Environmental pollutants and the immune response.

Environmental pollution is one of the most serious challenges to health in the modern world. Pollutants alter immune responses and can provoke immunotoxicity. In this Review, we summarize the major environmental pollutants that are attracting wide-ranging concern and the molecular basis underlying their effects on the immune system. Xenobiotic receptors, including the aryl hydrocarbon receptor (AHR), sense and respond to a subset of environmental pollutants by activating the expression of detoxification enzymes to protect the body. However, chronic activation of the AHR leads to immunotoxicity. KEAP1-NRF2 is another important system that protects the body against environmental pollutants. KEAP1 is a sensor protein that detects environmental pollutants, leading to activation of the transcription factor NRF2. NRF2 protects the body from immunotoxicity by inducing the expression of genes involved in detoxification, antioxidant and anti-inflammatory activities. Intervening in these sensor-response systems could protect the body from the devastating immunotoxicity that can be induced by environmental pollutants.

Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease.

Nutritional immunity is the sequestration of bioavailable trace metals such as iron, zinc and copper by the host to limit pathogenicity by invading microorganisms. As one of the most conserved activities of the innate immune system, limiting the availability of free trace metals by cells of the immune system serves not only to conceal these vital nutrients from invading bacteria but also operates to tightly regulate host immune cell responses and function. In the setting of chronic lung disease, the regulation of trace metals by the host is often disrupted, leading to the altered availability of these nutrients to commensal and invading opportunistic pathogenic microbes. Similarly, alterations in the uptake, secretion, turnover and redox activity of these vitally important metals has significant repercussions for immune cell function including the response to and resolution of infection. This review will discuss the intricate role of nutritional immunity in host immune cells of the lung and how changes in this fundamental process as a result of chronic lung disease may alter the airway microbiome, disease progression and the response to infection.

The role of metal patch testing in evaluating patients for metallic prosthetic joint failure.

BACKGROUND: Metal allergy may be an uncommon cause of prosthetic joint failure. There exist little data on patch testing to metals in this context and its impact on outcomes of joint revision in these patients. OBJECTIVE: To explore the use and indications for metal patch testing in the evaluation of patients suspected of having metal allergy as a cause of failed joint replacements and to clarify the outcomes of patients revised with alternative metallic joints because of positive patch testing result. METHODS: A retrospective analysis from January 2016 to April 2020 was completed on a patient cohort referred for evaluation of metal hypersensitivity. Charts were reviewed for age, biological sex, referring specialty, patch testing results, joint, revision status, and outcome measures. Biostatistical analysis and descriptive statistics were performed to determine patch testing performance and functional outcome trends among this patient cohort. RESULTS: The sensitivity and specificity of patch testing, in general, are limited when evaluating patients with metallic joint replacements. However, the predictive value of testing seemed to improve with strongly positive patch testing results. Functional outcomes in patients when positive results were used to guide revision prosthesis revealed clinical improvement. CONCLUSION: The attribution of metal allergy or hypersensitivity as a cause of failure in metal prosthetic joint replacement remains unproven. Some patients with positive histories and patch testing results that were used to modify the implanted prosthesis had improved functional outcomes. These results suggest that patch testing may be useful in patients with history of metal sensitivity and prosthetic failure.

Do Battlefield Injury-acquired Indwelling Metal Fragments Induce Metal Immunogenicity?

BACKGROUND: A battlefield-related injury results in increased local and systemic innate immune inflammatory responses, resulting in wound-specific complications and an increased incidence of osteoarthritis. However, little is known about whether severe injuries affect long-term systemic homeostasis, for example, immune function. Moreover, it also remains unknown whether battlefield-acquired metal fragments retained over the long term result in residual systemic effects such as altered immune reactivity to metals. QUESTIONS/PURPOSES: Does a retained metal fragment from a battlefield injury contribute to increased (1) adaptive metal-specific immune responses, (2) systemically elevated metal ion serum levels, and (3) serum immunoglobulin levels compared with combat injuries that did not result in a retained metal fragment? METHODS: In this pilot study, we analyzed metal-immunogenicity in injured military personnel and noninjured control participants using lymphocyte transformation testing (LTT, lymphocyte proliferation responses to cobalt, chromium and nickel challenge at 0.001, 0.01 and 0.1-mM concentrations in triplicate for each participant), serum metal ion analysis (ICP-mass spectroscopy), and serum immunoglobulin analysis (IgE, IgG, IgA, and IgM ). Military personnel with a battlefield-sustained injury self-recruited without any exclusion for sex, age, degree of injury. Those with battlefield injury resulting in retained metal fragments (INJ-FRAG, n = 20 male, mean time since injury ± SD was 12 ± 10 years) were compared with those with a battlefield injury but without retained metal fragments (INJ-NO-FRAG, n = 12 male, mean time since injury ± SD was 13 ± 12 years). A control group comprised of male noninjured participants was used to compare measured immunogenicity metrics (n = 11, males were selected to match battlefield injury group demographics). RESULTS: Military participants with sustained metal fragments had increased levels of metal-induced lymphocyte responses. The lymphocyte stimulation index among military participants with metal fragments was higher than in those with nonretained metal fragments (stimulation index = 4.2 ± 6.0 versus stimulation index = 2.1 ± 1.2 (mean difference 2.1 ± 1.4 [95% confidence interval 5.1 to 0.8]; p = 0.07) and an average stimulation index = 2 ± 1 in noninjured controls. Four of 20 participants injured with retained fragments had a lymphocyte proliferation index greater than 2 to cobalt compared with 0 in the group without a retained metal fragment or 0 in the control participants. However, with the numbers available, military personnel with retained metal fragments did not have higher serum metal ion levels than military participants without retained metal fragment-related injuries or control participants. Military personnel with retained metal fragments had lower serum immunoglobulin levels (IgG, IgA, and IgM) than military personnel without retained metal fragments and noninjured controls, except for IgE. Individuals who were metal-reactive positive (that is, a stimulation index > 2) with retained metal fragments had higher median IgE serum levels than participants who metal-reactive with nonmetal injuries (1198 ± 383 IU/mL versus 171 ± 67 IU/mL, mean difference 1027 ± 477 IU/mL [95% CI 2029 to 25]; p = 0.02). CONCLUSIONS: We found that males with retained metal fragments after a battlefield-related injury had altered adaptive immune responses compared with battlefield-injured military personnel without indwelling metal fragments. Military participants with a retained metal fragment had an increased proportion of group members and increased average lymphocyte reactivity to common implant metals such as nickel and cobalt. Further studies are needed to determine a causal association between exposure to amounts of retained metal fragments, type of injury, personnel demographics and general immune function/reactivity that may affect personal health or future metal implant performance. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Prevalence of metal hypersensitivity in patients with shoulder pathologies.

BACKGROUND: To date, medical history and dedicated questionnaires are the fastest and easiest way to assess risks of joint metal hypersensitivity. No published studies determined the overall prevalence of hypersensitivity to metals in patients with shoulder pathologies. The purpose of this study was therefore to estimate the prevalence of metal hypersensitivity reported by patients with shoulder pathologies, and to identify patients at risk of joint metal hypersensitivity based on a dedicated questionnaire. METHODS: The authors prospectively asked all adult patients consulting for shoulder pathologies between September 2018 and February 2019 at 10 centers to fill in a form. The main outcome was "reported hypersensitivity to metals," comprising belt buckles, coins, earrings, fancy jewelry, keys, leather, metallic buttons, piercings, spectacles, watch bracelets, or zips. RESULTS: A total of 3217 patients agreed to fill in the survey, aged 55 ± 16 (range, 18-101) with equal proportions of men (51%) and women (49%), and a majority of patients consulting for cuff pathology (55%). A total of 891 (28%) patients had professions considered at risk for metal hypersensitivity. The most frequently reported metal hypersensitivities were fancy jewelry (15%), earrings (13%), and watch bracelets (9%). A total of 629 (20%) patients, of which the vast majority were women, reported hypersensitivity to 1 or more metals. CONCLUSIONS: This survey of 3217 patients identified 20% who reported metal hypersensitivities, though only 2.2% had done patch tests. Matching profiles of those with positive patch tests to those with no patch tests revealed that 9.4% of the total cohort had similar sex and self-reported metal hypersensitivities. Factors associated with a positive patch test were female sex, self-reported cutaneous allergy, and self-reported metal hypersensitivity. The clinical applicability of these estimates remains uncertain as there is insufficient evidence that allergy to metal implants can be predicted by questionnaires or patch tests.

Rate of actual metal allergy prior to dental treatment in subjects complaining of possible metal allergy.

BACKGROUND: Dental treatment for patients with self-reported metal allergy or concern about the possibility of having such an allergy is often difficult; such patients often undergo dermatological consultations for metal patch test (PT). OBJECTIVE: This study compared PT results for metal allergens and the clinical relevance of this among patients visiting Fukuoka Dental College Hospital. METHODS: We performed PT with metal allergens on patients with oral mucosa- or skin-related symptoms, or those concerned about adverse events associated with upcoming dental treatment. RESULTS: Fifty-nine patients were patch-tested with metal allergens. Thirty-four cases (58.8%) had self-reported metal allergy. Regarding comorbidities, atopic dermatitis was the most common (7 cases), followed by hand eczema, palmoplantar pustulosis, lichen planus, and abnormal sensation in the mouth. Overall, 25 of 59 cases had at least one positive PT reaction. The most common positive allergen was nickel sulfate (17 cases), followed by cobalt chloride, zinc chloride, and palladium chloride. The rate of positivity of metal PT was significantly higher in the self-reported metal allergy cases than in the others (P < 0.001). Other comorbidities were not significantly associated with those with or without self-reported metal allergy. Five of those without self-reported metal allergy showed positive PT reaction. CONCLUSIONS: Patients with self-reported metal allergy exhibited more metal PT reactions than those without this. One fifth of those without this showed positive metal PT reaction, implying the importance of PT for both with and without self-reported metal allergy. PT results are helpful for selecting dental metals for future prosthetic and orthodontic treatments.

Improved metal allergen reactivity of artificial skin models by integration of Toll-like receptor 4-positive cells.

BACKGROUND: Reconstructed human epidermis (RhE) is widely used to replace animal models in order to assess the proinflammatory and allergenic effects of chemicals. Unfortunately, RhE lacks proinflammatory responsiveness for metal haptens, which are the most prevalent human contact allergens, raising concerns about its reliability for predicting skin allergens. OBJECTIVES: To investigate whether this limitation of RhE might be attributable to a lack of functional expression of Toll-like receptor 4 (TLR4), which governs proinflammatory sensitivity to nickel and cobalt. MATERIALS AND METHODS: RhE, dendritic cell (DC)-containing RhE and full-thickness skin equivalent (FTSE) were compared regarding their proinflammatory responsiveness to metal allergens. RESULTS: The incorporation of dermal fibroblasts was sufficient to confer metal sensitivity to RhE. Unlike keratinocytes, normal human fibroblasts expressed high levels of TLR4 mRNA and induced interleukin-8 expression upon stimulation with nickel or cobalt. Consistently, dermal isolates from FTSE expressed considerable amounts of TLR4 mRNA, whereas RhE or epidermis isolated from FTSE, normal human epidermis or inflamed human epidermis failed to express TLR4. Similarly, co-culture with TLR4-positive DCs bestowed RhE with proinflammatory responsiveness to metals. CONCLUSION: Our data suggest that FTSE or DC/RhE co-culture models can circumvent the shortcomings of RhE assays, and combine the benefits of complex and monoculture-based test systems in a single assay.

Host-specific factors affect the pathogenesis of adverse reaction to metal debris.

BACKGROUND: Adverse Reaction to Metal Debris (ARMD) is a major reason for revision surgeries in patients with metal-on-metal (MoM) hip replacements. Most failures are related to excessively wearing implant producing harmful metal debris (extrinsic factor). As ARMD may also occur in patients with low-wearing implants, it has been suggested that there are differences in host-specific intrinsic factors contributing to the development of ARMD. However, there are no studies that have directly assessed whether the development of ARMD is actually affected by these intrinsic factors. METHODS: We included all 29 patients (out of 33 patients) with sufficient data who had undergone bilateral revision of ASR MoM hips (58 hips) at our institution. Samples of the inflamed synovia and/or pseudotumour were obtained perioperatively and sent to histopathological analysis. Total wear volumes of the implants were assessed. Patients underwent MARS-MRI imaging of the hips preoperatively. Histological findings, imaging findings and total wear volumes between the hips of each patient were compared. RESULTS: The difference in wear volume between the hips was clinically and statistically significant (median difference 15.35 mm3, range 1 to 39 mm3, IQR 6 to 23 mm3) (p < 0.001). The median ratio of total wear volume between the hips was 2.0 (range 1.09 to 10.0, IQR 1.67 to 3.72). In majority of the histological features and in presence of pseudotumour, there were no differences between the left and right hip of each patient (p > 0.05 for all comparisons). These features included macrophage sheet thickness, perivascular lymphocyte cuff thickness, presence of plasma cells, presence of diffuse lymphocytic infiltration and presence of germinal centers. CONCLUSIONS: Despite the significantly differing amounts of wear (extrinsic factor) seen between the sides, majority of the histological findings were similar in both hips and the presence of pseudotumour was symmetrical in most hips. As a direct consequence, it follows that there must be intrinsic factors which contribute to the symmetry of the findings, ie. the pathogenesis of ARMD, on individual level. This has been hypothesized in the literature but no studies have been conducted to confirm the hypothesis. Further, as the threshold of metal debris needed to develop ARMD appears to be largely variable based on the previous literature, it is likely that there are between-patient differences in these intrinsic factors, ie. the host response to metal debris is individual.

Hypersensitivity to biomedical implants: Prevention and diagnosis.

BACKGROUND: There has been growing interest in the potential for adverse immunologic reactions to metals in biomedical devices and increasing referrals for the evaluation and management of metal hypersensitivity reactions reported in orthopedic, cardiac, gynecologic, and dental implant devices. However, there are few studies that give evidence-based recommendations on how to evaluate this issue in our practices. METHODS: We reviewed reasonable evidence and expert opinion on biomedical device hypersensitivity and published guidelines on pre- and postimplantation evaluation of delayed hypersensitivity reactions in patients suspected of possible metal hypersensitivity to biomedical devices. RESULTS: There is consensus that routine preimplantation evaluation in individuals with no history of adverse cutaneous reactions to metals or a history of implant-related adverse events is not necessary. However, patients with a history of metal hypersensitivity of a magnitude sufficient to cause concern for the patient or health care provider may benefit from evaluation by patch testing (PT) before device implantation. Patients after implantation and with chronic unexplained implant failure or with dermatitis may benefit from patch test evaluation after other causes, such as infection and biomechanical issues, are ruled out. However, a positive metal patch test result does not prove symptom causality, and the decision regarding implant revision can only be made after a thorough discussion among the patient, the allergist or dermatologist, and the orthopedic surgeon. CONCLUSION: Consensus guidelines for the evaluation of hypersensitivity to biomedical devices can be used by the practicing physician while awaiting for the results of further investigations.

Making Sense of Metal Allergy and Hypersensitivity to Metallic Implants in Relation to Hand Surgery.

All metals implanted into a biological system undergo some degree of corrosion depending upon its composition. The electrochemical process of corrosion produces free metal ions, which may activate the host's immune system through a variety of mechanisms. Whereas dermal metal hypersensitivity is common, affecting 10% to 15% of the population, the immune reaction from implanted metals is much less common (< 0.1%), but has been associated with metal allergy and hypersensitivity producing a multitude of patient symptoms. Superficial symptoms may be mild to severe forms of dermatitis, urticaria, pruritus, and vasculitis, whereas deep sequelae include metallosis-related pseudotumor, implant loosening, and joint stiffness. Currently, there are clinical tests to evaluate patients for metal hypersensitivity, but there is little agreement regarding the ideal timing and clinical situation prompting the work-up of a patient for a metal allergy or hypersensitivity. An understanding of the epidemiology, etiology, basic science, diagnostic testing, and treatment of patients with suspected metal allergy, as it pertains to the current literature, will aid orthopedic and plastic surgeons of all subspecialties in the management of patients requiring metallic implants.

Immunotoxicological and neurotoxicological profile of health effects following subacute exposure to geogenic dust from sand dunes at the Nellis Dunes Recreation Area, Las Vegas, NV.

Exposure to geogenic particulate matter (PM) comprised of mineral particles has been linked to human health effects. However, very little data exist on health effects associated with geogenic dust exposure in natural settings. Therefore, we characterized particulate matter size, metal chemistry, and health effects of dust collected from the Nellis Dunes Recreation Area (NDRA), a popular off-road vehicle area located near Las Vegas, NV. Adult female B6C3F1 mice were exposed to several concentrations of mineral dust collected from active and vegetated sand dunes in NDRA. Dust samples (median diameter: 4.4 µm) were suspended in phosphate-buffered saline and delivered at concentrations ranging from 0.01 to 100 mg dust/kg body weight by oropharyngeal aspiration. ICP-MS analyses of total dissolution of the dust resulted in aluminum (55,090 µg/g), vanadium (70 µg/g), chromium (33 µg/g), manganese (511 µg/g), iron (21,600 µg/g), cobalt (9.4 µg/g), copper (69 µg/g), zinc (79 µg/g), arsenic (62 µg/g), strontium (620 µg/g), cesium (13 µg/g), lead 25 µg/g) and uranium (4.7 µg/g). Arsenic was present only as As(V). Mice received four exposures, once/week over 28-days to mimic a month of weekend exposures. Descriptive and functional assays to assess immunotoxicity and neurotoxicity were performed 24 h after the final exposure. The primary observation was that 0.1 to 100 mg/kg of this sand dune derived dust dose-responsively reduced antigen-specific IgM antibody responses, suggesting that dust from this area of NDRA may present a potential health risk.

Hypersensitivity Reactions to Implanted Metal Devices: Facts and Fictions.

The use of metals in the medical field has become increasingly prevalent over the past few decades. Patients find themselves being exposed to metals in a variety of ways, ranging from external exposure to instruments such as the stainless steel in surgical blades to internal exposure via medical devices being implanted in their bodies. There has been growing interest in the possibility of developing hypersensitivity reactions to constituent metals in medical implant devices, both in cutaneous and systemic forms. Hypersensitivity reactions to metals are uncommon, but they are reported and require appropriate evaluation and management, particularly if they are symptomatic. In view of the lack of consensus in the field on the appropriate steps to evaluate and manage patients with suspected metal hypersensitivity reactions, this review aims to analyze current evidence on hypersensitivity reactions to metallic implants in orthopedic surgery, endovascular surgery, obstetrics and gynecology, and dental surgery.

Patient-Reported Metal Allergy: A Risk Factor for Poor Outcomes After Total Joint Arthroplasty?

BACKGROUND: Metal sensitivity after total joint arthroplasty has been of increased concern, but the impact of a patient-reported metal allergy on clinical outcomes has not been investigated. The purpose of this study was to report the incidence and impact of patient-reported metal allergy after total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: This was a retrospective, institutional review board-approved investigation of patients undergoing a primary, elective total joint arthroplasty between 2009 and 2011. All patients completed a preoperative questionnaire asking about drug and environmental allergies. In January 2010, a specific question was added regarding the presence of a metal allergy. University of California at Los Angeles Activity, Short Form 12 (SF-12), Modified Harris Hip, and Knee Society scores were collected preoperatively and at most recent follow-up. Overall cohorts of metal allergy and nonmetal allergy patients were compared, and a 1:2 matching analysis was also performed. RESULTS: Nine hundred six primary THAs and 589 primary TKAs were included. The incidence of patient-reported metal allergy was 1.7% before January 2010 and 4.0% after (overall 2.3% of THAs and 4.1% of TKAs); 97.8% of metal allergy patients were female. After TKA, postoperative Knee Society Function, Symptoms, Satisfaction, and Expectation scores were all decreased in the metal allergy cohort (P < .001-.002). After THA, metal allergy patients had a decreased postoperative SF-12 Mental Component Score and less incremental improvement in their SF-12 Mental Component Score vs the nonmetal allergy cohort (P < .0001 and P = .001, respectively). CONCLUSION: Patient-reported metal allergy is associated with decreased functional outcomes after TKA and decreased mental health scores after THA.

Systemic lupus erythematosus: molecular cloning and analysis of 22 individual recombinant monoclonal kappa light chains specifically hydrolyzing human myelin basic protein.

Antibodies hydrolyzing myelin basic protein (MBP) can play an important role in the pathogenesis of multiple sclerosis (MS) and systemic lupus erythematosus (SLE). An immunoglobulin light chain phagemid library derived from peripheral blood lymphocytes of patients with SLE was used. Small pools of phage particles displaying light chains with different affinities for MBP were isolated by affinity chromatography on MBP-Sepharose, and the fraction eluted with 0.5 M NaCl was used for preparation of individual monoclonal light chains (MLChs, 26-27 kDa). Seventy-two of 440 individual colonies were randomly chosen, expressed in Escherichia coli in a soluble form, and MLChs were purified by metal chelating chromatography. Twenty-two of 72 MLChs have high affinity and efficiently hydrolyze only MBP (not other control proteins) demonstrating various pH optima in a 5.7-9.0 range and different substrate specificity in the hydrolysis of four different MBP oligopeptides. Four MLChs demonstrated serine protease-like and three thiol protease-like activities, while 11 MLChs were metalloproteases. The activity of three MLChs was inhibited by both phenylmethylsulfonyl fluoride (PMSF) and Ethylenediaminetetraacetic acid (EDTA), two other by EDTA and iodoacetamide, and one by PMSF, EDTA, and iodoacetamide. The ratio of relative activity in the presence of Ca(2+), Mg(2+), Mn(2+), Ni(2+), Zn(2+), Cu(2+), and Co(2+) was individual for each of 22 MLCh preparations. It is the first examples of human MLChs, which probably can possess two or even three different proteolytic activities. These observations suggest an extreme diversity of anti-MBP abzymes in SLE patients. The immune systems of individual SLE patients can generate a variety of anti-MBP abzymes, which can attack MBP of myelin-proteolipid sheath of axons and play an important role in MS and SLE pathogenesis.

Immunology of metal allergies.

Allergic contact hypersensitivity to metal allergens is a common health concern worldwide, greatly impacting affected individuals with regard to both quality of life and their ability to work. With an estimated 15-20 % of the Western population hypersensitive to at least one metal allergen, sensitization rates for metallic haptens by far outnumber those reported for other common triggers of allergic contact dermatitis such as fragrances and rubber. Unfortunately, the prevalence of metal-induced hypersensitivity remains high despite extensive legislative efforts to ban/reduce the content of allergy-causing metals in recreational and occupational products. Recently, much progress has been made regarding the perception mechanisms underlying the inflammatory responses to this unique group of contact allergens. This review summarizes recent advances in our understanding of this enigmatic disease. Particular emphasis is put on the mechanisms of innate immune activation and T cell activation by common metal allergens such as nickel, cobalt, palladium, and chromate.

Metal hypersensitivity in total joint arthroplasty.

OBJECTIVE: To review the clinical manifestations, testing methods, and treatment options for hypersensitivity reactions to total joint arthroplasty procedures. DATA SOURCES: Studies were identified using MEDLINE and reference lists of key articles. STUDY SELECTIONS: Randomized controlled trials were selected when available. Systematic reviews and meta-analyses of peer-reviewed literature were included, as were case series and observational studies of clinical interest. RESULTS: Total joint arthroplasty procedures are increasing, as are the hypersensitivity reactions to these implants. Evidence is not conclusive as to whether metal joint implants increase metal sensitivity or whether metal sensitivity leads to prosthesis failure. Currently, patch testing is still the most widely used method for determining metal hypersensitivity; however, there are no standardized commercial panels specific for total joint replacements available currently. In vitro testing has shown comparable results in some studies, but its use in the clinical setting may be limited by the cost and need for specialized laboratories. Hypersensitivity testing is generally recommended before surgery for patients with a reported history of metal sensitivity. In cases of metal hypersensitivity-related joint failure, surgical revision ultimately may be required. Knowledge about joint replacement hypersensitivity reactions becomes vital because the approach to the evaluation depends on appropriate testing to guide recommendations for future arthroplasty procedures. CONCLUSION: Evaluation of hypersensitivity reactions after total joint arthroplasty requires a systematic approach, including a careful history, targeted evaluation with skin testing, and in vitro studies.

Metals as a common trigger of inflammation resulting in non-specific symptoms: diagnosis and treatment.

BACKGROUND: The multiple symptoms of chronic fatigue syndrome (CFS) and fibromyalgia resemble those described in patients suffering from autoimmune/inflammatory syndrome induced by adjuvants (ASIA). It has been suggested that chronic metal-induced inflammation might play a role both in CFS and fibromyalgia as well as in ASIA. Humans are exposed to metals mainly through the release of metal ions from corroding dental restorations and orthopedic implants, food, vaccines and jewelry. Metals readily bind to sulphur and other groups in the mitochondria, enzymes and cell proteins. Metal-bound proteins are recognized by the immune system of susceptible subjects and might trigger an abnormal immune response, including allergy and autoimmunity. OBJECTIVES: To study three subjects with CFS and two with fibromyalgia, all of whom suspected metal exposure as a trigger for their ill health. METHODS: We measured delayed-type hypersensitivity to metals (metal allergy) using a validated lymphocyte transformation test, LTT-MELISA. All patients except one were sensitized to metals present in their dental restorations. The remaining patient reacted to metals in his skull implant. The removal of sensitizing metals resulted in long-term health improvement. Nine healthy controls matched for gender and age showed only marginal reactivity to the metals tested. CONCLUSIONS: Patients with CFS and fibromyalgia are frequently sensitized to metals found in the environment or used in dentistry and surgery. This allergy to metals might initiate or aggravate non-specific symptoms in metal-sensitized patients.

A prospective study concerning the relationship between metal allergy and post-operative pain following total hip and knee arthroplasty.

PURPOSE: A prospective study was conducted to detect whether a relationship exists between metal allergy and post-operative pain in total hip and knee arthroplasty patients. We postulated that to some extent a relationship does exist between them. MATERIALS AND METHODS: Patients who had undergone total hip and knee arthroplasty surgery because of hip and knee disease were included. The exclusion criteria were patients who were treated with immunosuppressor two weeks pre-operatively, skin conditions around the patch testing site, and other uncontrollable factors. Each patient agreed to patch testing for three days before surgery. Photographic images before patch testing, two and three days after patch testing were obtained to evaluate the final incidence of metal allergy. The patch tests contained 12 metal elements; chromium, cobalt, nickel, molybdenum, titanium, aluminium, vanadium, iron, manganese, tin, zirconium, and copper. Two independent observers evaluated the images. The results were divided into a non-metal allergy group and a metal allergy group. Pre-operative and postoperative VAS score, lymphocyte transforming test, and X-rays were collected to detect the relationship between metal allergy and post-operative pain following total hip and knee arthroplasty. RESULTS: There were 96 patients who underwent pre-operative patch testing. The overall metal allergy rate was 51.1% (49/96) in our study. Nickel, cobalt, manganese, and tin were the most common allergic metal elements in our study. Nine inappropriate cases were excluded, and 87 patients were finally included in our study. There were 36 metal allergy and 26 non-metal allergy patients in the THA group, while 11 metal allergy and 14 non-metal allergy patients were found in the TKA group. We found no relationship existed between metal allergy and post-surgery pain in total hip and knee arthroplasty. CONCLUSION: Pain caused by metal allergy usually presents as persistent and recurrent pain. The white cell count, C-reactive protein, erythrocyte sedimentation rate and postoperative radiographs were not affected. Currently, patch testing and lymphocyte transforming tests are used for metal allergy diagnosis. We deemed that a relationship between post-surgery pain and metal allergy in total hip and knee patients may exist to some extent. Larger samples and longer follow-up time are essential for further study.

[Allergies to dental materials and effectiveness of treatment in the north-eastern region of Hungary]. / Fogászati anyagokkal szemben kialakuló allergiás megbetegedések és ellátásuk hatékonyságának vizsgálata az észak-alföldi régióban.

The recognition and treatment of allergy is a great challenge for all fields of medicine. The high prevalence of allergic reactions to dental materials and the related financial burden of their treatment make investigation of this disease very important. Our investigation was carried out on patients assigned to our outpatient department for dental allergy test between 1996 and 1998. We determined the distribution of gender and age among the allergic patients in the examined population. We also studied the prevalence of allergic reactions to different dental allergens and the distribution of dental allergens. In a follow-up study we determined the proportion of those patients, who were retreated in conformity with the results of epicutan tests and we followed up the positive effects of these treatments. We have found that dental allergy occurred five times more frequently in women (84%) than in men (16%) and the most affected age group was between 20 to 39 and 40-49 years (31%). Seventy-five percent of the patients suffered from a combination of metal and polymer allergy. The most frequent metal allergen was TEGDMA (triethylene glycol dimethacrylate) (49.7%). The suggested treatment plan was carried out in 63% of the allergic patients. The applied treatment was successful in 48% of these cases. We experienced that 48% of these patients got rid of their earlier signs and symptoms.

Metal-induced autoimmunity in neurological disorders: A review of current understanding and future directions.

Autoimmunity is a multifaceted disorder influenced by both genetic and environmental factors, and metal exposure has been implicated as a potential catalyst, especially in autoimmune diseases affecting the central nervous system. Notably, metals like mercury, lead, and aluminum exhibit well-established neurotoxic effects, yet the precise mechanisms by which they elicit autoimmune responses in susceptible individuals remain unclear. Recent studies propose that metal-induced autoimmunity may arise from direct toxic effects on immune cells and tissues, coupled with indirect impacts on the gut microbiome and the blood-brain barrier. These effects can activate self-reactive T cells, prompting the production of autoantibodies, inflammatory responses, and tissue damage. Diagnosing metal-induced autoimmunity proves challenging due to nonspecific symptoms and a lack of reliable biomarkers. Treatment typically involves chelation therapy to eliminate excess metals and immunomodulatory agents to suppress autoimmune responses. Prevention strategies include lifestyle adjustments to reduce metal exposure and avoiding occupational and environmental risks. Prognosis is generally favorable with proper treatment; however, untreated cases may lead to autoimmune disorder progression and irreversible organ damage, particularly in the brain. Future research aims to identify genetic and environmental risk factors, enhance diagnostic precision, and explore novel treatment approaches for improved prevention and management of this intricate and debilitating disease.