COVID-19 vaccination of patients with allergies and type-2 inflammation with concurrent antibody therapy (biologicals) - A Position Paper of the German Society of Allergology and Clinical Immunology (DGAKI) and the German Society for Applied Allergology (AeDA).

BACKGROUND: After the beginning and during the worldwide pandemic caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), patients with allergic and atopic diseases have felt and still feel insecure. Currently, four vaccines against SARS-CoV-2 have been approved by the Paul Ehrlich Institute in Germany, and vaccination campaigns have been started nationwide. In this respect, it is of utmost importance to give recommendations on possible immunological interactions and potential risks of immunomodulatory substances (monoclonal antibodies, biologicals) during concurrent vaccination with the approved vaccines. MATERIALS AND METHODS: This position paper provides specific recommendations on the use of immunomodulatory drugs in the context of concurrent SARS-CoV-2 vaccinations based on current literature. RESULTS: The recommendations are covering the following conditions in which biologicals are indicated and approved: 1) chronic inflammatory skin diseases (atopic dermatitis, chronic spontaneous urticaria), 2) bronchial asthma, and 3) chronic rhinosinusitis with nasal polyps (CRSwNP). Patients with atopic dermatitis or chronic spontaneous urticaria are not at increased risk for allergic reactions after COVID-19 vaccination. Nevertheless, vaccination may result in transient eczema exacerbation due to general immune stimulation. Vaccination in patients receiving systemic therapy with biologicals can be performed. Patients with severe asthma and concomitant treatment with biologicals also do not have an increased risk of allergic reaction following COVID-19 vaccination which is recommended in these patients. Patients with CRSwNP are also not known to be at increased risk for allergic vaccine reactions, and continuation or initiation of a treatment with biologicals is also recommended with concurrent COVID-19 vaccination. In general, COVID-19 vaccination should be given within the interval between two applications of the respective biological, that is, with a time-lag of at least 1 week after the previous or at least 1 week before the next biological treatment planned. CONCLUSION: Biologicals for the treatment of atopic dermatitis, chronic spontaneous urticaria, bronchial asthma, and CRSwNP should be continued during the current COVID-19 vaccination campaigns. However, the intervals of biological treatment may need to be slightly adjusted (DGAKI/AeDA recommendations as of March 22, 2021).

Distinct Expression and Function of FcεRII in Human B Cells and Monocytes.

FcεRII is a multifunctional low-affinity IgER that is involved in the pathogenesis of allergic, inflammatory, and neoplastic diseases. Although discrepancies in FcεRII-mediated functions are being increasingly recognized, the consequences of FcεRII activation are not completely understood. In this study, we evaluated the expression of FcεRII on human blood cells and found that it was primarily expressed on monocytes and B cells. Although IL-4 promoted expression of the FcεRIIb isoform on B cells and monocytes, the expression of the FcεRIIa isoform was not dependent on IL-4. Furthermore, FcεRII predominantly bound allergen-IgE complexes on B cells but not on monocytes. FcεRII-mediated allergen-IgE complex uptake by B cells directed Ags to MHC class II-rich compartments. FcεRII-bearing monocytes and B cells expressed high levels of the FcεRII sheddase a disintegrin and metalloproteinase 10, which implies that they are important sources of soluble FcεRII. Moreover, we identified that IgE immune complex stimulation of FcεRII activated intracellular tyrosine phosphorylation via Syk in B cells but not in monocytes. Importantly, FcεRII-mediated signaling by allergen-IgE immune complexes increased IFN-γ production in B cells of allergic patients during the build-up phase of allergen-specific immunotherapy. Together, our results demonstrate that FcεRII mediates cell type-dependent function in allergic reactions. In addition, the results identify a novel allergen-IgE complex/FcεRII/Syk/IFN-γ pathway in allergic responses and suggest that FcεRII may play a role in regulating allergic reactions via modulating IFN-γ production in B cells.

Cellular Distribution and Gene Expression Pattern of Metastasin (S100A4), Calgranulin A (S100A8), and Calgranulin B (S100A9) in Oral Lesions as Markers for Molecular Pathology.

The objective of this study was to analyze cellular localization and expression levels of oncologic relevant members of the S100 family in common oral lesions.Biopsies of various oral lesions were analyzed. S100A4 showed a higher expression rate in leukoplakias and oral squamous cell carcinomas. Transcript levels of S100A8 and S100A9 were significantly decreased in malignant OSCCs. A correlation could be drawn between the expression levels of these genes and the pathological characteristics of the investigated lesions. S100A4, A8, and A9 proteins represent promising marker genes to evaluate the risk potential of suspicious oral lesions in molecular pathology.

Pin p 1 is a major allergen in pine nut and the first food allergen described in the plant group of gymnosperms.

This study aimed to report the complete sequence of a 2S albumin purified from pine nut and to analyze its allergenic properties. Individual recognition of this protein by serum IgE from pine nut-allergic patients was assessed. IgE cross-linking capacity was analyzed in a basophil activation test. Inhibition of IgE-binding and stability to heating was also assessed. The complete nucleotide sequence was obtained and a phylogenetic study was carried out. 2S albumin from pine nut (registered as Pin p 1.0101) was recognized by IgE of 75% of sera. The allergen was heat-stable and had a robust capacity to inhibit IgE-binding to whole pine nut extract. The IgE cross-linking capacity of Pin p 1 on basophils was also demonstrated. Despite the low homology of Pin p 1 sequence with other allergenic 2S albumins from angiosperms, Pin p 1 contains the typical skeleton of 8 cysteine residues, important for its α-helixes enriched structure.

Ghrelin promotes oral tumor cell proliferation by modifying GLUT1 expression.

In our study, ghrelin was investigated with respect to its capacity on proliferative effects and molecular correlations on oral tumor cells. The presence of all molecular components of the ghrelin system, i.e., ghrelin and its receptors, was analyzed and could be detected using real-time PCR and immunohistochemistry. To examine cellular effects caused by ghrelin and to clarify downstream-regulatory mechanisms, two different oral tumor cell lines (BHY and HN) were used in cell culture experiments. Stimulation of either cell line with ghrelin led to a significantly increased proliferation. Signal transduction occurred through phosphorylation of GSK-3ß and nuclear translocation of ß-catenin. This effect could be inhibited by blocking protein kinase A. Glucose transporter1 (GLUT1), as an important factor for delivering sufficient amounts of glucose to tumor cells having high requirements for this carbohydrate (Warburg effect) was up-regulated by exogenous and endogenous ghrelin. Silencing intracellular ghrelin concentrations using siRNA led to a significant decreased expression of GLUT1 and proliferation. In conclusion, our study describes the role for the appetite-stimulating peptide hormone ghrelin in oral cancer proliferation under the particular aspect of glucose uptake: (1) tumor cells are a source of ghrelin. (2) Ghrelin affects tumor cell proliferation through autocrine and/or paracrine activity. (3) Ghrelin modulates GLUT1 expression and thus indirectly enhances tumor cell proliferation. These findings are of major relevance, because glucose uptake is assumed to be a promising target for cancer treatment.

Allergenic properties and differential response of walnut subjected to processing treatments.

The aim of this study was to investigate changes in walnut allergenicity after processing treatments by in vitro techniques and physiologically relevant assays. The allergenicity of walnuts subjected to high hydrostatic pressure and thermal/pressure treatments was evaluated by IgE-immunoblot and antibodies against walnut major allergen Jug r 4. The ability of processed walnut to cross-link IgE on effector cells was evaluated using a rat basophil leukaemia cell line and by skin prick testing. Susceptibility to gastric and duodenal digestion was also evaluated. The results showed that walnuts subjected to pressure treatment at 256 kPa, 138 °C, were able to diminish the IgE cross-linking capacity on effector cells more efficiently than high pressure treated walnuts. IgE immunoblot confirmed these results. Moreover, higher susceptibility to digestion of pressure treated walnut proteins was observed. The use of processed walnuts with decreased IgE binding capacity could be a potential strategy for walnut tolerance induction.

Verification of IL-17A and IL-17F in oral tissues and modulation of their expression pattern by steroid hormones.

Interleukin (IL-) 17A and IL-17F mediate immune responses by inducing both proinflammatory and regulatory mechanisms. Immunological processes are modulated by steroids, which also affect periodontal pathophysiology. It was the aim of this study to investigate the expression profile of IL-17A and IL-17F in periodontal tissues and to analyze the significance of testosterone and estradiol on IL-17 expression in periodontal cells. In vivo incidence of IL-17A and IL-17F was immunohistochemically quantified in human periodontal tissues. In vitro expression of IL-17A and IL-17F was analyzed in human gingival epithelial cells, gingival fibroblasts and periodontal ligament cells via qRT-PCR. Gene expression alterations of IL-17 were assessed following challenge with testosterone and 17ß-estradiol under simulated inflammatory conditions (±IL-1ß). Analyses proved IL-17 expression in periodontal hard and soft tissues and in resident cells, showing distinct patterns for the subtypes IL-17A and IL-17F. IL-17F was discriminatively regulated by testosterone and 17ß-estradiol in resident periodontal cells.

Increased circulating levels of neurotrophins and elevated expression of their high-affinity receptors on skin and gut mast cells in mastocytosis.

Mastocytosis is a rare heterogeneous disease characterized by increase of mast cells (MCs) in different organs. Neurotrophins (NTs) have been shown to promote differentiation and survival of MCs, which in turn represent a major source of NTs. Thus, a contribution of NTs to mastocytosis seems highly conceivable but has not yet been investigated. We could demonstrate expression of high-affinity NT receptors tropomyosin-related kinase A (TrkA) for nerve growth factor (NGF)-ß, TrkB for brain-derived neurotrophic factor, and NT-4 and TrkC for NT-3 on skin MCs; and of TrkA and TrkC on intestinal MCs of patients with mastocytosis. Moreover, increased expression of NGF-ß; NT-3; TrkA, TrkB, and TrkC; and isoforms truncated TrkB-T1 and truncated TrkC were observed on skin MCs. Patients with mastocytosis featured elevated serum levels of NGF, NT-3, and NT-4. Levels of NGF-ß and NT-4 correlated with tryptase levels, suggesting a link between MC load and blood levels of NGF and NT-4. Migration of CD117+ progenitor cells from the blood was enhanced toward NGF-ß gradient in both mastocytosis and controls. Together with enhanced NT levels, the elevated expression of modified Trk receptors on skin and gut MCs might contribute to the pathophysiology of mastocytosis in autocrine and paracrine loops.

Attenuated TGF-ß1 responsiveness of dendritic cells and their precursors in atopic dermatitis.

The responsiveness of DCs and their precursors to transforming growth factor beta1 (TGF-ß1) affects the nature of differentiating DC subsets, which are essential for the severity of atopic dermatitis (AD). To evaluate TGF-ß signaling in monocytes and monocyte-derived DCs of AD patients compared with that of controls, in vitro generated Langerhans cell (LC) like DCs, expression of TGF-ß receptors, phospho-Smad2/3 and Smad7 were evaluated. Furthermore, TNF-α expression and synergistic effects of TNF-α upon TGF-ß signaling and DC generation were evaluated. We found LC-like DC differentiation of monocytes from AD patients in response to TGF-ß1 was remarkably reduced and TGF-ß1 receptor expression was significantly lower compared with that of healthy controls. Attenuated TGF-ß1 responsiveness mirrored by lower phospho-Smad2/3 expression after TGF-ß1 stimulation and higher expression of inhibitory Smad7 was observed in monocytes from AD patients. During DC generation, mRNA expression of Smad7 was relatively higher in LC-like DCs of AD patients. Lower TNF-α expression of monocytes from AD patients might further contribute to attenuated TGF-ß signaling in the disease since TNF-α had synergistic effects on TGF-ß1 signaling and LC generation through mediating the degradation of Smad7. Our results demonstrate alleviated TGF-ß1 signaling together with the amount of soluble co-factors might direct the nature of differentiating DCs.

Human α-defensin (DEFA) gene expression helps to characterise benign and malignant salivary gland tumours.

BACKGROUND: Because of the infrequence of salivary gland tumours and their complex histopathological diagnosis it is still difficult to exactly predict their clinical course by means of recurrence, malignant progression and metastasis. In order to define new proliferation associated genes, purpose of this study was to investigate the expression of human α-defensins (DEFA) 1/3 and 4 in different tumour entities of the salivary glands with respect to malignancy. METHODS: Tissue of salivary glands (n=10), pleomorphic adenomas (n=10), cystadenolymphomas (n=10), adenocarcinomas (n=10), adenoidcystic carcinomas (n=10), and mucoepidermoid carcinomas (n=10) was obtained during routine surgical procedures. RNA was extracted according to standard protocols. Transcript levels of DEFA 1/3 and 4 were analyzed by quantitative realtime PCR and compared with healthy salivary gland tissue. Additionally, the proteins encoded by DEFA 1/3 and DEFA 4 were visualized in paraffin-embedded tissue sections by immunohistochemical staining. RESULTS: Human α-defensins are traceable in healthy as well as in pathological altered salivary gland tissue. In comparison with healthy tissue, the gene expression of DEFA 1/3 and 4 was significantly (p<0.05) increased in all tumours - except for a significant decrease of DEFA 4 gene expression in pleomorphic adenomas and a similar transcript level for DEFA 1/3 compared to healthy salivary glands. CONCLUSIONS: A decreased gene expression of DEFA 1/3 and 4 might protect pleomorphic adenomas from malignant transformation into adenocarcinomas. A similar expression pattern of DEFA-1/3 and -4 in cystadenolymphomas and inflamed salivary glands underlines a potential importance of immunological reactions during the formation of Warthin's tumour.

Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis.

BACKGROUND: Enhanced apoptosis of keratinocytes is the main cause of eczema and spongiosis in patients with the common inflammatory skin disease atopic dermatitis (AD). OBJECTIVE: The aim of the study was to investigate molecular mechanisms of AD-related apoptosis of keratinocytes. METHODS: Primary keratinocytes isolated from patients with AD and healthy donors were used to study apoptosis by using annexin V/7-aminoactinomycin D staining. Illumina mRNA Expression BeadChips, quantitative RT-PCR, and immunofluorescence were used to study gene expression. In silico analysis of candidate genes was performed on genome-wide single nucleotide polymorphism data. RESULTS: We demonstrate that keratinocytes of patients with AD exhibit increased IFN-γ-induced apoptosis compared with keratinocytes from healthy subjects. Further mRNA expression analyses revealed differential expression of apoptosis-related genes in AD keratinocytes and skin and the upregulation of immune system-related genes in skin biopsy specimens of chronic AD lesions. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-γ in primary keratinocytes. The protein expression of IFITM1, CCL5, and CCL8 was verified in AD skin. In line with the functional studies and AD-related mRNA expression changes, in silico analysis of genome-wide single nucleotide polymorphism data revealed evidence of an association between AD and genetic markers close to or within the IFITM cluster or RAB31, DUSP1, and ADM genes. CONCLUSION: Our results demonstrate increased IFN-γ responses in skin of patients with AD and suggest involvement of multiple new apoptosis- and inflammation-related factors in the development of AD.

IL-23-producing CD68(+) macrophage-like cells predominate within an IL-17-polarized infiltrate in chronic periodontitis lesions.

AIM: To analyse antigen-presenting cells (APCs), such as dendritic cells (DCs), macrophages (Mo) or B cells depending on the regional site of chronic periodontitis (CP), and to investigate their relation to Th17 cells. MATERIAL AND METHODS: Biopsies from oral mucosa as well as the coronal and bottom regions of CP were analysed by immunhistochemistry, immunofluorescence, flow cytometry and real-time PCR. RESULTS: A predominance of CD68(+) Mo-like cells and CD20(+) B cells and strong Th17 infiltration was observed in the bottom region of CP lesions, while CD1a(+) DCs were only detected in the coronal regions, where Th17 infiltration was low. Furthermore, CD68(+) Mo-like cells displayed CD163 expression as a typical Mo-marker, but expressed in parallel typical DCs markers, such as CD11c or CD209 and TLR4. Interestingly, Th17-inducing cytokine IL-23p19 was produced by CD68(+) Mo-like cells, but not CD20(+) B cells. Moreover, the stimulation of in vitro generated CD68(+) Mo-like cells by Porphyromonas gingivalis-derived (Pg) lipopolysaccharide resulted in the upregulation of their IL-23p19 mRNA expression, which was inhibited by the blockage of TLR4. CONCLUSIONS: In view of these data, a picture emerges that IL-17-producing cells in CP could be in part directed by CD68(+) Mo-like cells, which produce IL-23p19 upon TLR4 activation by Pg.

Risk estimation for a malignant transformation of oral lesions by S100A7 and Doc-1 gene expression.

The objective of this study was the correlation of Doc-1- and S100A7-gene expression in common oral lesions with their cancerous-transformation risk. Biopsies (n = 15 each) of healthy gingiva, irritation fibromas, leukoplakias and Oral squamous cell carcinoma (OSCCs) were obtained, and after RNA-extraction, transcripts of Doc-1 and S100A7 were quantified by RT-PCR. In comparison with the healthy gingiva, the expression of Doc-1 was decreased, whereas the expression of S100A7 was upregulated in all lesions. As the extent of Doc-1-inactivation and S100A7-overexpression is correlated with their biological behavior, the combined investigation of both genes could be a promising marker in intraoral lesions to estimate the risk for their malignant transformation.

Reduced IFN-γ receptor expression and attenuated IFN-γ response by dendritic cells in patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is characterized by a predominance of T(H)2 immune reactions but weaker T(H)1 immune responses in acute skin lesions. OBJECTIVES: To evaluate whether enhanced T(H)2 immunity in patients with AD might impair T(H)1 immune responses by affecting the IFN-γ responsiveness of antigen-presenting cells, we investigated IFN-γ receptor and IL-4 receptor α chain expression, IFN-γ signaling, and the expression of IFN-γ-responsive mediators in dendritic cells (DCs) and their precursors from patients with AD compared with those from healthy subjects. METHODS: Skin biopsy specimens were obtained and both monocytes and monocyte-derived dendritic cells (MoDCs) from patients with AD (n = 86) and control subjects (n = 84) were analyzed by means of flow cytometry, real-time PCR, ELISA, and HPLC. RESULTS: We observed lower IFN-γ receptor II expression combined with higher IL-4 receptor α chain expression on epidermal DCs, monocytes, and MoDCs from patients with AD. Induction of IFN-γ-inducible factors, such as interferon regulatory factor 1, interferon-inducible protein 10, and indoleamine 2,3-dioxygenase, was attenuated in IFN-γ-pulsed MoDCs from patients with AD. Weaker signal transducer and activator of transcription 1 activation mirrored by lower phosphorylated signal transducer and activator of transcription 1 levels in response to IFN-γ stimulation could be observed in epidermal DCs, monocytes, and MoDCs from patients with AD. CONCLUSION: Impaired IFN-γ signaling together with attenuated IFN-γ responses in DCs and their precursor cells might contribute to the T(H)2 bias in patients with AD.

A comprehensive analysis of the COL29A1 gene does not support a role in eczema.

BACKGROUND: Based on a recent positional cloning approach, it was claimed that the collagen 29A1 gene (COL29A1), which encodes an epidermal collagen, represents a major risk gene for eczema underlying a previously reported linkage to chromosome 3q21. However, thus far, not a single replication attempt has been published, and no definitive functional data have been provided. OBJECTIVES: We aimed to determine whether COL29A1 polymorphisms contribute to eczema susceptibility and whether COL29A1 expression is altered in eczema. METHODS: We investigated the reported association of COL29A1 variants with eczema, subtypes of eczema, and eczema-related traits in 5 independent and large study populations comprehensively phenotyped for allergic diseases: a set of 1687 German patients with eczema and 2387 population control subjects, a collection of 274 German families with eczema-diseases children, a cross-sectional population of German children (n = 3099), the Swedish population-based birth cohort Children Allergy and Milieu in Stockholm, an Epidemiologic Study (BAMSE) (n = 2033), and the European cross-sectional Prevention of Allergy-Risk Factors for Sensitization Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n = 3113). An additional set of 19 COL29A1 coding single nucleotide polymorphisms was analyzed in BAMSE and PARSIFAL. COL29A1 expression was investigated by using in situ hybridization. RESULTS: We found no evidence for a relationship between COL29A1 polymorphisms and eczema. The equivalence test rejected the hypothesis of association even excluding small effects. In situ hybridization carried out on biopsy specimens from lesional and nonlesional skin of patients with eczema and from healthy control subjects did not show any differences in the cellular distribution pattern of COL29A1 expression at the mRNA level. CONCLUSIONS: Our results suggest that COL29A1 is unlikely to contain genetic variants that have a major effect on eczema or atopy susceptibility.

Human beta-defensin-1, -2, and -3 exhibit opposite effects on oral squamous cell carcinoma cell proliferation.

The objective of this study was to investigate the impact of human beta-defensins (hBDs) on oral squamous cell carcinoma (OSCC) proliferation and hBD expression in vitro. BHY-OSCC cell lines were stimulated with hBD-1, -2, and -3. Proliferation of BHY cells was ascertained and hBD-mRNA expression was evaluated by real-time PCR. Proliferation of BHY cells decreased by 25% in response to hBD-1 stimulation but increased after stimulation with hBD-2 and -3. HBD-1 stimulation enhanced hBD-3 expression, whereas HBD-2 stimulation decreased early hBD-3 expression. HBD-3 stimulation enhanced hBD-1 expression. HBDs profoundly impact on OSCC proliferation and hBD expression in vitro. Therefore, hBD-1 might function as a tumor suppressor gene in OSCCs, while hBD-2 and -3 might be protooncogenes.

Neuropeptide blood levels correlate with mast cell load in patients with mastocytosis.

BACKGROUND: Mastocytosis is characterized by abnormal growth and accumulation of mast cells (MCs) in different organs. MCs have been shown to express receptors for neuropeptides. Furthermore, neuropeptides can activate MCs inducing cytokine production and MC mediator release, which further contribute to MC chemotaxis and stimulate the release of vasoactive peptides from sensory nerves. Thus, a contribution of neuropeptides to mastocytosis seems highly conceivable, but has not been investigated sufficiently yet. This study aimed to analyse blood levels of the neuropeptides substance P (SP), somatostatin (SST), vasoactive intestinal peptide (VIP), calcitonine gene--related peptide (CGRP) and expression of the SP receptor NK-1R in the skin of patients with mastocytosis (n = 46) compared to healthy controls (n = 69). METHODS: Substance P, SST, VIP and CGRP plasma levels were analysed by ELISA, serum tryptase levels with the UniCAP System and NK-1R expression in the skin by immunohistochemistry. RESULTS: Plasma levels of SP (P < 0.0001), SST, (P = 0.007), VIP (P < 0.0001) and CGRP (P = 0.003) were significantly increased in patients with mastocytosis compared to controls. Tryptase serum levels correlated significantly with neuropeptide levels, implying a link between MC load and neuropeptide blood levels in mastocytosis. NK-1R was expressed on the majority of MCs, and NK-1R-positive cells were increased in lesional mastocytosis skin compared to control skin (P = 0.01). CONCLUSIONS: Elevated blood levels of the neuropeptides SP, SST, VIP and CGRP correlate with MC load and together with an increased expression of NK-1R in the skin of patients with mastocytosis indicate a role of neuropeptides in the pathophysiology of mastocytosis.

Effects of exogenous agmatine in human leukemia HMC-1 and HL-60 cells on proliferation, polyamine metabolism and cell cycle.

Impairment of agmatine homeostasis is involved in the regulation of cell proliferation in malignant solid tumors. The present study aimed at analyzing the relevance of agmatine homeostasis in pathophysiology of human leukemia. Proliferation of the human leukemia cells HMC-1 and HL-60 was determined in the absence or presence of agmatine. Apoptosis and cell cycle distribution was investigated by determination of caspase-3 activity and/or flow cytometry after staining with propidium iodide. Expression analysis was performed by qPCR and by a microarray genechip. Exogenous agmatine inhibited proliferation of both HMC-1 and HL-60 cells. The antiproliferative effect was due to interference of agmatine with the cell cycle with no evident signs of apoptosis. Comparative analysis of expression of mRNA in untreated HMC-1 cells and in non-leukemic human mast cells revealed a much lower expression of agmatinase and diamine oxidase in HMC-1 cells indicating a significantly reduced agmatine catabolism in the leukemic cells. At the mRNA level, inhibition of proliferation of both cell lines by agmatine was associated with cell type-specific alterations of the expression of enzymes of the polyamine pathway. The present results point to a significant role of agmatine homeostasis in the (patho)physiology of cell proliferation of leukemic cells, at least in HMC-1 and HL-60 cells, that may serve as a potential target for an adjuvant therapy in the treatment of human leukemia.

High α-defensin and S100A7 expression and missing DOC-1 down-regulation characterize irritation fibromas of the oral cavity and may counteract malignant transformation.

PURPOSE: The purposes of this study were to analyze the gene expression pattern of antimicrobial peptides, tumor suppressors, growth factors, matrix metalloproteases, and inflammatory cytokines and chemokines in oral irritation fibromas and to identify genes with protective effects against malignant transformation in benign proliferating tumors of the oral mucosa. MATERIALS AND METHODS: Biopsies of irritation fibromas (n = 15) and healthy gingiva (n = 15) were obtained during routine surgical procedures. RNA was extracted according to standard protocols, and transcription levels of CCL20, DEFA 1/3, DEFA 4, S100A7, DOC-1, interleukin (IL) 1ß, IL-6, IL-8, IL-10, tumor necrosis factor α, Cox-2, matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-8, MMP-9, transforming growth factor ß1, transforming growth factor α, and keratinocyte growth factor were analyzed by real-time polymerase chain reaction. In addition, immunostaining was performed to visualize the transcription products of the genes of interest in fibroma tissue as well as in healthy gingiva. RESULTS: The gene expression of S100A7 was 11.3-fold and that of DEFA 1/3 was 14-fold higher in irritation fibromas than in healthy gingiva, whereas the expression of MMP-3 and of inflammation markers IL-1ß, IL-6, IL-8, tumor necrosis factor α, and Cox-2 was reduced. Profound down-regulation of DOC-1 gene expression, characteristic for proliferating malignant tumors of the oral cavity, was in irritation fibromas not verifiable. CONCLUSIONS: Changes in the expression pattern of S100A7, DEFA 1/3, and MMP-3 seem to be involved in the development of irritation fibromas, whereas chronic inflammation might be of less importance. Overexpression of S100A7, but missing down-regulation of the tumor-suppressor gene DOC-1, might exert protective effects and counteract malignant transformation of benign, proliferating lesions of the oral cavity.