Effects of miR-26a/miR-146a/miR-31 on airway inflammation of asthma mice and asthma children.

OBJECTIVE: This study detected the expressions of microRNA-26a (miR-26a), miR-146a and miR-31 in lung tissues and BALF (bronchoalveolar lavage fluid) of asthma mice and children. Besides, cytokine levels of interleukin-5 (IL-5), IL-8, IL-12 and tumor necrosis factor-α (TNF-α) were detected as well. We aim to provide an experimental basis for clinical treatment of asthma. PATIENTS AND METHODS: Forty female BALB/c mice were randomly assigned into control group and asthma group, respectively. Mice in asthma group (n=20) were immunized by intraperitoneal injection of OVA (ovalbumin) and provoked by atomization inhalation of OVA from the 15th day for 10 days. Mice in control group (n=20) were immunized and provoked with isodose saline during the same period. At the 26th day, mice were sacrificed for collecting lung tissues and BALF. Besides, we enrolled 17 cases of asthma children and 13 cases of children with airway foreign body as controls. BALF of each subject was collected. Total cellular score and differential counting in BALF were recorded. Expression levels of miR-26a, miR-146a, and miR-31 were detected by reverse transcription-polymerase chain reaction (RT-PCR). Levels of IL-5, IL-8, IL-12, and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The total cellular score in BALF of asthma mice and asthma children was higher than that of controls (p<0.05). Percentages of eosinophils, neutrophils, and lymphocytes in BALF of asthma mice and asthma children were higher than those of controls, whereas the percentage of macrophages was lower (p<0.05). Levels of IL-5, IL-8, IL-12, and TNF-α in lung tissues of asthma mice were markedly elevated compared with those of controls (p<0.05). Similarly, levels of IL-5, IL-8, IL-12, and TNF-α were higher in BALF of asthma children than controls (p<0.05). RT-PCR data showed higher mRNA levels of miR-26a, miR-146a, and miR-31 in lung tissues of asthma mice than controls (p<0.05). The mRNA levels of miR-26a, miR-146a, and miR-31 in BALF of asthma children were highly expressed compared with those of controls as well (p<0.05). CONCLUSIONS: MiR-26a, miR-146a, and miR-31 are involved in asthma progression mainly through regulating inflammatory factors and cells.

Regulation of immune response by bioactive ions released from silicate bioceramics for bone regeneration.

Silicate bioceramics have been considered to possess a wide prospect of clinical application for orthopedic tissue regeneration due to their excellent osteogenesis and angiogenesis. However, the mechanism for silicate bioceramics stimulating bone formation is not fully understood. The host immune defense to implants is proved to greatly influence the osteogenesis and new bone formation, but up to now, few studies are focused on the silicate bioceramics modulated host immune responses. In our present study, two representative silicate bioceramics, akermanite (AKT) and nagelschmidtite (NAGEL) were used as model materials to investigate the inflammation responses in vitro and in vivo, and ß-tricalcium phosphate (ß-TCP) bioceramics were used as a control. It was found that the mouse macrophage cell RAW264.7 that cultured on AKT and NAGEL bioceramics displayed not only less viability and proliferation, but also a significant less inflammatory cytokine secretion than those on ß-TCP in vitro. The formation of foreign body giant cells and fibrous capsules, the invasion of macrophages, as well as the detected inflammatory cytokines around the implanted materials were much lower in both AKT and NAGEL bioceramic groups as compared with those in the ß-TCP controls in vivo. Furthermore, it was found that not just the certain concentration of extracellular Si-containing ionic products released from the silicate bioceramics, but also the separate Si, Mg and Ca ions revealed the activity to inhibit the macrophage inflammatory responses by the way of suppressing the activated inflammatory MAPK and NF-κB signaling pathway and promoting the caspase-dependent apoptosis of macrophages. In general, our study suggests that the silicate bioceramics could regulate immune responses by altering the ionic microenvironment between the implants and hosts, which may offer new insight about the mechanism of the bioactivity of silicate bioceramics in bone regeneration and provide profitable guidance for designing new biomaterials for bone tissue engineering. STATEMENT OF SIGNIFICANCE: Silicate bioceramics have been widely used for orthopedic tissue regeneration because of their excellent characteristics in bone formation. However, there are few studies concerning their interrelationships with the host immune defense that has been proved to greatly influence osteogenesis. In our present study, the akermanite and nagelschmidtite were used as two representative silicate bioceramics to investigate the inflammation responses in vitro and in vivo; and for the first time, the bioactive ions released from the silicate bioceramics were discovered to regulate the macrophage immune responses through both inhibiting the inflammatory signaling and activating apoptosis of macrophages. Our findings in this study may not only increase the understanding in osteogenic activity of silicate bioceramics, but also provide profitable guidance for designing and manufacturing new biomaterials for bone tissue engineering.

In vitro study of central nervous system foreign body response towards hydrogel particle modified planar substrate.

Central nervous system (CNS) neural device functionality hinges on effective communication with surrounding neurons. This depends on both the permissiveness of the device material to promote neuron integration and the ability of the device to avoid a chronic inflammatory response. Previously our lab developed a method using surface adsorbed hydrogel particles (HPs) to promote neuron integration onto typically non-neural-permissive substrates. However, little information is known regarding CNS inflammatory cell type responses towards the modified HP surface. In vitro adhesion, proliferation, and activation studies were implemented using NIH 3T3, RAW 264.7, and A172 cell lines to model fibroblast, macrophages and activated microglia, and astrocytes, respectively. For all cell types, the HP modified substrates elicited cell adhesion and sustained cell metabolic activity during a 3-day culture. RAW 264.7 cell activation was evaluated using a tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay and scanning electron microscope (SEM) imaging. Quantified TNF-α levels from the LbL/HP cells were greater than the control substrate, however, investigation with SEM suggested these cells' morphology was different from a typical activated state. A172 cell activation was evaluated by fluorescent staining of glial fibrillary acidic protein (GFAP) and SEM imaging, which revealed similarly low GFAP levels on both bare and HP modified substrates. A172 cell morphology showed mainly an undifferentiated and non-activated state. These results help lay the groundwork to design the HP system for future in vitro and in vivo investigations to ultimately realize stable long-term neural device communication. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3242-3250, 2017.

Opening borders for foreign bodies.

Targeting macrophage-specific receptors involved in host immune response against foreign bodies eliminates the fibrotic processes responsible for failure of many implantable biomedical devices.

Inflammation and Peritoneal Dialysis.

Inflammation is one of the well-recognized nontraditional risk factors that contributes to the excessive cardiovascular mortality in peritoneal dialysis (PD) patients. Serum C-reactive protein and interleukin-6 levels are common surrogate markers used to measure inflammatory burden and predict adverse clinical outcomes in PD patients. Causes of inflammation are complex and can be categorized into factors related to a decrease in renal function and factors related to dialysis. They interact with each other and finally result in systemic and intraperitoneal inflammation. This review discusses the various causes and clinical implications of inflammation in PD patients. More importantly, potential therapeutic options that target the underlying pathogenic mechanisms are explored.

[Foreign material in the gingival tissues admixed with a clinical picture of Mucous Membrane Pemphigoid: A coincidence or inter-related conditions?].

We present a case of a 74-year old female who complained of chronic vesicular and ulcerative lesions distributed on her gingivae. The lesions did not respond to conventional periodontal treatment. The clinical appearance was consistent - with vesiculo-bullous conditions, such as Pemphigus Vulgaris and Mucous Membrane Pemphigoid. These conditions have an auto- immune etiology, whereby pathologic auto-antibodies are generated against structures that constitute the epithelial cell-cell or cell-connective tissue attachment systems. Accurate diagnosis is mandatory due to the high risk, at least in part of them, to spread to extra- oral sites, such skin, eyes and other types of mucosae and cause severe morbidity and even death. Diagnosis is based on routine biopsy aimed to identify the characteristic histomorphological features and on direct immunofluorescence that highlights the type and pattern of the deposition of the auto-antibodies with the affected tissue. The present biopsy did not show features of a vesiculo-bullous condition. However, the presence of a foreign material in the form of fine granules was highlighted by polarized microscopy. Immunofluorescence revealed a %pattern of auto-antibodies that was supportive of Mucous Membrane Pemphigoid. In lack of involvement of any other oral site, the patient has been treated with local agents, as commonly accepted. The present case emphasizes the need to consult specialists from various disciplines, especially in those cases where the clinical response to a common practice is not as expected. Furthermore, diagnosis is not always straightforward, and sometimes a pathologic condition may be the "product" of more than one single etiology.

Azithromycin-Ciprofloxacin-Impregnated Urinary Catheters Avert Bacterial Colonization, Biofilm Formation, and Inflammation in a Murine Model of Foreign-Body-Associated Urinary Tract Infections Caused by Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a multifaceted pathogen causing a variety of biofilm-mediated infections, including catheter-associated urinary tract infections (CAUTIs). The high prevalence of CAUTIs in hospitals, their clinical manifestations, such as urethritis, cystitis, pyelonephritis, meningitis, urosepsis, and death, and the associated economic challenges underscore the need for management of these infections. Biomaterial modification of urinary catheters with two drugs seems an interesting approach to combat CAUTIs by inhibiting biofilm. Previously, we demonstrated the in vitro efficacy of urinary catheters impregnated with azithromycin (AZM) and ciprofloxacin (CIP) against P. aeruginosa Here, we report how these coated catheters impact the course of CAUTI induced by P. aeruginosa in a murine model. CAUTI was established in female LACA mice with uncoated or AZM-CIP-coated silicone implants in the bladder, followed by transurethral inoculation of 108 CFU/ml of biofilm cells of P. aeruginosa PAO1. AZM-CIP-coated implants (i) prevented biofilm formation on the implant's surface (P ≤ 0.01), (ii) restricted bacterial colonization in the bladder and kidney (P < 0.0001), (iii) averted bacteriuria (P < 0.0001), and (iv) exhibited no major histopathological changes for 28 days in comparison to uncoated implants, which showed persistent CAUTI. Antibiotic implants also overcame implant-mediated inflammation, as characterized by trivial levels of inflammatory markers such as malondialdehyde (P < 0.001), myeloperoxidase (P < 0.05), reactive oxygen species (P ≤ 0.001), and reactive nitrogen intermediates (P < 0.01) in comparison to those in uncoated implants. Further, AZM-CIP-coated implants showed immunomodulation by manipulating the release of inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-10 to the benefit of the host. Overall, the study demonstrates long-term in vivo effectiveness of AZM-CIP-impregnated catheters, which may possibly be a key to success in preventing CAUTIs.

Inflammasome components ASC and AIM2 modulate the acute phase of biomaterial implant-induced foreign body responses.

Detailing the inflammatory mechanisms of biomaterial-implant induced foreign body responses (FBR) has implications for revealing targetable pathways that may reduce leukocyte activation and fibrotic encapsulation of the implant. We have adapted a model of poly(methylmethacrylate) (PMMA) bead injection to perform an assessment of the mechanistic role of the ASC-dependent inflammasome in this process. We first demonstrate that ASC(-/-) mice subjected to PMMA bead injections had reduced cell infiltration and altered collagen deposition, suggesting a role for the inflammasome in the FBR. We next investigated the NLRP3 and AIM2 sensors because of their known contributions in recognising damaged and apoptotic cells. We found that NLRP3 was dispensable for the fibrotic encapsulation; however AIM2 expression influenced leukocyte infiltration and controlled collagen deposition, suggesting a previously unexplored link between AIM2 and biomaterial-induced FBR.

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates.

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.

A polymeric conjugate foreignizing tumor cells for targeted immunotherapy in vivo.

Antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) are key elements of immunological rejection in transplantation as well as cancer immunotherapy. Most tumors, however, are not immunologically rejected because they have self antigens, which are not recognized as the foreigner by CTLs. In this study, we hypothesized that "foreignizing" tumor cells by delivering non-self foreign antigens into the tumors would result in rejection by foreign antigen-reactive CTLs. As the model system to foreignize the tumors, we prepared a polymeric conjugate consisting of hyaluronic acid as the CD44(+) tumor-targeting ligand and ovalbumin (OVA) as a foreign antigen. When the conjugate was treated with CD44(high) TC-1 tumor cells, it was effectively taken up and allowed for displaying of antigenic OVA257-264 peptide at MHC class I on the surface of the cells. In addition, the conjugate was effectively accumulated into tumor tissue after its systemic administration to mice which are immunized with a vaccine for a vaccinia virus expressing OVA to generate OVA257-264 specific CTLs, resulting in substantial inhibition of tumor growth. Overall, these results suggest that the polymeric conjugates bearing foreign antigens may be innovative and promising cancer immunotherapeutic agents by foreignizing tumor cells, leading to immunological rejection.

Towards an in vitro model mimicking the foreign body response: tailoring the surface properties of biomaterials to modulate extracellular matrix.

Despite various studies to minimize host reaction following a biomaterial implantation, an appealing strategy in regenerative medicine is to actively use such an immune response to trigger and control tissue regeneration. We have developed an in vitro model to modulate the host response by tuning biomaterials' surface properties through surface modifications techniques as a new strategy for tissue regeneration applications. Results showed tunable surface topography, roughness, wettability, and chemistry by varying treatment type and exposure, allowing for the first time to correlate the effect of these surface properties on cell attachment, morphology, strength and proliferation, as well as proinflammatory (IL-1ß, IL-6) and antiinflammatory cytokines (TGF-ß1, IL-10) secreted in medium, and protein expression of collagen and elastin. Surface microstructuring, derived from chloroform partial etching, increased surface roughness and oxygen content. This resulted in enhanced cell adhesion, strength and proliferation as well as a balance of soluble factors for optimum collagen and elastin synthesis for tissue regeneration. By linking surface parameters to cell activity, we could determine the fate of the regenerated tissue to create successful soft tissue-engineered replacement.

The sarcoidal granuloma: A unifying hypothesis for an enigmatic response.

Although the cause of sarcoidosis is unknown, there is growing support for the concept that sarcoidal granulomas result from a hypersensitivity reaction producing a nonspecific response to an extrinsic or intrinsic (autoimmune) antigen in genetically susceptible individuals. The immune milieu associated with these antigens, localized in a specific cutaneous area, produces a variant of Ruocco's "immunocompromised district." This may explain the predilection for sarcoidal granulomas in association with foreign bodies, tattoos, herpes zoster-affected dermatomes, and scars. Similar antigenic stimulation produces sarcoidal granulomas surrounding internal tumors. Finally, systemic sarcoidosis, as manifested by hilar adenopathy, may reflect the lymphatic spread of foreign antigens.

Foreign body response to subcutaneous biomaterial implants in a mast cell-deficient Kit(w-Sh) murine model.

Mast cells (MCs)_are recognized for their functional role in wound-healing and allergic and inflammatory responses - host responses that are frequently detrimental to implanted biomaterials if extended beyond acute reactivity. These tissue reactions impact especially on the performance of sensing implants such as continuous glucose monitoring (CGM) devices. Our hypothesis that effective blockade of MC activity around implants could alter the host foreign body response (FBR) and enhance the in vivo lifetime of these implantable devices motivated this study. Stem cell factor and its ligand c-KIT receptor are critically important for MC survival, differentiation and degranulation. Therefore, an MC-deficient sash mouse model was used to assess MC relationships to the in vivo performance of CGM implants. Additionally, local delivery of a tyrosine kinase inhibitor (TKI) that inhibits c-KIT activity was also used to evaluate the role of MCs in modulating the FBR. Model sensor implants comprising polyester fibers coated with a rapidly dissolving polymer coating containing drug-releasing degradable microspheres were implanted subcutaneously in sash mice for various time points, and the FBR was evaluated for chronic inflammation and fibrous capsule formation around the implants. No significant differences were observed in the foreign body capsule formation between control and drug-releasing implant groups in MC-deficient mice. However, fibrous encapsulation was significantly greater around the drug-releasing implants in sash mice compared to drug-releasing implants in wild-type (e.g. MC-competent) mice. These results provide insights into the role of MCs in the FBR, suggesting that MC deficiency provides alternative pathways for host inflammatory responses to implanted biomaterials.

Foreign body response induced by tissue expander implantation.

The foreign body response (FBR) is described as the host's response to implanted biomaterials, which involves a complex cascade of immune modulators. The dynamic changes of immune cells, inflammatory cytokines and the formation of a fibrous capsule remain to be elucidated. In the present study, a model of subcutaneous implantation of a tissue expander was used. The results revealed that macrophages, the main immune cells in FBR, infiltrated into the expanded tissue and located at the tissue­material interface from day 1­90. Following the decrease of the number of macrophages, collagen deposited and fibroblasts transformed into myofibroblasts at the tissue­material interface, leading to the formation of a fibrous capsule from day 14. The persistent existing macrophages led to a high expression of proinflammatory cytokines, including tumor necrosis factor­α and interleukin­1ß, both of which initiated the NK-κB and JNK inflammatory pathways, mediating the FBR to tissue expander implantation.

Reaction of the rat tissues to implantation of polyhydroxyalkanoate films and ultrafine fibers.

The reaction of various tissues of rats to implantation of polyhydroxyalkanoate films and ultrafine fibers was studied by optic microscopy. Implantation of polyhydroxyalkanoate films into the abdominal cavity caused a peritoneal reaction, leading after 1 month to the formation of fibrous adhesions between polyhydroxyalkanoate and intestinal loops. Under the skin and in the muscle tissue polyhydroxyalkanoate films were encapsulated in a thick fibrous capsule. Implantation of polyhydroxyalkanoate ultrathin fibers led to formation of foreign body granulomas in all tissues with perifocal inflammation and sclerosis of the adjacent tissues. The polymer was fragmented in these granulomas and phagocytosed by macrophages with the formation of giant foreign body cells. Hence, polyhydroxyalkanoate materials implanted in vivo caused chronic granulomatous inflammatory reaction and were very slowly destroyed by macrophages.

Human adjuvant disease induced by foreign substances: a new model of ASIA (Shoenfeld's syndrome).

OBJECTIVE: To investigate the clinical, laboratory and histological manifestations of patients who received illegal injections of foreign substances for cosmetic purposes. PATIENTS AND METHODS: We studied patients who met the following inclusion criteria: 1) history of application of foreign substances for cosmetic purposes, 2) clinical data of autoimmune disease or non-specific autoimmune manifestation (i.e. arthralgias, myalgia, malaise, fever, and weight loss), 3) detection of autoantibodies in patients' sera, 4) histological evidence of chronic inflammation and/or granulomatous reaction to foreign body. RESULTS: Fifty female patients aged 44.4 ± 10 years were studied. The mean time between application of foreign substances and onset of symptoms was 4.5 ± 4.3 years. Patients were followed for 12 ± 7.5 years. Forty-one patients were injected with mineral oil, nine patients received other substances: three iodine gadital, one guayacol, one guayacol plus silicone fluid, two collagen, two silicone fluid. The sites of application were: buttocks (36), legs and/or thighs (11), breasts (eight) hands and face (one), face (two) (seven patients received an injection to more than one site). Thirty patients presented with non-specific autoimmune manifestations, whereas 20 patients fulfilled the criteria for a defined autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, overlap syndrome, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune hepatitis, and ulcerative colitis. CONCLUSIONS: Cases of human adjuvant disease following illegal injections of oil substances for cosmetic purposes are reported. Patients presented with defined autoimmune diseases as well as with non-specific autoimmune manifestations. Illegal injection of these substances could lead to serious local and systemic complications, even to death. These cases represent another model of Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA). The use of these substances should be prohibited.

Biologic response to orthopedic sutures: a histologic study in a rabbit model.

Biologic reactivity to suture materials can have an effect on patient outcomes. The goal of this study was to determine the histologic response to 8 commonly used orthopedic sutures--Ethibond (Ethicon, Somerville, New Jersey), Ticron (Tyco, Waltham, Massachusetts), HiFi (Linvatec, Largo, Florida), Ultrabraid (Smith & Nephew, Memphis, Tennessee), MaxBraid (Biomet, Warsaw, Indiana), Orthocord (Mitek, Raynham, Massachusetts), MagnumWire (Opus Medical, San Juan Capistrano, California), and FiberWire (Arthrex, Naples, Florida)--using a rabbit model. The suture granuloms were evaluated at 30, 60, and 120 days with measurement of the fibrous capsule, the number of giant cells in and near the capsule, and the overall inflammatory grade: 1 (mild), 2 (moderate), and 3 (severe). MagnumWire and Ticron sutures initiated a more intense inflammatory reaction when compared to the other sutures. By 120 days, MagnumWire (P=.0297) and Ticron (P=.1855) had fewer giant cells at the soft tissue-suture interface, fewer giant cells within the capsule (P=.0074 and P=.0377, respectively), and the greatest capsular thickness of all suture types (P<.0001 and P=.1378, respectively). Differences exist between the biologic reactivity of commonly used orthopedic sutures that may be attributable to their material composition and/or braid characteristics. In comparison to other high-strength sutures, MagnumWire and Ticron stimulated a more intense foreign body inflammatory response.

The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells.

We examined the role of phagocyte-derived oxygen radicals in tumor cell acquisition of metastatic phenotype by comparing gp91(phox-/-) mice and C57BL/6J wild-type (WT) mice. The gp91(phox-/-) mouse is deficient in the gp91(phox) gene, an essential subunit of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase that generates superoxide anion. QR-32 fibrosarcoma cells are nonmetastatic but are converted into metastatic tumors once in contact with foreign body (gelatin sponge)-induced phagocytes in vivo. Compared to QR-32 cells co-implanted with the foreign body in WT mice, those in gp91(phox-/-) mice exhibited reduced metastasis. There was no difference in the incidence of primary tumors after injection of B16BL6 melanoma cells in WT and gp91(phox-/-) mice. However, after resection of the primary tumors, metastases were reduced in gp91(phox-/-) mice. Thymosin beta4 gene expression and cell motility/invasion were seen in the tumors from WT mice but not in those from gp91(phox-/-) mice. Adoptive transfer of phagocytes from WT mice, but not those from gp91(phox-/-) mice, restored the metastatic ability of tumors grown in gp91(phox-/-) mice. These findings show that tumor metastatic behavior can primarily be endowed by phagocyte-derived superoxide anion and its oxidative metabolites, which are generated through activation of nicotinamide adenine dinucleotide phosphate oxidase.

Inorganic particles in the skin of inhabitants of volcanic areas of Central America: their possible immunomodulatory influence in leishmaniasis and leprosy.

We have evaluated biopsies from patients with atypical nodular and typical ulcerated lesions of cutaneous leishmaniasis, from leishmanin reactions and skin from normal individuals from Nicaragua, Honduras and Guatemala for the presence of inorganic particles using confocal microscopy with a polarised light source and conventional histopathological techniques. Analysis by semiquantitative confocal microscopy permitted the demonstration of significantly larger numbers of particles in atypical lesions. Silica and aluminium, important components of these particles, were less abundant in particles from normal skin. The histology of these atypical lesions, characterised by 'naked' sarcoidal granulomas with epithelioid differentiation but very few lymphocytes, was very similar to the histological reaction observed after 14 days in persisting inflammation at leishmanin skin test sites. The presence of these unusual lesions in areas of Central American countries characterised by the presence of large amounts of volcanic ash, as well the unexpectedly low prevalence of leprosy in Central America, suggest that environmental factors may contribute significantly to the frequency and clinical manifestations of these infections. Among possible environmental features, the presence of inorganic particles with immunomodulatory properties in the skin may be a significant factor.