Formaldehyde exposure induces regulatory T cell-mediated immunosuppression via calcineurin-NFAT signalling pathway.

In this study, we investigated the effects of Formaldehyde (FA) exposure on splenic immune responses wherein helper T cells become activated and differentiate into effector T and regulatory T cells. BALB/c mice were exposed to two FA concentrations (1.38 mg/m3 and 5.36 mg/m3) for 4 h/day and 5 days/week for 2 weeks. FA-induced immune responses were examined by the production of cytokines, expression of mRNAs, and distributions of helper T cells and regulatory T cells. Moreover, expression of calcineurin and NFATs, regulatory T cell-related signalling proteins, were evaluated. FA exposure suppressed Th2-, Th1-, and Th17-related splenic cytokines in a dose-dependent manner. mRNA expression of splenic cytokines was also decreased by FA exposure, which correlated with decreased cytokine expression. In parallel, FA exposure promoted T cell differentiation into regulatory T cells in a dose-dependent manner supported by the expression of calcineurin and NFAT1. Taken together, our results indicated that FA exposure increases the number of regulatory T cells via calcineurin-NFAT signalling, thereby leading to effector T cell activity suppression with decreased T cell-related cytokine secretion and mRNA expression. These findings provide insight into the mechanisms underlying the adverse effects of FA and accordingly have general implications for human health, particularly in occupational settings.

Elevation of Circulating Th17/Th22 Cells Exposed to Low-Level Formaldehyde and Its Relevance to Formaldehyde-Induced Occupational Allergic Contact Dermatitis.

OBJECTIVES: The aim of this study was to investigate the effects of formaldehyde exposure on Th17 and Th22 cells and its relevance to human occupational allergic contact dermatitis (OACD). METHODS: Circulating IL17-/IL22-secreting cells and serum IL17/IL22 levels in formaldehyde-exposed workers at Occupational Exposure Limit and nonexposed controls were assessed. RESULTS: The IL17 and IL22 cell population were detected in both CD3CD8 and CD3CD8 cells. The percentages of circulating IL17 and IL22 T cells in the workers with and without ACD history were all elevated, which were more remarkable in the ones with ACD history. Serum levels of IL17 and IL22 between the workers and controls were not significantly different. CONCLUSIONS: Low-level formaldehyde exposure may increase circulating IL17-/IL22-producing T cells (CD8 and CD8), possibly involved in the development of human OACD. But it may not alter serum levels of IL17/IL22 before the appearance of OACD symptoms.

Differential effects of formaldehyde exposure on airway inflammation and bronchial hyperresponsiveness in BALB/c and C57BL/6 mice.

Epidemiological evidence suggests that formaldehyde (FA) exposure may influence the prevalence and severity of allergic asthma. However, the role of genetic background in FA-induced asthma-like responses is poorly understood. In the present study, we investigated the nature and severity of asthma-like responses triggered by exposure to different doses of FA together with or without ovalbumin (OVA) in two genetically different mouse strains-BALB/c and C57BL/6. Both mouse strains were divided into two main groups: the non-sensitized group and the OVA-sensitized group. All the groups were exposed to 0, 0.5 or 3.0 mg/m3 FA for 6 h/day over 25 consecutive days. At 24 h after the final FA exposure, the pulmonary parameters were evaluated. We found that FA exposure induced Th2-type allergic responses in non-sensitized BALB/c and C57BL/6 mice. In addition, FA-induced allergic responses were significantly more prominent in BALB/c mice than in C57BL/6 mice. In sensitized BALB/c mice, however, FA exposure suppressed the development of OVA-induced allergic responses. Exposure to 3.0 mg/m3 FA in sensitized C57BL/6 mice also led to suppressed allergic responses, whereas exposure to 0.5 mg/m3 FA resulted in exacerbated allergic responses to OVA. Our findings suggest that FA exposure can induce differential airway inflammation and bronchial hyperresponsiveness in BALB/c and C57BL/6 mice.

Debunking the Myth of Wool Allergy: Reviewing the Evidence for Immune and Non-immune Cutaneous Reactions.

Although wool is commonly believed to cause irritant (non-immune) and hypersensitivity (immune) cutaneous reactions, the evidence basis for this belief and its validity for modern garments have not been critically examined. Publications from the last 100 years, using MEDLINE and Google Scholar, were analysed for evidence that wool causes cutaneous reactions, both immune-mediated (atopic dermatitis exacerbation, contact urticaria, allergic contact dermatitis) and non-immune-mediated (irritant contact dermatitis, itch). Secondary aims of this paper were to examine evidence that lanolin and textile-processing additives (formaldehyde, chromium) cause cutaneous reactions in the context of modern wool-processing techniques. Current evidence does not suggest that wool-fibre is a cutaneous allergen. Furthermore, contact allergy from lanolin, chromium and formaldehyde is highly unlikely with modern wool garments. Cutaneous irritation from wool relates to high fibre diameters (≥ 30-32 µm). Superfine and ultrafine Merino wool do not activate sufficient c-fibres to cause itch, are well tolerated and may benefit eczema management.

Sensitization to Formaldehyde in Northeastern Italy, 1996 to 2012.

BACKGROUND: Formaldehyde is a widely used organic compound, used in several applications (hard thermoset resins, adhesives, disinfectants, tissue fixatives, etc), in its free form or released by formaldehyde releaser products. Its use is under control due to its toxic, carcinogenic, and allergenic properties. OBJECTIVE: The aim of this study was to investigate the frequency of formaldehyde sensitization, time trend, and correlation to occupations. METHODS: This study is a cross-sectional study on a population of 23,774 patients tested from 1996 to 2012 in Northeastern Italy. RESULTS: Frequency of sensitization was 3.3%, without any significant time trend. Hands (39.8% overall) and face (25.6% females, 15.5% males) were mainly involved. We found a trend toward decrease by age in females (3.11% in first quintile [14-26 years], 2.29% in fifth quintile [59-97 years], P < 0.01). On a logistic regression analysis (control group: white-collar workers), we found associations in health care (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.04-1.81), wood (OR, 2.14; 95% CI, 1.30-3.51), and textile (OR, 1.79; 95% CI, 1.14-2.79) sectors and professional drivers (OR, 1.94; 95% CI, 1.05-3.60). We found a high rate of cosensitization to formaldehyde in patients with positive patch test reactions to quaternium-15 (OR, 18.7; 95% CI, 12.6-27.7). CONCLUSIONS: Sensitization to formaldehyde is relevant in our population, especially in the health care sector, wood and textile industries, and professional drivers. No significant time trend was found.

[Binding properties of components removable from dental base plate, analysed by Fourier-Transform Surface Plasmon Resonance (FT-SPR) method]. / Fogsor alaplemezbol kioldódó allergének kötodésének vizsgálata Fourier-Transzformációs Felületi Plazmon Rezonancia (FT-SPR) módszerrel.

In parallel with the emergence of new dental materials the number of allergic diseases is continuously increasing. Extremely small quantities of the allergens are capable to inducing an allergic reaction. Therefore it is particularly important to examine these materials as antigens and investigate their binding properties to proteins (e.g. formaldehyde, methacrylic acid, benzoyl-peroxide...). The Fourier Transform Surface Plasmon Resonance Spectroscopy (FT-SPR) is a suitable examination method for this type of procedure. FT-SPR measurement is performed at a fixed angel of incident light, and reflectivity is measured over a range of wavelength in the near infrared. The advantages of this method are the outstanding sensitivity, the label-free detection capability and the possibility of the real-time testing procedure. Formaldehyde and methacrylic acid are among the most common dental allergens. In our study we examined these molecules by FT-SPR spectroscopy. The aim of this work was to investigate the suitability of this method to the detection of these materials, with special focuses on the analysis and evaluation concentration-dependent measurements. Different concentrations (0.01 %-0.2%) of formaldehyde and methacrylic acid solutions were measured. The individual spectra were measured for all of the solutions, and calibration curves were calculated for the materials for the possibility of the determination of an unknown concentration. The results confirmed that the method is theoretically capable to detect hundred-thousandths scale concentration-changes in the solution flowing above the SPR-chip. The concentration-dependent studies had proved that the method capable to measure directly these materials and can provide appropriate calibration for quantitative determination. These experiments show the broad applicability of the FT-SPR method, which can greatly facilitate the mapping and understanding of biomolecular interactions in the future.

Effects of formaldehyde on lymphocyte subsets and cytokines in the peripheral blood of exposed workers.

Formaldehyde (FA) is a well-known irritant, and it is suggested to increase the risk of immune diseases and cancer. The present study aimed to evaluate the distribution of major lymphocyte subsets and cytokine expression profiles in the peripheral blood of FA-exposed workers. A total of 118 FA-exposed workers and 79 controls were enrolled in the study. High performance liquid chromatography, flow cytometry, and cytometric bead array were used to analyze FA in air sample and formic acid in urine, blood lymphocyte subpopulations, and serum cytokines, respectively. The FA-exposed workers were divided into low and high exposure groups according to their exposure levels. The results showed that both the low and high FA-exposed groups had a significant increase of formic acid in urine when compared to the controls. Both the low and high exposure groups had a significant increase in the percentage of B cells (CD19+) compared to the control group (p<0.01). A significant increase in the percentage of the natural killer (NK) cells (CD56+) was observed in the low exposure group compared to the control (p = 0.013). Moreover, the FA-exposed workers in both exposure groups showed a significant higher level of IL-10 but lower level of IL-8 than the control (p<0.01). Subjects in the high exposure group had a higher level of IL-4 but a lower level of IFN-γ than the control (p<0.05). Finally, there is a significant correlation between the levels of IL-10, IL-4, and IL-8 and formic acid (p<0.05). The findings from the present study may explain, at least in part, the association between FA exposure and immune diseases and cancer.

Allergy to formaldehyde: basophil histamine-release test is useful for diagnosis.

We describe a case of formaldehyde-induced urticaria with a positive test result for serum IgE antibody against this substance. Formaldehyde's slow protein-binding property may explain why basophil histamine-release tests using fresh formaldehyde solutions are not diagnostic, whereas the tests are useful if formaldehyde that had been stored with albumin is used.

Exacerbation of allergic diseases by chemicals: role of TSLP.

Environmental chemicals, such as cigarette smoke and diesel exhaust, have been reported as risk factors that exacerbate allergic diseases. However, the exacerbation mechanisms induced by these chemicals are not yet fully understood. Thymic stromal lymphopoietin (TSLP) is produced mainly by epithelial cells and plays an important role as a master switch of allergic inflammation because it promotes Th2-type immune responses by inducing the activation of dendritic cells. Chemical compounds, such as formalin, have been shown to bind to proteins and form a new antigen that induces allergic responses. A second group of chemicals that enhance allergic responses to exogenous proteins have also been reported. We recently demonstrated that some of these chemicals induced TSLP production and may potentially augment Th2-type allergic responses. We proposed that TSLP-producing chemical compounds should be recognized as chemical allegro-accelerators.

Protection against avian necrotic enteritis after immunisation with NetB genetic or formaldehyde toxoids.

NetB (necrotic enteritis toxin B) is a recently identified ß-pore-forming toxin produced by Clostridium perfringens. This toxin has been shown to play a major role in avian necrotic enteritis. In recent years, a dramatic increase in necrotic enteritis has been observed, especially in countries where the use of antimicrobial growth promoters in animal feedstuffs has been banned. The aim of this work was to determine whether immunisation with a NetB toxoid would provide protection against necrotic enteritis. The immunisation of poultry with a formaldehyde NetB toxoid or with a NetB genetic toxoid (W262A) resulted in the induction of antibody responses against NetB and provided partial protection against disease.

Role of transient receptor potential ion channels and evoked levels of neuropeptides in a formaldehyde-induced model of asthma in BALB/c mice.

OBJECTIVE: Asthma is a complex pulmonary inflammatory disease characterized by the hyper-responsiveness, remodeling and inflammation of airways. Formaldehyde is a common indoor air pollutant that can cause asthma in people experiencing long-term exposure. The irritant effect and adjuvant effect are the two possible pathways of formaldehyde promoted asthma. METHODOLOGY/PRINCIPAL FINDINGS: To explore the neural mechanisms and adjuvant effect of formaldehyde, 48 Balb/c mice in six experimental groups were exposed to (a) vehicle control; (b) ovalbumin; (c) formaldehyde (3.0 mg/m(3)); (d) ovalbumin+formaldehyde (3.0 mg/m(3)); (e) ovalbumin+formaldehyde (3.0 mg/m(3))+HC-030031 (transient receptor potential ankyrin 1 antagonist); (f) ovalbumin+formaldehyde (3.0 mg/m(3))+ capsazepine (transient receptor potential vanilloid 1 antagonist). Experiments were conducted after 4 weeks of combined exposure and 1-week challenge with aerosolized ovalbumin. Airway hyper-responsiveness, pulmonary tissue damage, eosinophil infiltration, and increased levels of interleukin-4, interleukin-6, interleukin-1ß, immunoglobulin E, substance P and calcitonin gene-related peptide in lung tissues were found in the ovalbumin+formaldehyde (3.0 mg/m(3)) group compared with the values seen in ovalbumin -only immunized mice. Except for interleukin-1ß levels, other changes in the levels of biomarker could be inhibited by HC-030031 and capsazepine. CONCLUSIONS/SIGNIFICANCE: Formaldehyde might be a key risk factor for the rise in asthma cases. Transient receptor potential ion channels and neuropeptides have important roles in formaldehyde promoted-asthma.

Reduced in vitro T-cell responses induced by glutaraldehyde-modified allergen extracts are caused mainly by retarded internalization of dendritic cells.

Although allergen-specific immunotherapy is a clinically effective therapy for IgE-mediated allergic diseases, the risk of IgE-mediated adverse effects still exists. For this reason, chemically modified allergoids have been introduced, which may destroy IgE-binding sites while T-cell activation should be retained. The aim of the study was to analyse the differences between intact allergens and differently modified/aggregated allergoids concerning their internalization as well as T-cell and basophil activation. For this purpose human monocyte-derived immature dendritic cells (DC) were incubated with Phleum pratense or Betula verrucosa pollen extract or with the corresponding allergoids, modified with formaldehyde or glutaraldehyde. After an additional maturation process, the antigen-loaded mature DC were co-cultured with autologous CD4(+) T cells. Allergenicity was tested by leukotriene release from basophils. In addition, the uptake of intact allergens and allergoids by immature DC was analysed. The proliferation of, as well as the interleukin-4 (IL-4), IL-10, IL-13 and interferon-γ production by, CD4(+) T cells which had been stimulated with glutaraldehyde allergoid-treated DC was reduced compared with CD4(+) T cells stimulated with intact allergen-treated or formaldehyde allergoid-treated DC. In line with this, glutaraldehyde-modified allergoids were more aggregated and were internalized more slowly. Furthermore, only the allergoids modified with glutaraldehyde induced a decreased leukotriene release by activated basophils. These findings suggest that IgE-reactive epitopes were destroyed more efficiently by modification with glutaraldehyde than with formaldehyde under the conditions chosen for these investigations. Glutaraldehyde-modified allergoids also displayed lower T-cell stimulatory capacity, which is mainly the result of greater modification/aggregation and diminished uptake by DC.

Evaluation of the skin sensitization potential of chemicals in THP-1/keratinocyte co-cultures.

Many attempts have been made to develop in vitro sensitization tests that employ dendritic cells (DCs), DC-like cell lines or keratinocytes. The aim of the present investigation was to establish a co-culture of THP-1 cells and keratinocytes for evaluation of skin sensitization potential of chemicals. Co-cultures were constructed by THP-1 cells cultured in lower compartments and keratinocytes cultured in upper compartments of cell culture inserts. After 24 h exposure to sensitizers (2, 4-dinitrochlorobenzene, p-phenylenediamine, formaldehyde, nickel sulfate, isoeugenol and eugenol) and non-sensitizers (sodium lauryl sulfate, benzalkonium chloride and lactic acid), the expression of CD86 and CD54 on THP-1 cells were evaluated by flow cytometry, and cell viabilities were determined. The sensitizers induced the augmentation of CD86 and CD54 expression, but the non-sensitizers had no significant effect. Compared with mono-cultures of THP-1 cells, the augmentation of CD86 and CD54 could be detected even at a non-toxic concentration of sensitizers in THP-1 cell/keratinocyte co-cultures. Moreover, isoeugenol was distinguished as a sensitizer in co-cultures, but failed to be identified in mono-cultures. These results revealed that the co-cultures of THP-1 cells and keratinocytes were successfully established and suitable for identifying sensitizers using CD86 and CD54 expression as identification markers.

Exposure to formaldehyde and its potential human health hazards.

A widely used chemical, formaldehyde is normally present in both indoor and outdoor air. The rapid growth of formaldehyde-related industries in the past two decades reflects the result of its increased use in building materials and other commercial sectors. Consequently, formaldehyde is encountered almost every day from large segments of society due to its various sources. Many governments and agencies around the world have thus issued a series of standards to regulate its exposure in homes, office buildings, workshops, public places, and food. In light of the deleterious properties of formaldehyde, this article provides an overview of its market, regulation standards, and human health effects.

Frequency of sensitization to common allergens: comparison between Europe and the USA.

BACKGROUND: Previously, contact allergy to formaldehyde and quaternium-15 was found to be more prevalent in the United States than in Europe. No such data have been assessed for other contact allergens. OBJECTIVE: Determine any differences in frequencies of sensitization to contact allergens in the United States and Europe. METHODS: Literature study. Comparison of reported frequencies of sensitization to contact allergens routinely tested both in the United States and Europe in recent, large, multicentre studies. Because of the heterogeneity of studies and background parameters, statistical evaluation was not attempted. RESULTS: Major differences were found only for neomycin (USA 10.0-11.8%, mean 11.4%; Europe 1.2-5.4%, mean 2.6%). Most allergens had somewhat higher prevalence in the United States, with rates versus Europe ranging from 1.3 to 1.9. CONCLUSIONS: Contact allergy to neomycin is much more prevalent in the United States. Stricter selection of patients for patch testing in United States tertiary referral centres may result in 50% more positive reactions compared to European studies.

[Two cases of eosinophilic gastroenteritis whose causative allergens are usefully diagnosed by patch test].

Case 1: 67-years-old woman with pollinosis noticed oppressive feeling of chest and back, and heart burn after accidental ingestion of her dental filling and dental treatment. Oral famotidine did not improve her symptom. Her peripheral blood eosinophils increased to 38.0%. As for the specific IgE, only cedar and cypress were positive. Case 2: a 42-years-old-woman with pollinosis and asthma repeated urticaria, heart burn, diarrhea and peripheral eosinophilia (25%). At her first visit to our department, her blood eosinophil increased to 52.9%, her serum IgG markedly increased in polyclonal pattern and overt all subclasses. The specific IgE was positive only for cypress. Because they revealed a remarkable infiltrates of eosinophils in the mucosa of alimentary tract, we diagnosed the 2 patient as eosinophilic gastroenteritis. In case 1, based on the history and patch-test-positive finding of formalin and 2-hydroxyethyl methacrylate, we diagnosed the two may be causative allergens. In case 2, based on the patch-test-positive finding of garlic and sesame and improvement after removal of the two allergens, we diagnosed the two may be causative allergens. Although causative allergens of eosinophilic gastroenteritis are almost unknown, some cases are reported to be determined the allergens of foods and drugs. In our cases, patch test was useful to identify the allergens.

Effectiveness and immunomodulation of chemotherapeutants against scuticociliate Philasterides dicentrarchi in olive flounder.

Philasterides dicentrarchi is a histophagous scuticociliate causes fatal scuticociliatosis in farmed olive flounder Paralichthys olivaceus. The average monthly prevalence of scuticociliatosis due to P. dicentrarchi infections was increased from May to July (40+/-3.1% to 79.4+/-1.7%) and it decreased from August to November (63+/-2.3% to 30+/-2.6%) in olive flounder farms at Jeju Island, South Korea during 2000-2006. The prevalence of mixed infection along with Vibrio spp. bacterial infection was 49+/-7.2% than that of other mixed infection. At present no effective control measure for P. dicentrarchi infection has been described and large production losses continue. In the present study, formalin, hydrogen peroxide and Jenoclean chemotheraputants were used for bath treatment. Among Jenoclean at a low concentration of 50ppm proved effective. The results were confirmed with in vitro motility assessments and morphological changes scoring system in P. dicentrarchi. On the other hand, similar trend was noted following hydrogen peroxide treatment at this concentration, but formalin was only moderately effective. Either hydrogen peroxide or Jenoclean are the promising compounds effective at low concentrations with short application time for P. dicentrarchi. Therefore, these substances were evaluated on day 10, 20 and 30 for their ability to enhance innate immune response and disease resistance against P. dicentrarchi in olive flounder after chemotheraputants bath treatment with 100ppm for 30min per day. All the tested immune parameters were enhanced by treatment with Jenoclean, but not formalin and hydrogen peroxide. These findings suggest that Jenoclean bath treatment can be used for ensuring the heath of cultured marine fish against internal parasites such as P. dicentrarchi.

Occupational contact allergy to formaldehyde and formaldehyde releasers.

BACKGROUND: Formaldehyde allergy is common and usually derives from formaldehyde-releasing biocides in cosmetic and other products. OBJECTIVES: To analyse patterns of patch test reactions to formaldehyde and formaldehyde-releasing compounds and the sources of sensitization. PATIENTS/METHODS: At the Finnish Institute of Occupational Health, we screened the patch test files for allergic reactions to formaldehyde and 12 formaldehyde-releasing compounds. All patients with contact allergy to any of the substances were included, and their records were reviewed. RESULTS: Between January 2001 and May 2007, we had patch tested 81 patients with formaldehyde allergy and 18 with independent allergy to some formaldehyde releaser. Of the formaldehyde allergies, 60 were new sensitizations, 25 of which were considered to be occupational. The most common source of occupational sensitization was metalworking fluids followed by creams and related products. Exposure to formaldehyde-releasing preservatives in liquid soaps and other rinse-off products was common in both occupational and non-occupational cases. Reactions to formaldehyde-releasing compounds were seen in 79% of the formaldehyde-allergic patients. CONCLUSIONS: Occupational formaldehyde allergy was common and occurred in metalworkers, hairdressers, masseurs, and workers using protective creams, detergents, and liquid soaps. When compared with studies on general dermatological patients, contact allergy to formaldehyde releasers without formaldehyde allergy was rare.

Contact hypersensitivity to selected excipients of dermatological topical preparations and cosmetics in patients with chronic eczema.

OBJECTIVE: 1) Assessment of the frequency of contact sensitization to selected excipients of dermatological topical preparations and cosmetics in patients with chronic eczema. 2) Detection of the sources of sensitization. METHODS: 1,927 patients with chronic eczema (mean age 44.3 years, 601 males, 1,326 females) were patch tested with selected excipients. RESULTS: The main rates of sensitization observed were: thiomersal 11.3%, wool alcohols 4.0%, phenylmercuric acetate 3.1%, formaldehyde 2.5%, dodecyl gallate 2.0%, Bronopol 1.9%, dibromodicyanobutane/ phenoxyethanol (1:4) 1.7%, chloracetamide 1.6%, chlorhexidine digluconate 1.5%, Kathon CG 1.4%, parabens 1.1%, diazolidinyl urea 0.9%, imidazolidinyl urea 0.7%, benzalkonium chloride 0.7%, and Quaternium-15 (quaternary ammonium salt) 0.7%. CONCLUSION: The rate of sensitization to the excipients included in dermatological topical preparations and cosmetics in patients with chronic eczema is significant. Complete information on all the ingredients is necessary.