mice are also strain-specific, with differences in serum immunoglobulin levels and ANA responses, and humoral responses in mice persist throughout the exposure period [24, 25]. …”

Section: Factors That Induce Autoimmune Responses In Non-autoimmunmentioning

confidence: 99%

Animal models used to examine the role of the environment in the development of autoimmune disease: Findings from an NIEHS Expert Panel Workshop

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Pfau

et al. 2012

Journal of Autoimmunity

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Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. Environmental factors, such as chemicals, drugs or infectious agents, have been implicated in the expression of autoimmune disease, yet human studies are extremely limited in their ability to test isolated exposures to demonstrate causation or to assess pathogenic mechanisms. In this review we examine the research literature on the ability of chemical, physical and biological agents to induce and/or exacerbate autoimmunity in a variety of animal models. There is no single animal model capable of mimicking the features of human autoimmune disease, particularly as related to environmental exposures. An objective, therefore, was to assess the types of information that can be gleaned from the use of animal models, and how well that information can be used to translate back to human health. Our review notes the importance of genetic background to the types and severity of the autoimmune response following exposure to environmental factors, and emphasizes literature where animal model studies have led to increased confidence about environmental factors that affect expression of autoimmunity. A high level of confidence was reached if there were multiple studies from different laboratories confirming the same findings. Examples include mercury, pristane, and infection with Streptococcus or Coxsackie B virus. A second level of consensus identified those exposures likely to influence autoimmunity but requiring further confirmation. To fit into this category, there needed to be significant supporting data, perhaps by multiple studies from a single laboratory, or repetition of some but not all findings in multiple laboratories. Examples include silica, gold, TCE, TCDD, UV radiation, and Theiler’s murine encephalomyelitis virus. With the caveat that researchers must keep in mind the limitations and appropriate applications of the various approaches, animal models are shown to be extremely valuable tools for studying the induction or exacerbation of autoimmunity by environmental conditions and exposures.

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Gold causes genetically determined autoimmune and immunostimulatory responses in mice

Cited by 27 publications

References 56 publications

Inflammatory Response to Therapeutic Gold Bead Implantation in Canine Hip Joint Osteoarthritis

Inflammatory Response to Therapeutic Gold Bead Implantation in Canine Hip Joint Osteoarthritis

New uses for old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhibits potent antimalarial effects in vitro: Mechanistic and pharmacological implications

Animal models used to examine the role of the environment in the development of autoimmune disease: Findings from an NIEHS Expert Panel Workshop

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