Regulation of anti-tumor immunity by metal ion in the tumor microenvironment.

Metal ions play an essential role in regulating the functions of immune cells by transmitting intracellular and extracellular signals in tumor microenvironment (TME). Among these immune cells, we focused on the impact of metal ions on T cells because they can recognize and kill cancer cells and play an important role in immune-based cancer treatment. Metal ions are often used in nanomedicines for tumor immunotherapy. In this review, we discuss seven metal ions related to anti-tumor immunity, elucidate their roles in immunotherapy, and provide novel insights into tumor immunotherapy and clinical applications.

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.

Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy.

Nutritional metal ions play critical roles in many important immune processes. Hence, the effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn2+. We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn2+ promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn2+ coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN-Mn2+ particle, CMP) that effectively delivered STING agonists to immune cells. The CMP, administered either by local intratumoural or systemic intravenous injection, initiated robust anti-tumour immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumour models. Overall, the CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy.

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.

Understanding the relationship between viral infections and trace elements from a metallomics perspective: implications for COVID-19.

Recently, the World Health Organization (WHO) declared a pandemic situation due to a new viral infection (COVID-19) caused by a novel virus (Sars-CoV-2). COVID-19 is today the leading cause of death from viral infections in the world. It is known that many elements play important roles in viral infections, both in virus survival, and in the activation of the host's immune system, which depends on the presence of micronutrients to maintain the integrity of its functions. In this sense, the metallome can be an important object of study for understanding viral infections. Therefore, this work presents an overview of the role of trace elements in the immune system and the state of the art in metallomics, highlighting the challenges found in studies focusing on viral infections.

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.

Morbidity After Metal Allergy to a Total Ankle Implant.

Metal allergy to total ankle arthroplasty is rare but can be both an unpredictable and devastating complication. Current literature describing metal allergy in orthopaedics is limited with there being no report to date on metal allergy after total ankle arthroplasty. Our patient underwent a total ankle arthroplasty and developed a diffuse rash 7 weeks postoperatively. The patient then tested positive for a metal allergy and ultimately was converted to an arthrodesis. In the setting of postoperative pain, swelling, erythema, or rash, it is important that metal allergy be on the differential diagnosis. Interestingly, when the patient here underwent allergy testing, only the articulating sides of the implant caused a positive reaction. Thus, allergy testing of both the articular and nonarticular sides of the component is of the utmost importance, as evidenced by the discrepancy found in this case.Levels of Evidence: Level IV: Case report.

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.

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.

Multi-metal nutrient restriction and crosstalk in metallostasis systems in microbial pathogens.

Transition metals from manganese to zinc function as catalytic and structural cofactors for an amazing diversity of proteins and enzymes, and thus are essential for all forms of life. During infection, inflammatory host proteins limit the accessibility of multiple transition metals to invading pathogens in a process termed nutritional immunity. In order to respond to host-mediated metal starvation, bacteria employ both protein and RNA-based mechanisms to sense prevailing transition metal concentrations that collectively regulate systems-level strategies to maintain cellular metallostasis. In this review, we discuss a number of recent advances in our understanding of how bacteria orchestrate the adaptive response to host-mediated multi-metal restriction, highlighting crosstalk among these regulatory systems.

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.

Diagnosis of Metal Hypersensitivity in Total Knee Arthroplasty: A Case Report.

Delayed type hypersensitivity (DTH) reactions are considered infrequent complications in arthroplasty, but have been recognized to be associated with devastating morbidity and substantial decrease in quality of life of affected patients. Chronic inflammation of artificial joints and associated loss of peri-implant bone often require revision surgery. Methods for the diagnosis of implant-related DTH are available but infrequently considered to the full extent. Sequential diagnostics based on exclusion of septic complications, local and systemic metal level determination, lymphocyte transformation testing (LTT), and local T cell subset analysis are required for an unequivocal DTH diagnosis. Here, we report on a patient with a history of chronic rheumatoid arthritis and an unfavorable outcome of unilateral knee arthroplasty. This case illustrates pitfalls and difficulties in the course of recurrent inflammation following joint replacement. In the early course, suspicion of low-grade bacterial infection led to three two-stage revisions. Afterwards, the joint was proven to be sterile. However, metal level quantification revealed release of especially cobalt and chromium from the joint, LTT indicated persisting cobalt and nickel sensitization and subset analysis of T cells from the synovium suggested DTH as a root cause for the inflammatory symptoms. This report aims to recommend the depicted diagnostic algorithm as an adequate tool for future DTH detection. Yet, systemic to local subset ratios for effector memory and regulatory T cells should be derived from sufficient patient numbers to establish it as a diagnostic marker. Moreover, future prospects regarding implant-related DTH diagnostics are discussed. Therapeutic options for the portrayed patient are proposed, considering pharmaceutical, cell-therapeutic and surgical aspects. Patients who experience peri-implant inflammation but do not have obvious mechanical or infectious problems remain a diagnostic challenge and are at high risk of being treated inadequately. Since potentially sensitizing materials are regularly used in arthroplasty, it is essential to detect cases of acute DTH-derived inflammation of an artificial joint at early postoperative stages. This would reduce the severity of inflammation-related long-term consequences for affected patients and may avoid unnecessary revision surgery.

The Allergic Bone Marrow? The Immuno-Capacity of the Human Bone Marrow in Context of Metal-Associated Hypersensitivity Reactions.

Arthroplasty ranks among the greatest achievements of surgical medicine, with total hip replacement termed "the operation of the century." Despite its wide success, arthroplasty bears risks, such as local reactions to implant derived wear and corrosion products. Prevalence of allergies across Western society increases and along the number of reported hypersensitivity reactions to orthopedic implant materials. In this context the main focus is on delayed hypersensitivity (DTH). This mechanism is mainly attributed to T cells and an overreaction of the adaptive immune system. Arthroplasty implant materials are in direct contact with bone marrow (BM), which is discussed as a secondary lymphoid organ. However, the mechanisms of sensitization toward implant wear remain elusive. Nickel and cobalt ions can form haptens with native peptides to activate immune cell receptors and are therefore common T helper allergens in cutaneous DTH. The rising prevalence of metal-related allergy in the general population and evidence for the immune-modulating function of BM allow for the assumption hypersensitivity reactions could occur in peri-implant BM. There is evidence that pro-inflammatory factors released during DTH reactions enhance osteoclast activity and inhibit osteoblast function, an imbalance characteristic for osteolysis. Even though some mechanisms are understood, hypersensitivity has remained a diagnosis of exclusion. This review aims to summarize current views on the pathomechanism of DTH in arthroplasty with emphasis on BM and discusses recent advances and future directions for basic research and clinical diagnostics.

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.

Pathogenesis and causations of systemic contact dermatitis.

Systemic contact dermatitis (SCD) describes a hypersensitivity reaction following systemic re-exposure of the inciting allergen in previously sensitized individuals. Plants, drugs, and metals are the most common causes of SCD. In individuals with obstinate dermatitis, it is imperative to deliver history-focused patch testing with subsequent avoidance and elimination of the compound.

Pipeline Treatment of Intracranial Aneurysms Is Safe and Effective in Patients with Cutaneous Metal Allergy.

BACKGROUND: The Pipeline embolization device (PED) has expanded the range of aneurysms amenable to endovascular treatment, including some that were previously untreatable. The PED contains several metals, including nickel, cobalt, chromium, platinum, and tungsten. The safety of PED implantation in patients with cutaneous metal allergy is unknown. The aim of this study was to assess clinical and angiographic outcomes of PED treatment in patients with cutaneous metal allergy. METHODS: A single-institution neurointerventional database was retrospectively reviewed for patients with documented cutaneous metal allergy who were treated with the PED. Patient, aneurysm, and procedural data were collected, including perioperative and delayed complications. Posttreatment angiograms were reviewed for in-Pipeline stenosis and aneurysm occlusion. RESULTS: Twenty patients with metal allergy underwent 23 PED treatments for 26 aneurysms. The cohort was 95% (19/20) female; mean age was 55.7 years. Aneurysms were primarily anterior circulation (92%, 24/26) and saccular (92%; 24/26); mean size was 8.8 mm (range, 2-32 mm). One PED was implanted in 70% (14/20) of patients, 25% (5/20) had 2 devices placed, and 1 patient had 3 devices. One major procedural complication occurred (4.3%, 1/23) in which a stroke was caused by perioperative PED thrombosis. Angiographic follow-up was available for all patients (mean duration 15.7 months; range, 6-64 months), which demonstrated a complete aneurysm occlusion rate of 88% (23/26). Asymptomatic in-Pipeline stenosis occurred in 2 cases, resulting in 65% and 50% parent artery stenosis, respectively. CONCLUSIONS: Preliminary results suggest that PED implantation in patients with cutaneous metal allergy is safe and effective.