[show abstract][hide abstract] ABSTRACT: Palytoxin (PTX), a marine toxin isolated from the Cnidaria (zooanthid) Palythoa caribaeorum is one of the most potent non-protein substances known. It is a very complex molecule that presents both lipophilic and hydrophilic areas. The effect of PTX was investigated in a series of experiments conducted in head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.
Cell viability, and gene expression of the sodium/potassium-transporting ATPase subumit alpha1 (ATP1AL1) and GAPDH were analyzed in HNSCC cells and normal epithelial cells after treatment with PTX using cytotoxicity-, clonogenic-, and enzyme inhibitor assays as well as RT-PCR and Northern Blotting. For xenograft experiments severe combined immunodeficient (SCID) mice were used to analyze tumor regression. The data were statistically analyzed using One-Way Annova (SPSS vs20).
Significant toxic effects were observed in tumor cells treated with PTX (LD50 of 1.5 to 3.5 ng/ml) in contrast to normal cells. In tumor cells PTX affected both the release of LDH and the expression of the sodium/potassium-transporting ATPase subunit alpha1 gene suggesting loss of cellular integrity, primarily of the plasma membrane. Furthermore, strong repression of the c-Jun N-terminal kinase 3 (JNK3) mRNA expression was found in carcinoma cells which correlated with enhanced toxicity of PTX suggesting an essential role of the mitogen activated protein kinase (MAPK)/JNK signalling cascades pathway in the mechanisms of HNSCC cell resistance to PTX. In mice inoculated with carcinoma cells, injections of PTX into the xenografted tumors resulted within 24 days in extensive tumor destruction in 75% of the treated animals (LD50 of 68 ng/kg to 83 ng/kg) while no tumor regression occurred in control animals.
These results clearly provide evidence that PTX possesses preferential toxicity for head and neck carcinoma cells and therefore it is worth further studying its impact which may extend our knowledge of the biology of head and neck cancer.
Molecular Cancer 01/2013; 12:12. · 5.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: In granulomatosis with polyangiitis (GPA), a complex autoimmune small-vessel vasculitis frequently associated with chronic necrotizing inflammation of the nasal mucosa, elevated nasal Staphylococcus (S.) aureus carrier rates are a risk factor for relapse. As cytokines are primarily involved in the regulation of defense against potentially pathogenic microorganisms, the aim of this study was to compare healthy individuals and GPA patients with respect to their baseline cytokine expression of nasal epithelial cells (NEC), which form the first barrier against such triggers. The ability of S. aureus to influence the nasal microenvironment's cytokine secretion was assessed by exemplary stimulation experiments. METHODS: Baseline expression of 19 cytokines of primary NEC of GPA patients and normal controls (NC) was quantified by a multiplex cytokine assay. Stimulation experiments were performed with supernatants of S. aureus and expression of interleukin-8 was determined by ELISA. RESULTS: In GPA, an altered pattern of baseline cytokine expression with significantly up-regulated G-CSF and reduced interleukin (IL)-8 concentrations was observed. Both NEC of GPA patients and NC responded to stimulation with S. aureus, but GPA patients displayed a significantly lower IL-8 secretion and a diminished dynamic range of response towards the stimulus. CONCLUSIONS: The data presented underline the hypothesis of a disturbed epithelial nasal barrier function in GPA. The dysregulated baseline expression of G-CSF and IL-8 and the reduced response to microbial stimulation may facilitate changes in the composition of the nasal flora and favour an imbalanced inflammatory response, which might be relevant for the disease course.
Arthritis research & therapy 10/2012; 14(5):R203. · 4.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: First, to investigate the overall efficacy and safety of rituximab (RTX) in refractory granulomatosis with polyangiitis (GPA) in a tertiary referral centre. Second, to compare the efficacy of RTX in granulomatous and vasculitic manifestations in GPA.
This study comprised a retrospective, standardised data collection from all patients who received RTX for refractory Wegener's granulomatosis from 2002 to 2010. Patients were assessed by a standardised interdisciplinary diagnostic procedure (including ear, nose and throat and ophthalmology assessment, MRI, immunodiagnostics, B-cell levels and Birmingham Vasculitis Activity Score) and were treated by standardised therapeutic regimens according to available evidence.
59 patients received 75 cycles of RTX. 9.3% achieved complete remission. A response was documented in 61.3% (improvement in 52%, unchanged disease activity in 9.3%), 26.7% had refractory disease. Birmingham Vasculitis Activity Score, disease extent index, erythrocyte sedimentation rate, C-reactive protein and prednisolone demand decreased significantly. All patients achieved B-cell depletion. Granulomatous manifestations such as orbital granuloma and pachymeningitis were more frequently refractory to RTX than vasculitis or other granulomatous manifestations. Thus, for example, complete remission/improvement was found in 89.2% of patients with renal disease and in only 44.4% of those with orbital masses (p=0.003). The relapse rate was 44.4% after a median period of 13.5 months. Adverse events occurred in 29%, pneumonia in 15% and death in 3%.
The overall response rate of refractory GPA to RTX was high (61.3% complete remission or improvement). Response rates of vasculitic manifestations were excellent; failure of response/progress was mostly due to granulomatous manifestations, especially orbital masses. Relapse rates were high (40%) despite maintenance treatment.
Annals of the rheumatic diseases 03/2012; 71(3):327-33. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nasal carriage of Staphylococcus aureus in patients with chronic rhinosinusitis with nasal polyps (NP) is hypothesized to have pathophysiological impact on the disease. Antimicrobial peptides (AMP), especially human beta-defensin-3 (hBD-3) and LL-37, are an important part of the multifactorial defence against microorganisms in barrier organs like the nasal mucosa. The interaction of S. aureus colonization and AMP in nasal secretions and mucosa of NP were investigated in this study.
AMP were quantified in nasal secretions of 13 normal controls (NC) and 12 NP patients, each with and without S. aureus colonization, by ELISA. Immunohistochemistry was used to investigate the cellular sources of AMP in the nasal mucosa. To explore the AMP response of primary nasal epithelial cell cultures (NEC) towards S. aureus stimulation, a functional assay was established.
AMP could be demonstrated in nasal secretions of all groups without differences in hBD-3 concentrations comparing S. aureus carriers vs. non-carriers. In NC, higher LL-37 concentrations were observed in S. aureus colonized as compared to non-colonized patients. This effect was not detectable in NP patients. Epithelial cells, submucosal glands and cells of the connective tissue could be identified as sources of AMP by immunohistochemistry. An AMP response of NEC towards S. aureus stimulation was detected in all groups.
In NP patients, LL-37 response towards S. aureus colonization is disturbed while the ability of NEC to respond on S. aureus challenge is preserved. This deregulation of the nasal barrier could be involved in the multifactorial pathophysiology of NP.
[show abstract][hide abstract] ABSTRACT: Head and neck squamous cell carcinomas (HNSCC) represent the sixth largest group among all human malignancies. However, the exact molecular mechanisms inducing the genesis and the progression of metastasis in these tumors are poorly understood. The identification of molecular alterations involved in metastasis of HNSCC might influence the value of clinical diagnostics, impact therapy strategies and finally improve the prognosis of the patients. The purpose of this study was to identify clinically relevant alterations at the transcriptional and translational levels, when comparing metastatic (N+) and non-metastatic (N0) primary HNSCC. Three transcripts HERPUD1, SLPI and RAD51 were selected for further validation based on their association with carcinogenesis and metastasis. Quantitative real-time-PCR was performed to determine the mRNA expression levels. For subsequent confirmation of the results, immunohistochemistry was performed applying a monoclonal anti-SLPI antibody on 121 HNSCC tumor specimens (N0, n=40; N+, n=81). In metastatic primary cancer, SLPI mRNA showed 5.9-fold lower expression in comparison with non-metastatic primary cancer (p=0.0092). Immunohistochemical staining revealed a fold change of -1.79 between the N+ and the N0 group (p=0.0002). The results presented here clearly indicate the repression of SLPI, measurable on both, mRNA and protein levels in metastatic primary HNSCC as compared to non-metastatic HNSCC. Therefore, it can be assumed that SLPI might have a substantial protective effect on the metastasis process of HNSCC.
International Journal of Oncology 07/2011; 39(1):185-91. · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several different methods can be applied for repairing total nasal defects. Most of them are based on some common principles and techniques widely accepted and adopted by experienced surgeons. We have been using most of these techniques during the past two decades, however modifying and refining them several times. Our observations and sometimes disappointing experiences led to a concept that has remained unchanged for the past 6 years. It comprises three regular operative steps and sometimes a fourth surgical intervention for repair and refinement. First stage: Reconstruction of the septum using a bipedicled composite septal pivot flap (SPF), of the intranasal lining (INL), and the cover being established by elevating a full-thickness paramedian forehead flap (PMFF). Second stage: Re-elevation of the PMFF, thinning of its layers, and reconstruction of the subsurface framework using autogenous rib cartilage. Third stage: Division of the pedicle and minor corrections. We have been using this technique presented here since 2004 in nine consecutive patients with subtotal to supratotal nasal defects. Seven cases have been repaired completely by now and can be evaluated carefully. With this technique, results have significantly improved and have been stable to date.
Facial Plastic Surgery 06/2011; 27(3):266-75. · 0.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nasal S. aureus carrier rates are significantly higher in patients with Wegener's granulomatosis (WG) compared to healthy controls (HC), and nasal colonisation is a risk-factor for relapse. Antimicrobial peptides (AMP) are important defence molecules maintaining an intact barrier function. It is the aim of this study to see if there is a possible link between the nasal AMP pattern and S. aureus colonisation, a link which has not been investigated so far.
ELISA was applied to quantify LL-37 and hBD-3 concentrations in nasal secretions (14 WG patients, 13 HC) with and without nasal S. aureus colonisation. Immunohistochemistry was used to detect the cellular sources of AMP in the nasal mucosa. Functional analyses of primary nasal epithelial cell cultures (NEC) of these groups stimulated with S. aureus were performed.
LL-37 was found in significantly higher concentrations in colonised individuals (WG: p=0.001; HC: p=0.014).Using immunohistochemistry, local cellular sources for AMP could be demonstrated. After stimulation with S. aureus, significantly higher concentrations of LL-37 and hBD-3 could be detected in the supernatant of NEC of WG patients (LL-37: p=0.001; hBD-3: p=0.001) and HC (LL-37: p=0.019; hBD-3: p=0.001). HBD-3 concentrations were significantly lower in the supernatant of stimulated NEC of WG patients compared to the NEC of HC (p=0.032), and the dynamic range of the hBD-3 answer was significantly smaller in WG compared to HC (p=0.016).
The dynamic response towards challenges with microbes is dysregulated in WG, and this might be one reason for higher S. aureus colonisation rates in WG.
[show abstract][hide abstract] ABSTRACT: Wegener's granulomatosis (WG) is a complex autoimmune disease of unknown etiology, frequently involving localized inflammation of the nasal mucosa as an early manifestation. The current hypothesis suggests that the disease is triggered by a disturbed interaction between genetic and environmental effects, such as an altered microflora at mucosal layers. In this study, a systematic assessment of 49 transcripts with potential pathophysiological relevance was performed using quantitative real-time PCR in nasal mucosa samples of more than 80 individuals, including normal control (NC) individuals and disease controls. In addition, colonization with Staphylococcus aureus was quantified in the same individuals to assess its impact on transcriptomic signatures. Transcription profiles show an increased heterogeneity in diseased individuals. In all, 10 transcripts were identified to be differentially expressed (P≤0.05, false discovery rate ≤0.05) between patients with WG and NC individuals. These transcripts include antimicrobial peptides (human β-defensin (DEFB)1: fold-change WG vs. controls: +4.45, lysozyme: -3.4, DEFB4 and S100A7 (S100 calcium-binding protein A7): both "switched on" in WG), innate immune receptors (Toll-like receptor 4: -2.1, NOD-like receptor C3: -2.1, scavenger receptor CD36: +2.9), and cytokines (interferon-γ: -14, transforming growth factor-β 1: -1.4, interleukin-17D: -2.7). These transcriptional profiles are independent of S. aureus colonization. This study for the first time describes that, on the basis of data obtained from the primary nasal tissue, WG exhibits molecular features that allow its differentiation from other inflammatory disorders with involvement of the nasal mucosa. Further studies based on these findings may enable the identification of subphenotypes, which are currently discussed as an important target for a personalized medicine approach, aiming to reduce side effects and the number of therapy non-responders.
[show abstract][hide abstract] ABSTRACT: The principles of open vs. laser microsurgical approaches for partial resections of the larynx are described, oncological as well as functional results discussed and corresponding outcomes following primary radiotherapy are opposed. Over the last decade, the endoscopic partial resection of the larynx has developed to an accepted approach in the treatment of early glottic and supraglottic carcinomas thus leading to a remarkable decline in the use of open surgery. Comparing the various surgical approaches of laryngeal partial resections, the oncological outcome of the patients, as far as survival and organ preservation are concerned, are comparable, whereas functional results of the endoscopic procedures are superior with less morbidity. The surgical procedures put together, are all superior to radiotherapy concerning organ preservation. Transoral laser microsurgery has been used successfully for vocal cord carcinomas with impaired mobility or fixation of the vocal cord, supraglottic carcinomas with infiltration of the pre- and/or paraglottic space as well as for selected hypopharyngeal carcinomas. It has been well documented that laser microsurgery achieves good oncological as well as functional results with reasonable morbidity. However, patients with those tumours have been successfully treated by open partial resections of the larynx at medical centres with appropriate expertise. The initially enthusiastic assessment of study results concerning the efficacy of various protocols of chemoradiation with the intent of organ preservation for laryngeal and hypopharyngeal carcinomas are judged more cautious, today, due to recent reports of rather high rates of late toxicity complications.
[show abstract][hide abstract] ABSTRACT: The principles of open versus laser microsurgical approaches for partial resections of the larynx are described, oncologic as well as functional results discussed and corresponding outcomes following primary radiotherapy are opposed. Over the last decade, the endoscopic partial resection of the larynx has developed to an accepted approach in the treatment of early glottic and supraglottic carcinomas thus leading to a remarkable decline in the use of open surgery. Comparing the various surgical approaches of laryngeal partial resections, the oncological outcome of the patients, as far as survival and organ preservation are concerned, are comparable, whereas functional results of the endoscopic procedures are superior with less morbidity. The surgical procedures put together, are all superior to radiotherapy concerning organ preservation. Transoral laser microsurgery has been used successfully for vocal cord carcinomas with impaired mobility or fixation of the vocal cord, supraglottic carcinomas with infiltration of the pre- and/or paraglottic space as well as for selected hypopharyngeal carcinomas. It has been well documented that laser microsurgery achieves good oncological as well as functional results with reasonable morbidity. However, patients with those tumours have been successfully treated by open partial resections of the larynx at medical centres with appropriate expertise. The initially enthusiastic assessment of study results concerning the efficacy of various protocols of chemoradiation with the intent of organ preservation for laryngeal and hypopharyngeal carcinomas are judged more cautious, today, due to recent reports of rather high rates of late toxicity complications.
GMS current topics in otorhinolaryngology, head and neck surgery. 01/2011; 10:Doc02.
[show abstract][hide abstract] ABSTRACT: Wir berichten über einen Patienten, der sich mit einer unklaren malignen mesenchymalen Raumforderung der Anthelix in unserer
Therapie befand. Das histologische Ergebnis zeigte ein myofibroblastisches Sarkom. Myofibroblastische Sarkome sind sehr seltene
Tumoren, deren genaue Zuordnung im Rahmen proliferativer Erkrankungen schwierig ist. Differenzialdiagnostisch kommen sowohl
benigne als auch maligne mesenchymale Veränderungen in Betracht. Therapeutisch ist eine vollständige Resektion anzustreben,
gegebenenfalls eine Kombination aus Chirurgie und Strahlentherapie.
We report on a patient suffering from a mesenchymal tumour located at the antihelix. Histopathology of the tissue specimens
derived from this lesion reported a myofibroblastic sarcoma, a rare tumour entity with a slight predominance of occurrence
in the area of the head and neck. Grading of these tumours can be challenging since benign as well as malign phenotypes have
been described. Therefore, beside complete resection of the lesion additional radiotherapy should be discussed individually.
KeywordsSarcoma–Myofibroblastic–Antihelix–Mesenchymal lesion–SMA positivity
[show abstract][hide abstract] ABSTRACT: To determine the long-term outcome in patients with Wegener's granulomatosis (WG) over 4 decades in an academic hospital unit specializing in rheumatology.
We included 290 patients, divided them into 2 cohorts, and compared them with the historical cohort of 155 patients. Comparisons were retrospective regarding disease manifestations, therapy, mortality, and incidence of malignancies. The historical cohort (cohort 1) included 155 patients diagnosed between 1966 and 1993, cohort 2 included 123 patients diagnosed between 1994 and 1998, and cohort 3 included 167 patients diagnosed between 1999 and 2002.
Over time, the interval between first symptoms and diagnosis was reduced by half (from 8 months to 4 months). Organ manifestations were similar in the 3 cohorts, and more than 80% of patients still required cyclophosphamide (CYC); however, the median cumulative dose was reduced significantly (from 67 gm in cohort 1 to 36 gm in cohort 2 and to 24 gm in cohort 3). The standardized mortality ratios (SMRs) declined (from 2.1 in cohort 1 to 1.41 in cohort 2 and to 1.03 in cohort 3), with fewer deaths related to WG and/or therapy (86.4% in cohort 1, 76.9% in cohort 2, 50% in cohort 3), decreasing relapse rates (63.9% in cohort 1, 51.2% in cohort 2, 35.3% in cohort 3), and no increased rate of malignancies. Compared with young females, young males had a considerably higher SMR (8.87 [95% confidence interval 4.05-16.8]) and more frequent renal manifestations (54.4% versus 33.8%).
Mortality of WG patients declined over the last 4 decades, probably due to improved diagnostic and therapeutic procedures and increased awareness of WG, which led to earlier diagnosis and therapy, reduction in relapse rates, and lower cumulative CYC dose with fewer deaths related to therapy.
[show abstract][hide abstract] ABSTRACT: To identify patients with localised Wegener's granulomatosis (locWG) to assess whether it occurs as a long-term disease stage or phenotype and to characterise its outcome.
Patients in a 'localised stage' with histological criteria compatible with WG and a follow-up period of ≥1 year were included. They were prospectively followed at the Vasculitis Center Schleswig-Holstein from 1989 to 2009 and the clinical manifestations, antineutrophil cytoplasmic autoantibodies (ANCA) status and damage were evaluated. Immunosuppression was adapted to disease activity and severity in a step-up regimen.
Of 1024 patients with suspected WG, 99 were clinically diagnosed with locWG and 50 fulfilled the inclusion criteria (72% women, median age 43 years, 46% ANCA-positive). The median follow-up was 48 months. All achieved a response to treatment, 34% achieved complete remission, 1-4 relapses occurred in 46%, 5 (10%) had generalised disease (median 6 years after onset). ANCA status was not associated with relapse (p=0.98), transition to generalised disease (p=0.51) or refractory manifestations (p=0.60). 47% required cyclophosphamide for localised manifestations, 36% of them for pulmonary masses and 24% for orbital masses. 66% developed organ damage, mostly due to bony destruction or space obturation (28% saddle nose, 24% septal perforation, 10% orbital wall destruction). There were two deaths that were not related to WG.
There is evidence that locWG is a long-term disease stage or phenotype (5% of all patients with WG), 46% of whom are ANCA-positive. LocWG is characterised by destructive and/or space-consuming lesions associated with high relapse rates (46%) and local damage.
Annals of the rheumatic diseases 11/2010; 69(11):1934-9. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: We report on a patient suffering from a mesenchymal tumour located at the antihelix. Histopathology of the tissue specimens derived from this lesion reported a myofibroblastic sarcoma, a rare tumour entity with a slight predominance of occurrence in the area of the head and neck. Grading of these tumours can be challenging since benign as well as malign phenotypes have been described. Therefore, beside complete resection of the lesion additional radiotherapy should be discussed individually.
[show abstract][hide abstract] ABSTRACT: There is a clear correlation between proliferative activity and the biological behavior of cancer, which might have an impact on the patients' prognosis and consequences for the individual therapy concept. REPP86 (restrictedly expressed proliferation-associated protein 86) is a proliferation-associated protein expressed in S-, G(2)- and M-phases of the cell cycle, regarded as a promising proliferation marker and has not yet been examined in squamous cell carcinoma of the larynx (SCCL).
REPP86 was analyzed retrospectively in 104 SCCL using the monoclonal antibody Ki-S2. Proliferative activity was correlated with tumor stage, histopathological grading, patients' survival and the results we recently published on Ki-67 staining in SCCL. Median follow-up time was 47 months.
A significant correlation (p<0.05) between histopathological grading, N-status and proliferation activity was observed. The patient group consisting of low proliferating laryngeal cancer showed a statistically longer absolute (p<0.05) and relapse-free (p=0.001) 5-year survival time than the group with a high proliferating tumor. Compared to the Ki-67 staining results, the REPP86 antibody better predicts the relapse-free 5-year-survival.
Our results indicate that REPP86 staining of SCCL with Ki-S2 is a helpful prognostic indicator for SCCL and better predicts the relapse-free survival than Ki-67 staining in SCCL.
Anticancer research 09/2010; 30(9):3541-7. · 1.71 Impact Factor
[show abstract][hide abstract] ABSTRACT: The tumour suppressor protein p53 (wild-type = wt-p53) is of major importance in the genetic integrity of the cell. Mutations of the p53-gene (mt-p53) are the most frequent genetic aberrations identified in different tumour entities. As analyzed in a wide variety of human malignomas, mt-p53 evokes a specific immune response. Yet, the possible occurrence of p53-autoantibodies in patients with head and neck squamous cell carcinomas (HNSCC) correlated to p53-mutations, p53 in sera and p53-overexpression in tissue has not been previously investigated. For the first time, the p53 status in 24 HNSCC patients was analyzed in the present study. The following parameters were investigated: analysis of mutation frequency of the p53-gene by direct sequencing of the exons 5-9, immunohistochemical detection of p53, measurement of the wt- and mt-p53-protein in sera by ELISA and p53-autoantibodies in sera by ELISA. Mutations of the p53-gene were detected in four (17%) patients. Overexpression of wt-p53 was detected by immunohistochemistry in 18 out of 24 (75%) tumours. In 8 (33%) patients the p53-protein was also detectable in sera, whereas in just one of these eight patients p53-autoantibodies were detectable simultaneously. Overall 6 out of 24 (25%) patients were found to be positive for serum p53-autoantibodies. Of these 6 cases, 5 could be assigned to tumours with immunohistochemically measurable wt-p53-overexpression. There was no correlation between p53-overexpression in tissue and p53-protein levels in sera or between p53-autoantibody levels in sera, nor in mutation frequency of the p53-gene and p53-overexpression in tissue. The results presented herein support the hypothesis that strong accumulation of p53 in the tissue is an important prerequisite for development of p53-autoantibodies. However, there must be further, yet unknown factors that influence the p53-autoantibody production because p53-autoantibodies were not identified in sera in each case of p53-accumulation in the tissue.
[show abstract][hide abstract] ABSTRACT: Necrotizing granulomatous inflammation of the upper respiratory tract is one of the hallmarks of Wegener's granulomatosis (WG), which may explain the reason for olfactory dysfunction in WG. However, a systematic analysis using modem olfactory testing tools has not been performed and potential causes of dysfunction at different levels of olfactory information processing remain obscure so far. In this study a group of 76 WG-patients was examined with sniffin'sticks screening 12, odour threshold (T)/discrimination (D)/identification (I) TDI-score, active anterior rhinomanometry and a standardized questionnaire for olfactory function. WG-patients were aware of their olfactory dysfunction, as proven by psychophysiological test results. An altered olfactory function was significantly correlated to local administration of mupirocin and to the time interval between first diagnosis and study entry. None of the other variables had a statistical significant effect on the olfactory dysfunction.
[show abstract][hide abstract] ABSTRACT: Granuloma formation is a key pathologic finding in two of the anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides: Wegener's granulomatosis (WG) and Churg-Strauss syndrome (CSS). So far, no animal models have been established convincingly reproducing both vasculitic and granulomatous features typical of WG and CSS. In biopsies, granulomatous lesions are found both at distant extravascular sites and in the vicinity of inflamed vessels, e.g. in the lung. Intriguingly, WG-granulomata appear to display features of tertiary lymphoid tissue. Cartilaginous and osseous destruction is caused by granulomatous inflammation invading adjacent tissues. Rhinosinusitis is regularly encountered in WG and CSS. Septal perforation, saddle nose deformity, middle and inner ear symptoms, and granulomatous invasion of the palate, orbita, meninges, or the pituitary gland may complicate WG. Both common (e.g. FCGR3B copy number) and distinct (e.g. HLA-DP, IL-10.2) genetic factors have been identified in AAV potentially favouring inflammation and autoimmunity. The HLA-DPB1/RING1/RXRB region constitutes a quantitative trait locus for ANCA-positive WG with the strongest association to be reported up to now. A profound alteration of the T-cell response including Th1 and Th17 responses, anomalously NK-receptor-expressing 'NK-like' T cells, and dysfunctional regulatory T cells could facilitate and sustain granuloma formation and autoimmunity.
[show abstract][hide abstract] ABSTRACT: Lysyl oxidases are a family of five copper-dependent amine oxidases including LOX, LOXL, LOXL2, LOXL3 and LOXL4. LOX and LOXL are essential for the assembly and maintenance of extracellular matrixes. LOXL2, LOXL3 and LOXL4, secreted and active enzymes, were also noted in association with diverse tumor types. We have recently reported overexpression of the LOXL4 mRNA and protein and a close relation of LOXL4 with the pathogenesis of head and neck squamous cell carcinomas (HNSCC). In this study, we analyzed the organization of the LOXL4 gene and addressed the regulatory mechanisms responsible for the overexpression. We demonstrated de novo transcription of the LOXL4 gene in HNSCC, but not in normal squamous epithelial cells. Analysis of the consecutive promoter region spanning positions -960 to -1 identified binding sites for several transcription factors. Promoter constructs containing selected specific promoter regions and consensus binding sites exhibited significantly increased reporter gene activity in HNSCC cells, but not in normal epithelial cells in transient coexpression experiments. The activity profiles of some of these constructs were similar in both cell types indicating that elements of the basic transcriptional regulatory mechanisms remained intact in HNSCC cells. DNA-binding experiments demonstrated that nuclear extracts from HNSCC cells have increased binding activity to the TATA (-25) and the SP1 (-181) sites compared to normal epithelial cells, suggesting that these transcription factors are involved in the upregulation of LOXL4 gene expression in HNSCC.
International Journal of Oncology 12/2008; 33(5):1091-8. · 2.66 Impact Factor