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Kjell Ohlsson - One of the best experts on this subject based on the ideXlab platform.
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the effect of immediate hypersensitivity reactions on the level of SLPI granulocyte elastase α1 antitrypsin and albumin in nasal secretions by the method of unilateral antigen challenge
Allergy, 1999Co-Authors: Ulla Westin, Eva Lundberg, J A Wihl, Kjell OhlssonAbstract:Background: The aim of this paper was to investigate the role of SLPI in patients with allergic rhinitis. From this point of view, we also examined leukocyte elastase, α1-antitrypsin, and albumin. SLPI is an inhibitor of serine proteases such as leukocyte elastase, cathepsin G, and mast-cell chymase. Since chymase is considered to participate in mast-cell degranulation and histamine release, SLPI might act as a regulator of allergic reactions. Recent interest has been focused on leukocytes and allergy. Since SLPI is a strong inhibitor of leukocyte elastase, we also focused on the function of elastase in allergic rhinitis. Methods: We used the method of nasal lavage after unilateral nasal antigen challenge in atopic and healthy subjects. The ELISA quantified SLPI and elastase. Albumin and α1-antitrypsin were quantified by electroimmunoassay. Gel filtration was used to separate native SLPI from its complex with elastase. Results: There was a higher level of SLPI in lavage fluid from healthy subjects than from atopic patients. SLPI was increased on the contralateral side in atopic subjects after allergen challenge. The absence of increase in SLPI on the challenged side may be attributed to the increase in elastase and its binding to SLPI, which might have an effect on the immunoreactivity and interfere with the ELISA. It may then be assumed that there is an augmentation of SLPI on the challenged side as well. No increase was seen in healthy subjects. There was a higher concentration of elastase, α1-antitrypsin, and albumin before antigen challenge in atopic patients outside the pollen season than in healthy subjects. As expected, an increase was also seen in the challenged side exclusively in atopic subjects. Conclusions: The lower concentration of SLPI in nasal lavage fluid among the atopic patients than the healthy subjects indicates damaged mucosa. Neural reflexes are involved in SLPI release since there was an increase even in the contralateral nostril. A higher level of elastase and albumin before allergen challenge suggests chronic inflammation in nasal mucosa outside the pollen season. Leukocyte recruitment takes place in response to IgE-mediated reactions, which are reflected in an increase in elastase in response to allergen challenge. (Less)
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The effect of immediate‐hypersensitivity reactions on the level of SLPI, granulocyte elastase, α1‐antitrypsin, and albumin in nasal secretions, by the method of unilateral antigen challenge
Allergy, 1999Co-Authors: Ulla Westin, Eva Lundberg, Kjell OhlssonAbstract:Background: The aim of this paper was to investigate the role of SLPI in patients with allergic rhinitis. From this point of view, we also examined leukocyte elastase, α1-antitrypsin, and albumin. SLPI is an inhibitor of serine proteases such as leukocyte elastase, cathepsin G, and mast-cell chymase. Since chymase is considered to participate in mast-cell degranulation and histamine release, SLPI might act as a regulator of allergic reactions. Recent interest has been focused on leukocytes and allergy. Since SLPI is a strong inhibitor of leukocyte elastase, we also focused on the function of elastase in allergic rhinitis. Methods: We used the method of nasal lavage after unilateral nasal antigen challenge in atopic and healthy subjects. The ELISA quantified SLPI and elastase. Albumin and α1-antitrypsin were quantified by electroimmunoassay. Gel filtration was used to separate native SLPI from its complex with elastase. Results: There was a higher level of SLPI in lavage fluid from healthy subjects than from atopic patients. SLPI was increased on the contralateral side in atopic subjects after allergen challenge. The absence of increase in SLPI on the challenged side may be attributed to the increase in elastase and its binding to SLPI, which might have an effect on the immunoreactivity and interfere with the ELISA. It may then be assumed that there is an augmentation of SLPI on the challenged side as well. No increase was seen in healthy subjects. There was a higher concentration of elastase, α1-antitrypsin, and albumin before antigen challenge in atopic patients outside the pollen season than in healthy subjects. As expected, an increase was also seen in the challenged side exclusively in atopic subjects. Conclusions: The lower concentration of SLPI in nasal lavage fluid among the atopic patients than the healthy subjects indicates damaged mucosa. Neural reflexes are involved in SLPI release since there was an increase even in the contralateral nostril. A higher level of elastase and albumin before allergen challenge suggests chronic inflammation in nasal mucosa outside the pollen season. Leukocyte recruitment takes place in response to IgE-mediated reactions, which are reflected in an increase in elastase in response to allergen challenge. (Less)
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Production of secretory leucocyte protease inhibitor (SLPI) in human pancreatic beta-cells.
Mediators of inflammation, 1999Co-Authors: Max Nyström, M Bergenfeldt, Irena Ljungcrantz, A Lindeheim, Kjell OhlssonAbstract:Secretory leucocyte protease inhibitor (SLPI) is a potent inhibitor of granulocyte elastase and cathepsin G, and also an inhibitor of pancreatic enzymes like trypsin, chymotrypsin and pancreatic elastase. SLPI has also been shown to inhibit HIV-1 infections by blocking viral DNA synthesis. Since SLPI is an inhibitor of pancreatic proteases we wished to investigate whether SLPI was also actually produced in the pancreas. M-RNA from human pancreatic tissue showed evidence of SLPI production using the reverse transcriptase polymer chain reaction technique (RTPCR). Using immunohistochemical methods SLPI was demonstrated in the β-ce1ls of the islets of Langerhans. The function could be local protease/antiprotease regulation or antiviral/antibacterial defence in the close vicinity of the cell surface, or even inside the β-cell itself.
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Identification of SLPI (secretory leukocyte protease inhibitor) in human mast cells using immunohistochemistry and in situ hybridisation.
Biological chemistry, 1999Co-Authors: Ulla Westin, Åsa Polling, Irena Ljungkrantz, Kjell OhlssonAbstract:Recently interest has been focused on secretory leucocyte protease inhibitor (SLPI) and its role in immediate hypersensitive reactions, possibly by inhibiting mast cell chymase. The purpose of this investigation was to show whether or not SLPI is produced in mast cells. Double-immunolabelling revealed that SLPI coexists with mast cell tryptase (60%) and chymase (37%). On the other hand, in situ hybridisation studies demonstrated the expression of SLPI mRNA in all mast cells. The differences in results can be attributed to the fact that in situ hybridisation is a more sensitive method than immunohistochemistry. Hence, we conclude that SLPI is produced in human tonsillar mast cells.
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Localization of immunoreactive secretory leukocyte protease inhibitor (SLPI) in intestinal mucosa
Journal of Gastroenterology, 1996Co-Authors: Magnus Bergenfeldt, Max Nyström, Måns Bohe, Clas Lindström, Åsa Polling, Kjell OhlssonAbstract:Secretory leukocyte protease inhibitor (SLPI) is the dominant protease inhibitor in the mucus secretions of the repiratory and genital tracts, and local production seems likely, as immunoreactive SLPI has been found in the corresponding mucosa. To our knowledge, SLPI has not been previously demonstrated in intestinal epithelia or secretions. In an earlier study, however, we found surprisingly high levels of SLPI in peritonitis exudate from patients with gastrointestinal perforations. This study extends these observations by demonstrating the presence of immunoreactive SLPI in intestinal mucosa. In the small intestine, SLPI was present in Paneth cells and in scattered mucosa cells of goblet-type. In normal mucosa of the large bowel, SLPI was also found in scattered cells of goblet-type in the epithelium. In addition, immunoreactive SLPI was frequently found in colonic adenomas. The findings in this study raise several interesting questions on the possible role of SLPI in the gut epithelial defense against inflammatory assaults.
Markus Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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The interaction of smoking habit, SLPI and AnxA2 in HPV associated head and neck and other cancers.
Cancer treatment and research communications, 2020Co-Authors: Markus Hoffmann, Elgar Susanne Quabius, Alexander Fabian, Martin Laudien, Petra AmbroschAbstract:Abstract Six own studies confirm a correlation between smoking, expression of the secretory leukocyte protease inhibitor (SLPI, an antileukoproteinase) and expression of Annexin A2 (AnxA2), and their influence on human papilloma virus (HPV)-infections. SLPI and HPV are ligands of AnxA2. This correlation was tested on 928 tissue samples from 892 patients in six independent studies [squamous cell carcinoma of the head and neck (HNSCC), n=522; non-neoplastic tonsils n=214; clinically normal mucosa, n=93 (of these n=57 were obtained from patients treated for non-malignant diseases and n=36 were obtained from HNSCC-patients) and vulvar squamous cell carcinoma (VSCC) n=99]. HPV-DNA-status was determined by GP5+/GP6+-PCR, followed in case of HPV-positivity by Sanger sequencing and RT-PCR using HPV-type specific primers. SLPI- and AnxA2-gene-expression was determined by RT-q-PCR; SLPI-protein-expression was additionally determined by immunohistochemistry (IHC); the data were correlated with each other and with patient characteristics. Smoking results in increased SLPI-gene- and protein- and AnxA2-gene-expression with significantly higher SLPI- than AnxA2-gene-expression. SLPI is decreased in non-smokers with a continuous AnxA2-surplus. HPV-status correlates with smoking habit, with smokers being mostly HPV-negative and non-smokers HPV-positive. We hypothesize that smoking leads to SLPI-overexpression with SLPI-binding to AnxA2. Thus, HPV cannot bind to AnxA2 but this seems pivotal for HPV-cell-entry. Smoking favors SLPI-expression resulting in HPV-negative carcinomas, while HPV-positive carcinomas are more common in non-smokers possibly due to a surplus of unbound AnxA2. In addition, the hypothesis may contribute to understand why smokers show increased oral HPV-prevalence in natural history studies but do not necessarily develop HPV-associated lesions.
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Smoking-Induced SLPI Expression Hinders HPV Infections Also in Squamous Cell Carcinomas of the Vulva.
Translational oncology, 2018Co-Authors: Elgar Susanne Quabius, Christoph Röcken, Julius Loehr, Dirk Haaser, Veronika Günther, Nico Maass, Micaela Mathiak, Ibrahim Alkatout, Markus HoffmannAbstract:Abstract In HNSCC, protein- and mRNA-expression of the antileukoproteinase SLPI are significantly inverse correlated with HPV-infection suggesting that elevated expression of SLPI protects against HPV-infections. Moreover, SLPI-expression is up-regulated in HNSCC-patients reporting a smoking habit. Here, we investigate the described correlation in other HPV-driven cancers, namely vulvar squamous cell carcinoma (VSCC). FFPE samples of 99 VSCC were analyzed by PCR for HPV-DNA-expression and by RT-qPCR for SLPI-mRNA-expression. Of 99 VSCC 10 (10.1%) are HPV-positive; 9 were HPV16; 1 HPV18; all were E6/E7 mRNA-positive. 33 of the 99 patients (33.3%) reported a smoking habit; 7 (21.1%) of these were HPV-positive. Of 66 (66.7%) non-smokers 3 (4.5%) were HPV-positive. SLPI-expression was 4.0-fold lower in HPV-positive than HPV-negative patients. Smoking resulted in 2.3-fold higher SLPI expression. The data presented here indicate that SLPI plays a pivotal role in HPV-infection not only in HNSCC but also in VSCC and possibly also in other HPV-driven cancers. This however, needs to be analyzed in future studies. Furthermore these data lead to the hypothesis that the smoking induced SLPI-increase is systemic rather than local, as assumed based on the HNSCC data.
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mirna expression in tonsillar squamous cell carcinomas in relation to hpv infection and expression of the antileukoproteinase SLPI
Papillomavirus Research, 2017Co-Authors: Elgar Susanne Quabius, Jochen Haag, Jürgen Hedderich, Tibor Görögh, Christoph Röcken, Immanuel Merz, Petra Ambrosch, Markus HoffmannAbstract:The aim of this study was to determine if micro-(mi-)RNAs are involved in the previously reported inverse correlation between the antileukoproteinase SLPI, HPV, and smoking habit of head and neck squamous cells carcinoma (HNSCC) patients. HPV-status and SLPI-protein expression were determined in tonsillar SCC (TSCC; n=126). Differentially expressed miRNAs dependent on HPV-status and SLPI-expression were detected by microarray; possible binding-sites in SLPI- and HPVE6-mRNAs were determined in silico. Survival rates were estimated testing prognostic values of HPV-status, SLPI- and miRNA-expression. miRNA-array identified 24 up-regulated and 10 down-regulated miRNAs in HPV-positive versus HPV-negative TSCC (p<0.01; HPV-positivity: 42.1%). HPV-positivity resulted in two up-regulated miRNAs in SLPI-positive TSCC. Of 16 further miRNAs, eight miRNAs were up- and eight were down-regulated in SLPI-negative TSCC. RT-q-PCR-validation of the four most differentially expressed miRNAs showed that miR-363 is expressed strongest in SLPI-negative/HPV-positive TSSC. In silico-analysis of all differentially expressed miRNAs identified miR-363, miR-210, miR-130a, and miR-181a with possible binding sites in the HPV16-E6-mRNA, but none were predicted in the SLPI-mRNA. HPV-positivity, low SLPI-levels and high miR-363-levels are significantly associated with better survival rates. The data presented here show that miR-363 is associated with HPV-positive/SPLI-negative TSCC. The prognostic value of miR-363 suggests a role in the assumed inverse correlation of smoking and SPLI-expression in the mode of HPV-infections in tonsillar but possibly also other HNSCC.
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SLPI and anxa2 expression in neoplasm free palatine tonsils is associated with smoking habit of individuals
Current Opinion in Clinical Nutrition and Metabolic Care, 2017Co-Authors: Elgar Susanne Quabius, Tibor Görögh, Anna S. Hoffmann, Maximilian P. Gebhard, Berit Bögershausen, Lukas Getzin, Markus HoffmannAbstract:In order to confirm the inverse correlation between secretory leucocyte protease inhibitor (SLPI) expression, and human papillomavirus (HPV) infection previously observed in head and neck squamous-cell carcinoma, the present study retrospectively investigated the association between SLPI and Annexin A2 (AnxA2) expression, and HPV status in non-neoplastic chronic tonsillitis (n=118), and tonsillar hyperplasia (n=96) tissue. We hypothesised that smoking induces the upregulation of SLPI, resulting in reduced binding of HPV to AnxA2, a known modulator of HPV entry into the cell. SLPI and cyclin-dependent kinase inhibitor 2A (p16INK4A) protein expression was measured using immunohistochemistry in 214 specimens; SLPI and AnxA2 gene expression was measured using reverse transcription-quantitative polymerase chain reaction in 213 cases; and DNA was isolated from all the specimens to determine HPV status. The association between the results of the aforementioned analyses and the smoking habits of patients was analysed. The samples were HPV-negative. p16INK4A expression demonstrated moderate and strong staining in 38, and 0 cases, respectively. SLPI expression presented negative, weak and moderate signals in 163, 45, and 6 cases, respectively. A positive correlation was identified between smoking and SLPI (P=0.0001). Gene expression analysis (n=213) revealed that smoking (n=48) resulted in a significant increase in SLPI and AnxA2 expression. A significant positive correlation between AnxA2 and SLPI, indicating a surplus of AnxA2 in relation to SLPI, was exclusively identified in non-smokers. The data demonstrated that smoking results in increased SLPI and AnxA2 expression also in non-neoplastic tonsillar tissue. The observed surplus of AnxA2 in relation to SLPI identified exclusively in the tonsillar tissue of non-smokers indicates a higher possibility of a successful HPV infection of the tonsillar tissue of non-smokers, given the properties of AnxA2 to function as an infection modulator.
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SLPI and AnxA2 expression in neoplasm‑free palatine tonsils is associated with smoking habit of individuals
Molecular and clinical oncology, 2017Co-Authors: Elgar Susanne Quabius, Tibor Görögh, Anna S. Hoffmann, Maximilian P. Gebhard, Berit Bögershausen, Lukas Getzin, Markus HoffmannAbstract:In order to confirm the inverse correlation between secretory leucocyte protease inhibitor (SLPI) expression, and human papillomavirus (HPV) infection previously observed in head and neck squamous-cell carcinoma, the present study retrospectively investigated the association between SLPI and Annexin A2 (AnxA2) expression, and HPV status in non-neoplastic chronic tonsillitis (n=118), and tonsillar hyperplasia (n=96) tissue. We hypothesised that smoking induces the upregulation of SLPI, resulting in reduced binding of HPV to AnxA2, a known modulator of HPV entry into the cell. SLPI and cyclin-dependent kinase inhibitor 2A (p16INK4A) protein expression was measured using immunohistochemistry in 214 specimens; SLPI and AnxA2 gene expression was measured using reverse transcription-quantitative polymerase chain reaction in 213 cases; and DNA was isolated from all the specimens to determine HPV status. The association between the results of the aforementioned analyses and the smoking habits of patients was analysed. The samples were HPV-negative. p16INK4A expression demonstrated moderate and strong staining in 38, and 0 cases, respectively. SLPI expression presented negative, weak and moderate signals in 163, 45, and 6 cases, respectively. A positive correlation was identified between smoking and SLPI (P=0.0001). Gene expression analysis (n=213) revealed that smoking (n=48) resulted in a significant increase in SLPI and AnxA2 expression. A significant positive correlation between AnxA2 and SLPI, indicating a surplus of AnxA2 in relation to SLPI, was exclusively identified in non-smokers. The data demonstrated that smoking results in increased SLPI and AnxA2 expression also in non-neoplastic tonsillar tissue. The observed surplus of AnxA2 in relation to SLPI identified exclusively in the tonsillar tissue of non-smokers indicates a higher possibility of a successful HPV infection of the tonsillar tissue of non-smokers, given the properties of AnxA2 to function as an infection modulator.
Ulla Westin - One of the best experts on this subject based on the ideXlab platform.
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Human mast cells decrease SLPI levels in type II - like alveolar cell model, in vitro.
Cancer cell international, 2003Co-Authors: Camilla Hollander, Max Nyström, Sabina Janciauskiene, Ulla WestinAbstract:Background: Mast cells are known to accumulate at sites of inflammation and upon activation to release their granule content, e.g. histamine, cytokines and proteases. The secretory leukocyte protease inhibitor (SLPI) is produced in the respiratory mucous and plays a role in regulating the activity of the proteases. Result: We have used the HMC-1 cell line as a model for human mast cells to investigate their effect on SLPI expression and its levels in cell co-culture experiments, in vitro. In comparison with controls, we found a significant reduction in SLPI levels (by 2.35-fold, p < 0.01) in a SLPI-producing, type II-like alveolar cell line, (A549) when co-cultured with HMC-1 cells, but not in an HMC-1conditioned medium, for 96 hours. By contrast, increased SLPI mRNA expression (by 1.58-fold, p < 0.05) was found under the same experimental conditions. Immunohistochemical analysis revealed mast cell transmigration in co-culture with SLPI-producing A549 cells for 72 and 96 hours. Conclusion: These results indicate that SLPI-producing cells may assist mast cell migration and that the regulation of SLPI release and/or consumption by mast cells requires interaction between these cell types. Therefore, a "local relationship" between mast cells and airway epithelial cells might be an important step in the inflammatory response.
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Experimental and Clinical Studies of SLPI, with Special Reference to IgE-Mediated Allergic Reactions
2000Co-Authors: Ulla WestinAbstract:In this study we demonstrated the production of SLPI (Secretory Leukocyte Protease Inhibitor) in serous glands in the nasal mucosa. We have shown that the pattern of the expression of mRNA corresponds to the encoded protein. The encoded protein was detected by immunohistochemical methods and mRNA was discovered by in situ hybridisation. Nasal mucosa from 11 test subjects without atopic disposition was used for this in vitro study. We found that SLPI inhibits IgE mediated histamine release in a dose dependent way. SLPI had no influence on spontaneous histamine release. Double-immunolabelling revealed that SLPI coexists with tryptase and chymase in tonsilar mast cells. The proportion SLPI/tryptase was 60% and the proportion SLPI/chymase was 37%. SLPI was found in 31% of these cells. In situ hybridisation detected SLPI mRNA in all mast cells. In situ hybridisation was performed as a double immunostaining, using a mouse anti-human mast cell antibody as mast cell identification. Mast cells in nasal mucosa also showed immunoreactivity for SLPI. We investigated the role of SLPI in patients with allergic rhinitis. From this point of view, we also examined leokocyte elastase, a1- PI and albumin. We used the method of unilateral antigen challenge. There was a higher level of SLPI in lavage fluid from healthy subjects than from atopic patients. SLPI increased in response to allergen challenged in atopics but not in healthy subjects. SLPI also increased in the non challenged left nostril, indicating that neural reflexes are involved in the SLPI-release. There was a higher concentration of elastase, a1-PI and albumin before antigen challenge in atopics patients out of pollen season than in healthy subjects. An increase in elastase, a1-PI and albumin was seen in the right challenged nostril, but not in the left non-challenged side exclusively in the atopic subjects. An irrelevant antigen did not increase the secretion of SLPI, elastase, a1- PI and albumin in atopic or healthy subjects.
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the effect of immediate hypersensitivity reactions on the level of SLPI granulocyte elastase α1 antitrypsin and albumin in nasal secretions by the method of unilateral antigen challenge
Allergy, 1999Co-Authors: Ulla Westin, Eva Lundberg, J A Wihl, Kjell OhlssonAbstract:Background: The aim of this paper was to investigate the role of SLPI in patients with allergic rhinitis. From this point of view, we also examined leukocyte elastase, α1-antitrypsin, and albumin. SLPI is an inhibitor of serine proteases such as leukocyte elastase, cathepsin G, and mast-cell chymase. Since chymase is considered to participate in mast-cell degranulation and histamine release, SLPI might act as a regulator of allergic reactions. Recent interest has been focused on leukocytes and allergy. Since SLPI is a strong inhibitor of leukocyte elastase, we also focused on the function of elastase in allergic rhinitis. Methods: We used the method of nasal lavage after unilateral nasal antigen challenge in atopic and healthy subjects. The ELISA quantified SLPI and elastase. Albumin and α1-antitrypsin were quantified by electroimmunoassay. Gel filtration was used to separate native SLPI from its complex with elastase. Results: There was a higher level of SLPI in lavage fluid from healthy subjects than from atopic patients. SLPI was increased on the contralateral side in atopic subjects after allergen challenge. The absence of increase in SLPI on the challenged side may be attributed to the increase in elastase and its binding to SLPI, which might have an effect on the immunoreactivity and interfere with the ELISA. It may then be assumed that there is an augmentation of SLPI on the challenged side as well. No increase was seen in healthy subjects. There was a higher concentration of elastase, α1-antitrypsin, and albumin before antigen challenge in atopic patients outside the pollen season than in healthy subjects. As expected, an increase was also seen in the challenged side exclusively in atopic subjects. Conclusions: The lower concentration of SLPI in nasal lavage fluid among the atopic patients than the healthy subjects indicates damaged mucosa. Neural reflexes are involved in SLPI release since there was an increase even in the contralateral nostril. A higher level of elastase and albumin before allergen challenge suggests chronic inflammation in nasal mucosa outside the pollen season. Leukocyte recruitment takes place in response to IgE-mediated reactions, which are reflected in an increase in elastase in response to allergen challenge. (Less)
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The effect of immediate‐hypersensitivity reactions on the level of SLPI, granulocyte elastase, α1‐antitrypsin, and albumin in nasal secretions, by the method of unilateral antigen challenge
Allergy, 1999Co-Authors: Ulla Westin, Eva Lundberg, Kjell OhlssonAbstract:Background: The aim of this paper was to investigate the role of SLPI in patients with allergic rhinitis. From this point of view, we also examined leukocyte elastase, α1-antitrypsin, and albumin. SLPI is an inhibitor of serine proteases such as leukocyte elastase, cathepsin G, and mast-cell chymase. Since chymase is considered to participate in mast-cell degranulation and histamine release, SLPI might act as a regulator of allergic reactions. Recent interest has been focused on leukocytes and allergy. Since SLPI is a strong inhibitor of leukocyte elastase, we also focused on the function of elastase in allergic rhinitis. Methods: We used the method of nasal lavage after unilateral nasal antigen challenge in atopic and healthy subjects. The ELISA quantified SLPI and elastase. Albumin and α1-antitrypsin were quantified by electroimmunoassay. Gel filtration was used to separate native SLPI from its complex with elastase. Results: There was a higher level of SLPI in lavage fluid from healthy subjects than from atopic patients. SLPI was increased on the contralateral side in atopic subjects after allergen challenge. The absence of increase in SLPI on the challenged side may be attributed to the increase in elastase and its binding to SLPI, which might have an effect on the immunoreactivity and interfere with the ELISA. It may then be assumed that there is an augmentation of SLPI on the challenged side as well. No increase was seen in healthy subjects. There was a higher concentration of elastase, α1-antitrypsin, and albumin before antigen challenge in atopic patients outside the pollen season than in healthy subjects. As expected, an increase was also seen in the challenged side exclusively in atopic subjects. Conclusions: The lower concentration of SLPI in nasal lavage fluid among the atopic patients than the healthy subjects indicates damaged mucosa. Neural reflexes are involved in SLPI release since there was an increase even in the contralateral nostril. A higher level of elastase and albumin before allergen challenge suggests chronic inflammation in nasal mucosa outside the pollen season. Leukocyte recruitment takes place in response to IgE-mediated reactions, which are reflected in an increase in elastase in response to allergen challenge. (Less)
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Identification of SLPI (secretory leukocyte protease inhibitor) in human mast cells using immunohistochemistry and in situ hybridisation.
Biological chemistry, 1999Co-Authors: Ulla Westin, Åsa Polling, Irena Ljungkrantz, Kjell OhlssonAbstract:Recently interest has been focused on secretory leucocyte protease inhibitor (SLPI) and its role in immediate hypersensitive reactions, possibly by inhibiting mast cell chymase. The purpose of this investigation was to show whether or not SLPI is produced in mast cells. Double-immunolabelling revealed that SLPI coexists with mast cell tryptase (60%) and chymase (37%). On the other hand, in situ hybridisation studies demonstrated the expression of SLPI mRNA in all mast cells. The differences in results can be attributed to the fact that in situ hybridisation is a more sensitive method than immunohistochemistry. Hence, we conclude that SLPI is produced in human tonsillar mast cells.
Elise C. Kohn - One of the best experts on this subject based on the ideXlab platform.
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Paracrine SLPI secretion upregulates MMP-9 transcription and secretion in ovarian cancer cells.
Gynecologic oncology, 2011Co-Authors: Ebony Hoskins, Jasmine J. Han, Wafic Elmasri, Jaime Rodriguez-canales, Stephen M. Hewitt, Shing Han, Ben Davidson, Elise C. KohnAbstract:Abstract Objectives Secretory leukocyte protease inhibitor (SLPI) is amplified in serous ovarian cancer. We have dissected its function, showing it is a survival factor for ovarian cancer and promotes tumorigenesis and paclitaxel-resistance. We hypothesized that the protease inhibitory function was responsible for modulating SLPI's invasive capacity. Methods Stable HEYA8 ovarian cancer transfectants expressing vector, wild type SLPI, and protease inhibitor null (F-)SLPI were examined in vitro and in xenografts. Invasion, enzyme activity, and MMP production and function assays were applied. SLPI and MMP immunoexpression was graded on tissue microarray and clinical samples. Statistical comparisons used unpaired t test and ANOVA, where appropriate. Results SLPI and F-SLPI cells caused greater parenchymal and peritoneal dissemination over control cells in xenografts and invasion assays (p 2 =0.986) and a set of ovarian cancers (p Conclusions SLPI stimulates ovarian cancer invasion, modulated in part by its serine protease inhibitory activity attenuating MMP-9 release. However, SLPI induction of MMP-9, independent of protease inhibition activity, is greater yielding a net pro-invasive behavior. These findings further support SLPI as a molecular target for ovarian cancer.
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Abstract 1508: SLPI enhances the expression of PLSCR1 in the HEY-A8 ovarian cancer cell line
Tumor Biology, 2011Co-Authors: Gary Altwerger, Jasmine J. Han, Elise C. KohnAbstract:Secretory leukocyte protease inhibitor (SLPI) is a secreted protease inhibitor that governs inflammation and whose importance has been demonstrated in both pathologic and non-pathologic states. We have defined SLPI as an influential component of the tumor microenvironment promoting growth, survival, and tumor aggressiveness in ovarian cancer. Extracellular SLPI interacts with progranulin, an ovarian cancer growth factor and parental molecule of the pro-inflammatory granulins. Recently, intracellular SLPI has been shown to bind to the cytosolic domain of phospholipid scramblase 1 (PLSCR1) in CD4 T-cells. PLSCR1 is a ubiquitous transmembrane proinflammatory protein with oncogenic properties. PLSCR1 overexpression has been identified in malignant colorectal cancer and xenograft tumor models with increased metastatic and invasive potential. We hypothesized that SLPI remains cytosolic or reenters the cytosol from the tumor microenvironment where SLPI can influence its intracellular receptor, PLSCR1. Preliminary western blot data demonstrated PLSCR1 protein expression in both OVCAR8 and HEY-A8 human ovarian cancer cells with OVCAR8 expressing far less PLSCR1. OVCAR8 is also known, from previous studies, to express less SLPI than Hey-A8 cells. These data led us to investigate SLPI and PLSCR1 interactions using confocal microscopy where we stained HEY-A8 cells and found colocalization of SLPI and PLSCR1. Using HEYA8 with constitutively forced expression of SLPI and protease inhibitor null mutant Leu71PheSLPI, we examined the effect of SLPI on PLSCR1. The increased secretion of SLPI in these stably transfected cells is associated with increased PLSCR1 expression regardless of protease inhibitor activity; additional mutants are currently under examination. These data suggest a positive feedback mechanism between SLPI and its intracellular receptor, PLSCR1 in human ovarian cancer cells. Inhibition of SLPI, already credentialed as a molecular target in ovarian cancer, may be enhanced by interruption of its effects on PLSCR1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1508. doi:10.1158/1538-7445.AM2011-1508
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Abstract 3389: SLPI promotes EMT in HaCaT cells
Tumor Biology, 2010Co-Authors: Wafic Elmasri, Victoria M. Virador, Elise C. KohnAbstract:The majority of solid tumors are carcinomas. To invade, carcinomas must lose cell-cell adhesion and acquire motility: a process termed epithelial-to-mesenchymal transition (EMT). EMT is a highly conserved cellular program that enables polarized, immotile epithelial cells to convert to motile mesenchymal-like cells. Secretory leukocyte protease inhibitor (SLPI; 12-14 kD) is genomically, transcriptionally, and translationally upregulated in epithelial ovarian cancer. SLPI is anti-inflammatory, mediates wound healing, and stimulates cellular proliferation, angiogenesis, invasion, and metastasis. We previously showed that SLPI binds to and protects progranulin (pgrn), a survival factor for ovarian cancer, from elastase-mediated degradation. We also showed that overexpression of SLPI mediates paclitaxel resistance in 1A9 and HeyA8 ovarian cancer cells. We hypothesize that SLPI promotes metastasis via induction of EMT, which can be modulated by inhibition of its protease inhibitory (PI) activity or binding to pgrn. We stably transfected immortalized human skin keratinocytes (HaCaT cells) with wild type SLPI and three mutants: F-SLPI [loss of PI activity], KRK-SLPI [loss of pgrn binding], and F-KRK-SLPI [double mutant]. Overexpression of SLPI or the mutants did not transform the immortalized HaCaT cells; however, it increased colony proliferation, anchorage-independent growth, and resistance to anoikis. The SLPI mutants that do not bind pgrn were more aggressive. Transfection with SLPI and its mutants markedly decreased cell-cell adhesion, altered cellular adhesions to extracellular matrix components, and led to increased cell motility and wound healing in transfected HaCaT cells. SLPI and its mutants enhanced TGF-β induced EMT and effectively blocked TGF-β mediated growth inhibition of HaCaT cells. Thus, SLPI overexpression advances an EMT phenotype in immortalized HaCaT epithelial cells. We continue elucidating the role of SLPI in EMT and the mechanism of its interaction with proganulin for future therapeutic targeting in epithelial ovarian carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3389.
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Alternations of SLPI/GEP in paclitaxel resistant ovarian cancer cells
Cancer Research, 2006Co-Authors: Nabila Rasool, Joshua G. Cohen, Nick Devoogdt, Elise C. KohnAbstract:4678 Chemoresistance to paclitaxel in ovarian cancer patients is an important clinical problem. We have shown previously that secretory leukocyte protease inhibitor (SLPI) is a survival factor for ovarian cancer cells. We have also demonstrated granulin epithelin precursor (GEP), a cancer growth factor, is overproduced by ovarian cancer cells and interacts with SLPI. SLPI is a protease inhibitor and has been shown to prevent the degradation of GEP. Given the survival advantage that the GEP/SLPI interaction provides in ovarian cancer, these proteins could potentially serve as an explanation for the development of chemoresistance seen in patients treated with paclitaxel. Hey A8 ovarian cancer cells, the A2780 ovarian cancer cell subline 1A9, and its two paclitaxel resistant strains PTX10 and PTX22, were used to investigate this hypothesis. The paclitaxel IC50 of PTX10 and PTX22 are 47 nM and 48 nM, respectively. GEP and SLPI protein expression in the presence or absence of paclitaxel over the course of 24 to 72 hours was assessed by immunoblot in cell lysates and conditioned medium (CM). Both GEP and SLPI are secreted. Western blot analysis revealed that PTX10 and PTX 22 express a lower level of SLPI in their lysates compared to the parental 1A9 line. A reverse trend was noted for GEP expression in the conditioned medium. All cell lines responded to paclitaxel exposure with an upregulation of SLPI and down regulation of GEP, suggesting that SLPI expression may be increased as a survival mechanism. The SLPI plasmid as well as F/R SLPI mutants, which have diminished protease inhibitory activity, were transfected into the Hey A8 cell line to better evaluate overexpression of SLPI in relation to paclitaxel resistance. The XTT assay was used to determine cell viability in the parental and transfectants in response to paclitaxel treatment. These XTT assays revealed a survival advantage for the SLPI transfected cell lines, in comparison to the empty plasmid control. Further analysis of this survival advantage is pending. Initial studies show that expression of SLPI and GEP confers a survival advantage against treatment with paclitaxel. This may provide insight into potential therapeutic treatments that will make it possible to overcome chemoresistance seen in the treatment of ovarian cancer.
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alternations of SLPI gep in paclitaxel resistant ovarian cancer cells
Cancer Research, 2006Co-Authors: Nabila Rasool, Joshua G. Cohen, Nick Devoogdt, Elise C. KohnAbstract:4678 Chemoresistance to paclitaxel in ovarian cancer patients is an important clinical problem. We have shown previously that secretory leukocyte protease inhibitor (SLPI) is a survival factor for ovarian cancer cells. We have also demonstrated granulin epithelin precursor (GEP), a cancer growth factor, is overproduced by ovarian cancer cells and interacts with SLPI. SLPI is a protease inhibitor and has been shown to prevent the degradation of GEP. Given the survival advantage that the GEP/SLPI interaction provides in ovarian cancer, these proteins could potentially serve as an explanation for the development of chemoresistance seen in patients treated with paclitaxel. Hey A8 ovarian cancer cells, the A2780 ovarian cancer cell subline 1A9, and its two paclitaxel resistant strains PTX10 and PTX22, were used to investigate this hypothesis. The paclitaxel IC50 of PTX10 and PTX22 are 47 nM and 48 nM, respectively. GEP and SLPI protein expression in the presence or absence of paclitaxel over the course of 24 to 72 hours was assessed by immunoblot in cell lysates and conditioned medium (CM). Both GEP and SLPI are secreted. Western blot analysis revealed that PTX10 and PTX 22 express a lower level of SLPI in their lysates compared to the parental 1A9 line. A reverse trend was noted for GEP expression in the conditioned medium. All cell lines responded to paclitaxel exposure with an upregulation of SLPI and down regulation of GEP, suggesting that SLPI expression may be increased as a survival mechanism. The SLPI plasmid as well as F/R SLPI mutants, which have diminished protease inhibitory activity, were transfected into the Hey A8 cell line to better evaluate overexpression of SLPI in relation to paclitaxel resistance. The XTT assay was used to determine cell viability in the parental and transfectants in response to paclitaxel treatment. These XTT assays revealed a survival advantage for the SLPI transfected cell lines, in comparison to the empty plasmid control. Further analysis of this survival advantage is pending. Initial studies show that expression of SLPI and GEP confers a survival advantage against treatment with paclitaxel. This may provide insight into potential therapeutic treatments that will make it possible to overcome chemoresistance seen in the treatment of ovarian cancer.
Elgar Susanne Quabius - One of the best experts on this subject based on the ideXlab platform.
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The interaction of smoking habit, SLPI and AnxA2 in HPV associated head and neck and other cancers.
Cancer treatment and research communications, 2020Co-Authors: Markus Hoffmann, Elgar Susanne Quabius, Alexander Fabian, Martin Laudien, Petra AmbroschAbstract:Abstract Six own studies confirm a correlation between smoking, expression of the secretory leukocyte protease inhibitor (SLPI, an antileukoproteinase) and expression of Annexin A2 (AnxA2), and their influence on human papilloma virus (HPV)-infections. SLPI and HPV are ligands of AnxA2. This correlation was tested on 928 tissue samples from 892 patients in six independent studies [squamous cell carcinoma of the head and neck (HNSCC), n=522; non-neoplastic tonsils n=214; clinically normal mucosa, n=93 (of these n=57 were obtained from patients treated for non-malignant diseases and n=36 were obtained from HNSCC-patients) and vulvar squamous cell carcinoma (VSCC) n=99]. HPV-DNA-status was determined by GP5+/GP6+-PCR, followed in case of HPV-positivity by Sanger sequencing and RT-PCR using HPV-type specific primers. SLPI- and AnxA2-gene-expression was determined by RT-q-PCR; SLPI-protein-expression was additionally determined by immunohistochemistry (IHC); the data were correlated with each other and with patient characteristics. Smoking results in increased SLPI-gene- and protein- and AnxA2-gene-expression with significantly higher SLPI- than AnxA2-gene-expression. SLPI is decreased in non-smokers with a continuous AnxA2-surplus. HPV-status correlates with smoking habit, with smokers being mostly HPV-negative and non-smokers HPV-positive. We hypothesize that smoking leads to SLPI-overexpression with SLPI-binding to AnxA2. Thus, HPV cannot bind to AnxA2 but this seems pivotal for HPV-cell-entry. Smoking favors SLPI-expression resulting in HPV-negative carcinomas, while HPV-positive carcinomas are more common in non-smokers possibly due to a surplus of unbound AnxA2. In addition, the hypothesis may contribute to understand why smokers show increased oral HPV-prevalence in natural history studies but do not necessarily develop HPV-associated lesions.
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Smoking-Induced SLPI Expression Hinders HPV Infections Also in Squamous Cell Carcinomas of the Vulva.
Translational oncology, 2018Co-Authors: Elgar Susanne Quabius, Christoph Röcken, Julius Loehr, Dirk Haaser, Veronika Günther, Nico Maass, Micaela Mathiak, Ibrahim Alkatout, Markus HoffmannAbstract:Abstract In HNSCC, protein- and mRNA-expression of the antileukoproteinase SLPI are significantly inverse correlated with HPV-infection suggesting that elevated expression of SLPI protects against HPV-infections. Moreover, SLPI-expression is up-regulated in HNSCC-patients reporting a smoking habit. Here, we investigate the described correlation in other HPV-driven cancers, namely vulvar squamous cell carcinoma (VSCC). FFPE samples of 99 VSCC were analyzed by PCR for HPV-DNA-expression and by RT-qPCR for SLPI-mRNA-expression. Of 99 VSCC 10 (10.1%) are HPV-positive; 9 were HPV16; 1 HPV18; all were E6/E7 mRNA-positive. 33 of the 99 patients (33.3%) reported a smoking habit; 7 (21.1%) of these were HPV-positive. Of 66 (66.7%) non-smokers 3 (4.5%) were HPV-positive. SLPI-expression was 4.0-fold lower in HPV-positive than HPV-negative patients. Smoking resulted in 2.3-fold higher SLPI expression. The data presented here indicate that SLPI plays a pivotal role in HPV-infection not only in HNSCC but also in VSCC and possibly also in other HPV-driven cancers. This however, needs to be analyzed in future studies. Furthermore these data lead to the hypothesis that the smoking induced SLPI-increase is systemic rather than local, as assumed based on the HNSCC data.
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mirna expression in tonsillar squamous cell carcinomas in relation to hpv infection and expression of the antileukoproteinase SLPI
Papillomavirus Research, 2017Co-Authors: Elgar Susanne Quabius, Jochen Haag, Jürgen Hedderich, Tibor Görögh, Christoph Röcken, Immanuel Merz, Petra Ambrosch, Markus HoffmannAbstract:The aim of this study was to determine if micro-(mi-)RNAs are involved in the previously reported inverse correlation between the antileukoproteinase SLPI, HPV, and smoking habit of head and neck squamous cells carcinoma (HNSCC) patients. HPV-status and SLPI-protein expression were determined in tonsillar SCC (TSCC; n=126). Differentially expressed miRNAs dependent on HPV-status and SLPI-expression were detected by microarray; possible binding-sites in SLPI- and HPVE6-mRNAs were determined in silico. Survival rates were estimated testing prognostic values of HPV-status, SLPI- and miRNA-expression. miRNA-array identified 24 up-regulated and 10 down-regulated miRNAs in HPV-positive versus HPV-negative TSCC (p<0.01; HPV-positivity: 42.1%). HPV-positivity resulted in two up-regulated miRNAs in SLPI-positive TSCC. Of 16 further miRNAs, eight miRNAs were up- and eight were down-regulated in SLPI-negative TSCC. RT-q-PCR-validation of the four most differentially expressed miRNAs showed that miR-363 is expressed strongest in SLPI-negative/HPV-positive TSSC. In silico-analysis of all differentially expressed miRNAs identified miR-363, miR-210, miR-130a, and miR-181a with possible binding sites in the HPV16-E6-mRNA, but none were predicted in the SLPI-mRNA. HPV-positivity, low SLPI-levels and high miR-363-levels are significantly associated with better survival rates. The data presented here show that miR-363 is associated with HPV-positive/SPLI-negative TSCC. The prognostic value of miR-363 suggests a role in the assumed inverse correlation of smoking and SPLI-expression in the mode of HPV-infections in tonsillar but possibly also other HNSCC.
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SLPI and anxa2 expression in neoplasm free palatine tonsils is associated with smoking habit of individuals
Current Opinion in Clinical Nutrition and Metabolic Care, 2017Co-Authors: Elgar Susanne Quabius, Tibor Görögh, Anna S. Hoffmann, Maximilian P. Gebhard, Berit Bögershausen, Lukas Getzin, Markus HoffmannAbstract:In order to confirm the inverse correlation between secretory leucocyte protease inhibitor (SLPI) expression, and human papillomavirus (HPV) infection previously observed in head and neck squamous-cell carcinoma, the present study retrospectively investigated the association between SLPI and Annexin A2 (AnxA2) expression, and HPV status in non-neoplastic chronic tonsillitis (n=118), and tonsillar hyperplasia (n=96) tissue. We hypothesised that smoking induces the upregulation of SLPI, resulting in reduced binding of HPV to AnxA2, a known modulator of HPV entry into the cell. SLPI and cyclin-dependent kinase inhibitor 2A (p16INK4A) protein expression was measured using immunohistochemistry in 214 specimens; SLPI and AnxA2 gene expression was measured using reverse transcription-quantitative polymerase chain reaction in 213 cases; and DNA was isolated from all the specimens to determine HPV status. The association between the results of the aforementioned analyses and the smoking habits of patients was analysed. The samples were HPV-negative. p16INK4A expression demonstrated moderate and strong staining in 38, and 0 cases, respectively. SLPI expression presented negative, weak and moderate signals in 163, 45, and 6 cases, respectively. A positive correlation was identified between smoking and SLPI (P=0.0001). Gene expression analysis (n=213) revealed that smoking (n=48) resulted in a significant increase in SLPI and AnxA2 expression. A significant positive correlation between AnxA2 and SLPI, indicating a surplus of AnxA2 in relation to SLPI, was exclusively identified in non-smokers. The data demonstrated that smoking results in increased SLPI and AnxA2 expression also in non-neoplastic tonsillar tissue. The observed surplus of AnxA2 in relation to SLPI identified exclusively in the tonsillar tissue of non-smokers indicates a higher possibility of a successful HPV infection of the tonsillar tissue of non-smokers, given the properties of AnxA2 to function as an infection modulator.
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SLPI and AnxA2 expression in neoplasm‑free palatine tonsils is associated with smoking habit of individuals
Molecular and clinical oncology, 2017Co-Authors: Elgar Susanne Quabius, Tibor Görögh, Anna S. Hoffmann, Maximilian P. Gebhard, Berit Bögershausen, Lukas Getzin, Markus HoffmannAbstract:In order to confirm the inverse correlation between secretory leucocyte protease inhibitor (SLPI) expression, and human papillomavirus (HPV) infection previously observed in head and neck squamous-cell carcinoma, the present study retrospectively investigated the association between SLPI and Annexin A2 (AnxA2) expression, and HPV status in non-neoplastic chronic tonsillitis (n=118), and tonsillar hyperplasia (n=96) tissue. We hypothesised that smoking induces the upregulation of SLPI, resulting in reduced binding of HPV to AnxA2, a known modulator of HPV entry into the cell. SLPI and cyclin-dependent kinase inhibitor 2A (p16INK4A) protein expression was measured using immunohistochemistry in 214 specimens; SLPI and AnxA2 gene expression was measured using reverse transcription-quantitative polymerase chain reaction in 213 cases; and DNA was isolated from all the specimens to determine HPV status. The association between the results of the aforementioned analyses and the smoking habits of patients was analysed. The samples were HPV-negative. p16INK4A expression demonstrated moderate and strong staining in 38, and 0 cases, respectively. SLPI expression presented negative, weak and moderate signals in 163, 45, and 6 cases, respectively. A positive correlation was identified between smoking and SLPI (P=0.0001). Gene expression analysis (n=213) revealed that smoking (n=48) resulted in a significant increase in SLPI and AnxA2 expression. A significant positive correlation between AnxA2 and SLPI, indicating a surplus of AnxA2 in relation to SLPI, was exclusively identified in non-smokers. The data demonstrated that smoking results in increased SLPI and AnxA2 expression also in non-neoplastic tonsillar tissue. The observed surplus of AnxA2 in relation to SLPI identified exclusively in the tonsillar tissue of non-smokers indicates a higher possibility of a successful HPV infection of the tonsillar tissue of non-smokers, given the properties of AnxA2 to function as an infection modulator.
