Mast Cell Density Research Articles

Association Between Mast Cells and Collagen Maturation in Chronic Periodontitis in Humans.

Mast cells (MCs) can influence the maturation of collagen fibers. This study evaluated the relationship between the distribution and degranulation of MCs and collagen maturation in human gingival tissue in chronic periodontitis. A total of 16 specimens of patients clinically diagnosed as periodontitis and 18 controls clinically diagnosed as healthy or gingivitis were included. Immunohistochemistry and Picrosirius staining were performed to identify MCs and assess collagen fibers, respectively. Chi-square, t test, and Pearson's correlation test ( p<0.05) were used. In control specimens, there was a positive association between MCs in the connective tissue and the presence of immature collagen ( p=0.001); in periodontitis samples, this association was not confirmed ( p≥0.12). There was no significant relationship between periodontal diagnosis and collagen maturation or MC degranulation ( p≥0.35). MC density was significantly higher ( p=0.04) in periodontitis tissue (339.01 ± 188.94 MCs/mm2) than in control tissue (211.14 ± 131.13 MCs/mm2) in the area of connective tissue containing inflammatory infiltrate. There was a correlation between the number of MCs and probing depth ( r = 0.34, p=0.04). MCs are involved in the pathogenesis of periodontal diseases and might be associated with collagen maturation in periodontal tissue during the early stages of periodontal disease pathogenesis.

The distribution and heterogeneity of mast cells in tongue from five different avian species.

This study was conducted with the aim of determining the morphology, distribution and heterogeneity of mast cells in the tongues of seagull (Larus fuscus), common buzzard (Buteo buteo), goose (Anser anser), white stork (Ciconia ciconia) and Gerze rooster. The study used five samples of tongue material from each of the healthy adult avian species. The samples were fixed in 10% neutral-buffered formalin (NBF) solution, then, after routine tissue follow-up, the samples blocked with paraplast. Cross-sections with 5-6μm of thickness were stained with the 0.5% toluidine blue and alcian blue/safranin O (AB/SO). In all five avian species, it was found that the mast cells were in different sizes and round, oval or spindle-shaped based on their place of distribution. Mast cell numbers were determined in stained with toluidine blue, examined ×40 objectives in a 1mm2 area. It was observed that mast cell density in subepithelial lamina propria and microscopic papilla was higher in the tongues of all species. Mast cell distribution and heterogeneity varied through the tongue, and there were more mast cells in the dorsal side of the tongue than the ventral side. The highest amount of mast cells was found in the tongue of the Gerze rooster among all five species. In the tongue cross-sections stained with the combined method of alcian blue/safranin O (AB/SO), the mast cells were stained as AB (+), SO (+) and AB/SO (+) (mixed).

Detailed analysis of inflammatory cell infiltration and the prognostic impact on nasopharyngeal carcinoma.

One of the most striking characteristics of nasopharyngeal carcinoma (NPC) is the presence of a very abundant immune cells infiltrate containing mainly T-lymphocytes. The purpose of this study was to present our analysis providing a comprehensive characterization of antitumor inflammatory response in NPC. The densities of 9 types of inflammatory cells were assessed in 197 patients with NPC, including CD3 + T-lymphocytes, CD8 + cytotoxic T-lymphocytes, CD20 + B-lymphocytes, CD56 + natural killer (NK) cells, FOXP3 + regulatory T-lymphocytes, CD1a + immature dendritic cells, CD83 + mature dendritic cells, neutrophil elastase + neutrophils, and tryptase + mast cells. We characterized the inflammatory infiltrate in relation to clinical stage and patient survival. The expression of programmed death-1 (PD-1) on tumor-infiltrating lymphocytes (TILs) was also detected. The correlations between PD-1 expression and clinical characteristics and posttreatment outcome were analyzed. The patients with NPC with a low density of tumor-infiltrating FOXP3+, CD8 + T-lymphocytes, neutrophils, and mast cells showed a significantly longer overall survival (OS) and progression-free survival (PFS). However, patients with a high density of NK cells showed a better OS and PFS. The densities of NK cells and mast cells could be served as biomarkers for predicting recurrence or distant metastasis in patients with NPC. Moreover, PD-1 positivity predicted poor prognosis in patients with NPC. The densities of inflammatory cells are correlated with the prognosis of patients with NPC.

Effects of benzo[a]pyrene on the blood and liver of Physalaemus cuvieri and Leptodactylus fuscus (Anura: Leptodactylidae)

Benzo[a]pyrene (BaP) is a bio-accumulative toxic compound found in the atmosphere, water, and soil that may affect the life cycle of amphibians. In this study, a few contamination biomarkers, such as hepatic melanomacrophages (MMs), mast cells, erythrocyte micronuclei (MN) and white blood cells were used to determine how BaP acts in these cells in the anurans Physalaemus cuvieri and Leptodactylus fuscus. Animals of both species were divided into three treatment groups: 1 day, 7 days and 13 days, subcutaneously injected 2 mg/kg BaP diluted in mineral oil and control group with only mineral oil. After 7 days, BaP caused the frequency of MN to increase in both species while reducing melanin area. The micronucleus frequency increased due to the genotoxicity of BaP, while the decreasing melanin area may be related to the inhibition of tyrosinase activity, an enzyme responsible for regulating melanogenesis, decreasing the synthesis of melanin. The mast cell density increased in all groups and in both species as a response to the inflammatory action of BaP. These cells respond to nonspecific inflammatory effects leading, therefore, to this response in all treatments. The percentage of leukocytes remained unchanged probably due to great intraspecific variability. Additionally, the leukocyte profiles of both species were characterized and the differences were attributed to extrinsic factors. In short, BaP can affect the integrity of several organs and tissues, and cell functions leading to the conclusion that this compound is hepatotoxic, genotoxic and immunotoxic for anurans.

Quantitative analysis of mast cell count and density in chronic periodontal disease.

Background:Mast cells play a crucial role in activation of acquired immune response to inflammatory conditions of periodontal diseases. They promote inflammation by releasing pro-inflammatory mediators and bring about angiogenesis, degeneration of the extracellular matrix, and tissue remodeling. Since there is little literature regarding the role of mast cells in periodontitis, the present study was aimed to evaluate mast cell count (MCC) and density in periodontitis.Materials and Methods:A total of eighty participants, Group I (n = 40) healthy participants and Group II (n = 40) participants with moderate chronic periodontitis, were included in the study. Tissue samples of 5 micron were obtained from each participant and were fixed in 10% formalin. Inflammation assessment was carried out after staining the sections with hematoxylin/eosin (H and E) followed by toluidine blue and mast cells were counted.Results:MCC in healthy group (1.32 ± 0.43) was significantly smaller than periodontitis group (10.28 ± 1.15) and also mast cell density in healthy group (98.08 ± 37.40) was smaller than periodontitis group (803.43 ± 89.94) with P < 0.0001.Conclusions:It could be concluded that participants with chronic periodontitis have a higher MCC and density when compared with healthy participants.

Immunohistochemical evaluation of tumor angiogenesis and the role of mast cells in oral squamous cell carcinoma.

Increased angiogenesis has been associated with neoplastic progression, metastasis and outcome in several studies and in a number of malignancies. Among the various host immune cells, mast cells have been implicated in tumor progression by promoting angiogenesis. The aim of this study is to examine the relationship between angiogenesis, mast cells with that of the normal oral mucosa (NOM) and oral squamous cell carcinoma (OSCC). The study was conducted using routine haematoxylin and eosin staining procedure and included immunohistochemical staining for microvessels and toluidine blue staining for mast cells. The microvessel density (MVD) and mast cell density (MCD) of two groups (NOM and OSCC). The MVD and MCD in OSCC ranged from 59.18 to 263.31 microvessel/mm 2 and 41.65 to 193.28 cells/mm 2 respectively with mean (±standard deviation) 161.73 ± 48.27 microvessel/mm 2 and 83.59 ± 40.67 cells/mm 2. In both NOM and OSCC, the mean MCD was comparatively lower as compared to respective MVD (MCD < MVD) and comparatively lower in NOM as compared to OSCC (normal < OSCC). A significant correlation is present between MCD and MVD in OSCC and also that both these entities are significantly increased in the disease process when compared to that of the NOM.

Density of mast cells and intensity of pruritus in psoriasis vulgaris: a cross sectional study

Background:Psoriasis is a chronic and prevalent disease, and the associated pruritus is a common, difficult-to-control symptom. The mediators involved in psoriatic pruritus have not been fully established. Objective:To evaluate associations between the number of mast cells in psoriatic lesions and the intensity of pruritus. Methods:29 patients with plaque psoriasis were recruited. In all participants, Psoriasis Area and Severity Index and Body Surface Area were assessed. A questionnaire was administered to obtain clinical information and the Dermatology Life Quality Index. Pruritus was assessed using a visual analog scale and skin biopsies were performed for staining with Giemsa and Immunohistochemistry with C-Kit. Results:Pruritus was observed in 91.3% of our patients. Median VAS was 6 (p25-75: 2-8). The immunohistochemical method revealed a mean of 11.32 mast cells/field and Giemsa staining revealed a mean of 6.72 mast cells/field. There was no correlation between the intensity of pruritus and mast cell count, neither in Immunohistochemistry (p = 0.15; rho = -0.27) nor in Giemsa (p = 0.16; rho = -0.27). Pruritus did not impact on the Dermatology Life Quality Index (p = 0.51; rho = -0.13). Study limitations:The small sample size may be considered the main limitation of our study. Conclusions:Although mast cells are mediators of pruritus in many cutaneous diseases, our findings support that psoriatic pruritus is a complex disorder with multifactorial, complex pathophysiology, involving pruritogenic mediators others than mast cells.

Mast Cell Density and Lymph Node Metastasis in Gastric Carcinoma: Inferring the Role of Mast Cells in the Metastatic Cascade

Mast Cell Density and Lymph Node Metastasis in Gastric Carcinoma: Inferring the Role of Mast Cells in the Metastatic Cascade

Quantitative assessment of tumor-associated tissue eosinophilia and mast cells in tumor proper and lymph nodes of oral squamous cell carcinoma.

Background:Oral squamous cell carcinoma (OSCC) is the most common cancer of the oral cavity. Tumor stage, thickness, lymph node metastasis (LNM), extranodal spread, perineural invasion, tumor differentiation, mutations, human papillomavirus infection and tumor microenvironment are independent prognostic indicators of OSCC. However, clinically, among all factors, LNM is considered an important prognostic factor in OSCC as it not only determines the stage of disease but also the strongest independent factor which predicts recurrence of disease. Further research proves that there are several biologically important factors in tumor tissue and LNs which promote or defend LNM. While it is proposed that tumor-associated tissue eosinophils (TATE) and mast cells (MCs) have “immuno-protective” effect, this remains unproven and various researchers have conflicting opinion.Aim:The aim is to determine the presence of TATE and MCs in OSCC and to evaluate if any association exists between them and LNM.Study Design:It is a comparative retrospective study between two groups including 35 OSCC cases positive and 35 negative for LNM.Materials and Methodology:Quantification of cells was done by counting total number of cells in 10 high-power fields under ×40 objective lens using “zigzag” method and dividing it by total number of fields. Eosinophils stained bright red with carbol chromotrope and MCs purple-violet with toluidine blue.Statistics:Independent t-test and Pearson's correlation were done using STATA IC 0.2 software. The level of significance was at 5%. Comparison of eosinophil and MC infiltration was done based on gender, metastatic, nonmetastatic LN and in tumor proper.Results and Conclusion:Our study showed weak positive correlation between mean eosinophils count in tumor and LNs which implies a definite association between the microenvironment of tumor, its progression and LNM. There was a significant association between MC density and decreased LNM also. We conclude that an increased number of immunological cells (TATE and MCs) are a favorable prognostic indicator in OSCC. There is evidence of reduction in LNM with increasing density of these immunological cells. Recognition of TATE and MCs as integral to tumor biology opens an avenue for novel approaches to cancer therapies.

Histopathological evaluation of skin in cirrhotic patients with pruritus

Background: Cirrhosis often is a silent disease Clinical symptoms at presentation may include jaundice of the eyes or skin, pruritus, gastrointestinal bleeding, coagulopathy, increasing abdominal girth, and mental status changes. Pruritus may be the presenting symptom, arising years before any other classic clinical and laboratory markers of hepatic dysfunction. This study examines the clinical, laboratory and histopathological changes in the skins of cirrhotic patients with pruritus in comparison with cirrhotic patients without pruritus and healthy control skins . Patients and Methods: To evaluate clinical, laboratory and histopathological changes in cirrhotic patients with pruritus, cirrhotic patients without pruritus and corresponding healthy (control). skin biopsies (20 specimens each) using hematoxylin and eosin stain and to study mast cell density using gimesa stain. Results: In the skin biopsy specimens of the cirrhotic patients with pruritus we found several histological changes including: epidermal hyperplasia (acanthosis) ,vascular ectasia(dilated dermal blood vessels), hypertrophied dermal nerve endings, mixed inflammatory cellular infilterate and lymphocytic vasculopathy (swelling of the endothelial cell lining of the blood vessels without fibrinoid necrosis, leucocytoclasia or extravasation of red blood cells). Evaluation of mast cell count in Gimesa stained skin sections revealed an increased numbers of these cells in the group of cirrhotic patients with pruritus ( N=5-10). The cells noted in perivascular, perineural and interstitial distribution (between collagen bundles). Conclusions: We report, for the first time, some histopathologial changes in the skins of cirrhotic patients with pruritus in comparison with cirrhotic patients without pruritus and healthy control skins .

Role of Mast Cells in Oral Lichen Planus and Oral Lichenoid Reactions.

Introduction Oral lichen planus (OLP) is a chronic T cell mediated disease of oral mucosa, skin, and its appendages with a prevalence of 0.5 to 2.6% worldwide. Oral lichenoid reactions (OLR) are a group of lesions with diverse aetiologies but have clinical and histological features similar to OLP, thereby posing a great challenge in differentiating both lesions. Mast cells are multifunctional immune cells that play a major role in the pathogenesis of lichen planus by release of certain chemical mediators. Increased mast cell densities with significant percentage of degranulation have been observed as a consistent finding in pathogenesis of oral lichen planus. Aim The current study was aimed at quantifying the mast cells in histopathological sections of OLP and OLR thereby aiding a means of distinguishing these lesions. Materials and Methods The study group involved 21 cases of oral lichen planus, 21 cases of oral lichenoid reactions, and 10 control specimens of normal buccal mucosa. All the cases were stained with Toluidine Blue and routine haematoxylin and eosin and the mast cells were quantified. Statistical Analysis Used The results were analyzed using the Kruskal–Wallis test and an intergroup analysis was performed using Mann–Whitney U test. Conclusion The number of mast cells showed an increased value in oral lichen planus when compared to oral lichenoid reaction and thus an estimation of mast cells count could aid in distinguishing OLP from OLR histopathologically.

C-Kit receptor and tryptase expressing mast cells correlate with angiogenesis in breast cancer patients.

C-Kit protein is a transmembrane tyrosine kinase (TK) receptor (c-KitR-TK), which is predominantly expressed on mast cells (MCs) playing a role in tumor angiogenesis. It could be also expressed on epithelial breast cancer cells (EBCCs), but no data have been published regarding the correlation between mast cells positive to c-KitR (MCs-c-KitR), EBCCs positive to c-KitR (EBCCs-c-KitR), BC angiogenesis in terms of microvessel density (MVD) and the main clinic-pathological features. This study aims to evaluate the above parameters and their correlations in a series of selected 121 female early BC patients. It has been found a strong correlation between MVD and MCDPT, and MCs-c-KitR, MVD and MCs density positive to tryptase (MCDPT), and MCs-c-KitR and MCDPT by Pearson correlation. These data suggest an involvement of both MCDPT and MCs-c-KitR in BC tumor angiogenesis. Furthermore, BC tissue expressing c-KitR could be a putative predictive factor to c-KitR-TK inhibitors. In this way, selected patients with higher MCs-c-KitR could be candidate to receive c-KitR-TK inhibitors (e.g. masitinib, sunitinib) or tryptase inhibitors (e.g. nafamostat mesilate, gabexate mesilate).

The Effect of Smoking on Mast Cells Density and Angiogenesis in Chronic Periodontitis

Gingival bleeding reduction in smokers has been associated with decreased blood vessel density. The mechanism of suppressive effect of cigarette smoking on blood vessel density is not precisely defined. The aim of this study was to evaluate the impact of smoking on angiogenesis by assessing mast cells density and VEGF expression in chronic periodontitis. 52 paraffin embedded block of gingiva tissues with periodontitis obtained from 30 nonsmokers and 22 smokers undergoing flap surgery were examined immunohistochemically for VEGF expression. Mast cell counts was completed on toluidine blue stained slides. Exposure to cigarette smoking was calculated by the number of packs × year. Patients were classified into 4 groups based on the number of smoked cigarettes. The correlation between VEGF expression and mast cell counts was evaluated and compared in nonsmokers and smokers. The mean number of mast cells (p=0.004) and average value of VEGF expression (p = 0.000) in nonsmokers was significantly higher than smokers. No correlation was noted between VEGF expression / mast cell counts and number of smoked cigarettes in four groups of smokers (p=0.29,0.12 , 0.20 and 0.11, respectively). Mast cells and VEGF expression may account for suppressive effect of cigarette smoking on blood vessels in periodontitis.

85. Digital acuity measured by “the bumps” device correlates with degeneration of digital mechanoreceptors in peripheral neuropathies

“The bumps” is a sensitive test to quantify tactile threshold of fingerpads. We tested its ability to detect distal axonal degeneration in peripheral neuropathies. The bumps device is a checkerboard-like surface divided into squares. Each square includes 5 colored circles, one of which contains a round bump (height range 2.5–14 μm) to identify using the fingerpad. For each subject, we defined the height of the lowest bump such that it and the next 2 highest were detected. Functional data were compared to the density of Meissner corpuscles (MC) in fingertip skin biopsies processed and quantified according to standard procedures. Study population included 86 subjects (M/F = 51/35; age = 52.3 ± 15.1) affected by peripheral neuropathy and 15 subjects (M/F = 9/6; age = 50.4 ± 13.9) affected by CNS pathology as control group. Average threshold in the neuropathy group was 7.0 ± 4.4 μm, average MC density was 9.3 ± 7.3/mm2. Average threshold in the CNS pathology group was 7.4 ± 5.1 μm and average density of MC was 10.5 ± 6.8/mm2. Digital acuity threshold correlated with the density of Meissner corpuscles in the neuropathy group (r = 0.353; p < 0.01), but not in the CNS pathology group (r = 0.048; p = 0.865). The Bumps is a sensitive and easy-to-use tool, suitable to detect degeneration of sensory endings in peripheral neuropathies.

High mast cell density indicates a longer overall survival in oral squamous cell carcinoma

This study evaluates the effects of tumour-associated mast cells on the prognosis of patients suffering from oral squamous cell carcinoma (OSCC). Tryptase-positive (MCT+) and CD117-positive (CD117+) mast cells were immunohistochemically evaluated in tissue samples of 118 OSCC patients. Besides, various clinicopathological parameters, the influence of the MCT+ and CD117+ mast cell density on overall survival and the incidence of first local recurrence was analysed by Cox regression and competing risk regression. Among all investigated parameters, multiple Cox regression revealed a significant influence of the MCT+ (cut-off at 14.87 mast cells/mm2 stroma; p = 0.0027) and CD117+ mast cell density (cut-off at 33.19 mast cells/mm2 stroma; p = 0.004), the age at primary diagnosis, and the T and N stage (all p-values < 0.05) on overall survival. Patients with a low mast cell density showed a significantly poorer overall survival rate compared to those with a high mast cell density in the tumour-associated stroma. Competing risk regression revealed a significant influence of the resection status (R) on the incidence of first local recurrence (p = 0.0023). A high mast cell density in the tumour-associated stroma of oral squamous cell carcinoma indicates a longer patient survival.

The safety and efficacy of light emitting diodes-based ultraviolet A1 phototherapy in bleomycin-induced scleroderma in mice

PurposeTo define the efficacy and safety of narrowband ultraviolet A1 (UVA1) for the treatment of dermal fibrosis in bleomycin-induced mouse model of scleroderma. Materials and methods42 DBA/2 strain mice were included in the study: healthy mice and mice with established scleroderma, treated with high or medium dose of UVA1. Non-treated groups served as control. The equipment emitting 365±5nm UVA1 radiation was used in the study. The average cumulative doses were 1200J/cm2 for high and 600J/cm2 for medium dose course. Histological analysis was performed for the evaluation of the dermal thickness and mast cells density. The expressions of p53 and Ki-67 proteins were assessed by immunohistochemical analyses. ResultsSkin thickness of mice with scleroderma, treated with high and medium dose of UVA1, were lower (272.9±113.2μm and 394±125.9μm, respectively) in comparison to the dermal thickness of non-treated animals (599±55.7μm). The dermal mast cells count in mice with scleroderma was reduced after high and medium dose treatment to 11±1.7 and 13±2.2, respectively, as compared to that in non-treated mice (23±3.0). No significant upregulation of p53 nor Ki-67 proteins was observed in the skin of healthy mice and mice with scleroderma after high- and medium-dose of UVA1. ConclusionsThe results of this study indicate that 365nm UVA1 with the cumulative doses of 1200J/cm2 and 600J/cm2 is safe and effective for the dermal fibrosis treatment.

Evaluation of Mast Cell Density in the Tumor Microenvironment in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma.

The objective of this study was to compare mast cell density (MCD) in oral epithelial dysplasias (OED) and oral squamous cell carcinoma (OSCC) and determine its correlation with clinical and histopathologic parameters and the degree of tumor differentiation. Thirty OSCC samples, 14 OED samples, and 4 non-neoplastic oral mucosa samples were analyzed by immunohistochemistry to determine MCD based on the expression of MC tryptase. In addition, MCs were categorized morphologically into degranulated and granulated cells. MCD was significantly higher in OSCC lesions with a greater degree of differentiation (P=0.04). No significant difference in MCD was detected between mild and moderate OED samples (P=0.09). Our findings indicate that MCs are present in the tumor microenvironment and may be associated with a better prognosis.

Digital quantitative analysis of mast cell infiltration in interstitial cystitis.

To evaluate the significance of mast cell infiltration in interstitial cystitis (IC) by comparison with equally inflamed controls using a digital quantification technique. Bladder biopsy specimens from 31 patients with Hunner type IC and 38 patients with non-Hunner type IC were analyzed. Bladder biopsy specimens from 37 patients without IC, including 19 non-specific chronic cystitis ("non-IC cystitis") specimens and 18 non-inflamed bladder ("normal bladder") specimens, were used as controls. Mast cell tryptase-, CD3-, CD20-, and CD138-immunoreactive cells were quantified using digital image analysis software to evaluate both mast cell and lymphoplasmacytic cell densities. Mast cell and lymphoplasmacytic cell densities were counted independently in the entire lamina propria and detrusor areas and compared among the four groups. In the lamina propria, there were no significant differences in mast cell and lymphoplasmacytic cell densities between Hunner type IC and non-IC cystitis or between non-Hunner type IC and normal bladder specimens. In the detrusor, the mast cell densities were not significantly different among the four groups. Mast cell density was correlated with lymphoplasmacytic cell density, but not with clinical parameters. Mast cell density is not significantly different between IC specimens and non-IC control specimens with a similar degree of background inflammation. The intensity of mast cell infiltration generally correlated with that of lymphoplasmacytic cells. We conclude that mast cell count is of no value in the differential diagnosis between IC and other etiologies.

MicroRNAs expression pattern related to mast cell activation and angiogenesis in paraffin-embedded salivary gland tumors

The aim of this study was evaluate the expression profile of microRNAs related to mast cells activation and angiogenesis in salivary glands tumors. Method. We have analyzed the expression of miR-9, miR-16, miR-17, miR-132, miR-195 and miR-221 by real-time RT-PCR, in 11 adenoid cystic carcinomas, 9 mucoepidermoid carcinomas and 11 pleomorphic adenomas. Immunohistochemical investigation was performed to detect mast cells tryptase and CD-34 for microvessels biomarkers. miR-16, miR-17, miR-132, miR-195 and miR-221 showed a decreased expression, whereas miR-9 showed an increased expression in most cases compared to normal tissues. However, in all tumors studied only miR-9 showed a statistical significant negative correlation with microvessel density (p=0.001). It was observed a higher density of mast cells in mucoepidermoid carcinomas (10.55 cells/mm2) when compared to adenoid cystic carcinomas (6.27 cells/mm2) and between mucoepidermoid carcinomas and pleomorphic adenomas (5.97células/mm2). miR-17, miR-132, miR-195 and miR-221 seem to play an important role as tumor suppressor in salivary gland tumors. In addition, the significant correlation between mast cell and microvessel density contributes to the growth and pathogenesis of these tumors and they may become strong therapeutic targets in the future.

Late-gestation maternal dietary methyl donor and cofactor supplementation in sheep partially reverses protection against allergic sensitization by IUGR.

Perinatal exposures are associated with altered risks of childhood allergy. Human studies and our previous work suggest that restricted growth in utero (IUGR) is protective against allergic disease. The mechanisms are not clearly defined, but reduced fetal abundance and altered metabolism of methyl donors are hypothesized as possible underlying mechanisms. Therefore, we examined whether late-gestation maternal dietary methyl donor and cofactor supplementation of the placentally restricted (PR) sheep pregnancy would reverse allergic protection in progeny. Allergic outcomes were compared between progeny from control pregnancies (CON; n = 49), from PR pregnancies without intervention (PR; n = 28), and from PR pregnancies where the dam was fed a methyl donor plus cofactor supplement from day 120 of pregnancy until delivery (PR + Methyl; n = 25). Both PR and PR + Methyl progeny were smaller than CON; supplementation did not alter birth size. PR was protective against cutaneous hypersensitivity responses to ovalbumin (OVA; P < 0.01 in singletons). Cutaneous hypersensitivity responses to OVA in PR + Methyl progeny were intermediate to and not different from the responses of CON and PR sheep. Cutaneous hypersensitivity responses to house dust mites did not differ between treatments. In singleton progeny, upper dermal mast cell density was greater in PR + Methyl than in PR or CON (each P < 0.05). The differences in the cutaneous allergic response were not explained by treatment effects on circulating immune cells or antibodies. Our results suggest that mechanisms underlying in utero programming of allergic susceptibility by IUGR and methyl donor availability may differ and imply that late-gestation methyl donor supplementation may increase allergy risk.