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Thesis (doctoral)--Swedish University of Agricultural Sciences, 2006. / Thesis documentation sheet inserted. Appendix reproduces five manuscripts and journal articles co-authored with others. Includes bibliographical references. Also partially issued electronically via World Wide Web in PDF format; online version lacks appendix of papers.

OBJECTIVE: Lichen planus is a disease that can affect both skin and mucosa, in some cases both at the same time. Among patients with lichen planus, the oral version of lichen planus (OLP) can be observed in 50 – 70 %. OLP is the most common chronic inflammatory disease of oral mucosa. Today it is known that OLP is an inflammatory condition but it is not known exactly what substances are prominent and active during this specific inflammatory process. The aim of this study was to examine inflammatory factors involved in OLP. METHODS: A total of 24 individuals were included in this prospective study. 15 of these were patients diagnosed with mucosal LP, whereas the other nine were healthy controls. Blood samples were taken from all participants and sent to Life Science Lab in Uppsala where they used Olinks inflammation panel to analyse inflammatory markers in the blood samples. RESULTS: There were differences in inflammatory factors in blood between the controls and patients with mucosal lichen planus. The inflammatory factors that contributed the most to this difference were IL-5, SCF, FGF-19 and FGF-21. CONCLUSIONS: Due to the differences between LP-patients and controls we can conclude that there are tendencies to an inflammatory process going on systemically involving different levels of mainly IL-5, SCF, FGF-19 and FGF-21. The inflammatory factors that contributed the most to the differences between the two groups are not the typical ones that have been the resulting elevated inflammatory factors in other previous studies.

Magister Chirurgiae Dentium (MChD) / Oral lichen planus (OLP) is a T-cell mediated chronic inflammatory disease with different clinical types that remains inscrutable in respect of its pathogenetic mechanisms and effective therapy. Increased apoptosis may influence the histopathological criteria of oral lichen planus (decrease in thickness of the epithelium and band of inflammatory infiltrate). Null hypothesis: The apoptotic rate does not correlate with a decrease in the epithelial thickness as well as the thickness of the band of inflammatory infiltrate in OLP. Aim: The present study aims to quantify apoptotic activity and to correlate the apoptotic rate with epithelial thickness as well as thickness of the inflammatory infiltrate of OLP cases diagnosed at Tygerberg Hospital from 2006 – 2015. Further, the epithelial thickness and thickness of the inflammatory infiltrate were also assessed for their association, if any. Materials and Methods: The study sample comprised 17 diagnostically verified cases of OLP. Sections stained with Haematoxylin and Eosin (H&E) were used to identify and count the number of apoptotic cells as well as measure the thickness of epithelium and the thickness of the lymphocytic inflammatory infiltrate by using software morphometric analysis (Zen Blue lite 2012). Statistical analysis was applied to analyse the correlation between apoptotic cells and histopathological features of OLP. Results: The present study's results showed no statistically significant association between the apoptotic rate, the epithelial thickness and the thickness of the lymphocytic inflammatory infiltrate.

Introduction: The hair follicle bulge has recently been added to a growing list of human tissue compartments that exhibit a complex combination of immunosuppressive mechanisms, termed immune privilege (IP), which appear to restrict immune mediated injury in specific locations. As epithelial hair follicle stem cells (eHFSC) reside in the hair follicle bulge region it is conceivable that these IP mechanisms protect this vital compartment from immune-mediated damage, thereby ensuring the ongoing growth and cyclic regeneration of the hair follicle. Lichen planopilaris (and variants) are inflammatory hair disorders that result in hair follicle destruction and permanent alopecia. Growing evidence suggests that eHFSC destruction is a key factor in the permanent follicle loss seen in these conditions, and that IP collapse may predispose these cells to immune mediated injury. Aims: The overall aim of this project was to generate immunohistomorphometric, gene profiling, and limited functional evidence to probe the 'bulge immune privilege collapse' hypothesis in a carefully selected model disease for inflammation-induced epithelial stem cell death, lichen planopilaris (LPP). Methods: Adult patients with LPP (or variant frontal fibrosing alopecia) were recruited. Biopsies from lesional and non-lesional scalp skin were performed and either snap frozen in liquid nitrogen, fixed in formalin for paraffin embedding or transferred immediately for hair follicle organ culture. Both frozen and paraffin embedded tissue was processed for immunohistochemistry (IHC) analysis using various immune privilege, hair bulge (eHFSC) and immune cell markers. Cultured samples were supplemented with various chemicals know to influence hair follicle immune privilege with analysis performed using IHC. Further, additional paired lesional and non-lesional samples were sectioned horizontally for laser capture microdissection of bulge cells. Following extraction of RNA, reverse transcription and amplification of cDNA from these selected bulge cells; gene expression profiling was performed comparing lesional with non-lesional samples. Selected, differentially regulated genes were validated using IHC and quantitative real-time PCR. Results: Bulge IP collapse is present in active LPP, as suggested by increased expression of MHC class I, β2microglobulin and MHC class II, along with reduced expression of the locally produced immunosuppressant TGFβ2, at both the gene and protein level. Microarray pathway analysis supports these data with the antigen processing canonical pathway being prominently enriched. Cell mediated immune responses are prominent in active disease, suggested by significantly increased numbers of activated and cytotoxic T-cells infiltrating the bulge epithelium, along with greater numbers of mast cells and macrophages in the peri-follicular connective tissue sheath. Bulge cell eHFSC loss is suggested by loss of bulge cell markers (e.g. keratin 15) on IHC, microarray and qPCR, and supported by microarray analysis showing virtually global loss of recognised bulge eHFSC signatures. Hair follicle organ culture experiments confirm bulge IP collapse in a separate cohort of patients, and demonstrate that the pro-inflammatory cytokine, interferon-γ can further collapse IP in the bulge epithelium of cultured hair follicles. Conclusion: These data identify collapse of immune privilege in bulge cells in active LPP, and identify prominent cell-mediated immune responses and loss of eHFSC signatures in active disease. The pro-inflammatory cytokine, interferon-γ also appears to play a prominent role in IP collapse and contributes to immune cell trafficking into affected tissue. Future study is required to ascertain triggering factors of IP collapse and pursue other identified candidates from gene expression analysis.

ABSTRACT   The aim of this study is to chart a cohort of patients in the county of Västerbotten in Sweden who have been diagnosed with lichen planus. In addition to charting, the cohort has also been compared to similar previously studied groups.   The studied group consist of patients who have been referred to the Department of Medical Biosciences and Pathology between years 2009-2015 with suspicious diagnosis of LP.   After exclusion, 214 patients remained of which 130 were diagnosed with Oral LP and 84 with Genital LP. Different data such as age, medications and diseases was extracted from the dental journals.   In this cohort women were more likely to be affected by LP. The mean age for females was 63 years and 53 years for men. In the studied group 17 % were being treated for hypertension, 14 % were treated with 5 or more different medications. Tobacco use was found in 17 % and 12 % were diagnosed with an autoimmune disease.   The results from the studied cohort were in accordance with similar populations in previous studies. There is an undergoing discussion whether OLP and LP are the same disease that affects different sites.

Lichens are known producers of a variety of secondary metabolites. Fungal polyketides constitute a large family of these secondary metabolites that have a high degree of struc-tural diversity. Usnic acid is a lichen metabolite that has a broad range of biological ac-tivities. However the use of usnic acid in medical applications is limited due to the slow growth of the lichen in nature. In order to conduct in depth studies on compounds such as usnic acid it will be necessary to express their gene clusters in fast growing organisms. To achieve this goal, polyketide biosynthesis in the lichen fungi Cladonia uncialis has been investigated to identify the gene clusters that are responsible for secondary metabo-lites production. This thesis reports the de novo whole-genome sequencing of the lichen Cladonia un-cialis, in silico analysis of polyketide biosynthetic gene clusters, and putative identifica-tion and annotation of 56 different secondary metabolite gene clusters. The identified gene clusters include thirty two different type I polyketide synthase genes (non-reducing, partly reducing and highly reducing PKS genes) gene clusters besides two gene clusters of type III PKS gene, three independent, novel non-ribosomal peptide synthetases (NRPS) biosynthetic gene clusters, as well as seven noncanonical NRPS genes that did not contain condensation (C) domains, three polyketide non-ribosomal (PKS-NRP) hy-brid gene clusters, one lanthipeptide synthase gene and six different terpene synthase gene clusters. Out of 32 candidate genes a single PKS has been identified as being re-sponsible for usnic acid biosynthesis. The structure of one of the lichen non-reducing PKS genes that is responsible for produc-tion of a halogenated lichen metabolite was also studied. Based on the biosynthetic opera-tions of the gene cluster as well as catalogued examples of halogenated polyketides iso-lated from lichen fungi to date, this study suggests that the gene cluster is a biosynthetic gene for an unidentified anthraquinone. The ketosynthase and the acyltransferase do-mains among two different non reducing PKS genes from Cladonia uncialis genome se-quence are also studied. The amino acid sequences of the domains are confirmed by us-ing mass spectrometry. Protein homology modeling was performed using the Swiss-Model server. The generated protein models were visualized using LASERGENE Pro-tean 3D molecular visualization system. / May 2015

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Background: Lichen planus is a chronic inflammation of skin and mucosa with unknown cause. Oral Lichen Planus, OLP, affects around 2% of the population. Autoimmunity has been suggested as a possible cause as the disease has autoimmune features such as female predominance, cyclic nature and cytotoxic T-cell infiltrate. It has been suggested that the intense inflammatory response seen in OLP is caused by factors on the keratinocyte surface triggering the immune system. Chronic inflammation is one of the hallmarks of oral lichen planus and chronic inflammation is connected to increased risk of tumor development. WHO classifies OLP as a potentially malignant condition with increased risk of developing Squamous cell carcinoma of head and neck, SCCHN, but malignant transformation of OLP is a matter of controversy. The aim of these studies was to further elucidate the autoimmune and premalignant character of OLP. Factors involved in malignant transformation, autoimmunity and inflammation were analyzed in normal oral mucosa, OLP and SCCHN. Factors studied were the signal transducers of Transforming growth factor-β the Smad proteins, microRNAs, COX-2, the receptor CXCR-3 and its ligands CXCL-10 and -11 and ELF-3. Material and methods: In the study on Smad protein expression formalin fixed and paraffin embedded biopsies from normal oral mucosa, OLP and SCCHN was used. For the remaining studies fresh frozen biopsies from OLP and normal controls was used. All of the fresh frozen OLP samples and their controls were micro dissected to be able to analyze the epithelial part only as well as sections of the whole biopsy. Methods used are immunohistochemistry, qRT-PCR and Western blot. Results: Analyses of smad proteins expression showed a clear increase of smad3 and smad7 in OLP compared to normal oral mucosa. The expressions of smad proteins in the tumors were more heterogeneous. Some of the SCCHN samples showed a similar expression as OLP while others did not. Micro RNA analyzes showed that miR-21 and miR-203 was significantly increased in OLP epithelium compared to normal oral epithelium while the expression of miR-125b and their potential targets p53 and p63 was decreased in OLP. The presence of COX-2 was significantly higher in OLP than normal controls. At the same time the expression of miR-26b, a suggested repressor of COX-2 was decreased in OLP compared to normal mucosa. The receptor CXCR-3 and its ligands CXCL-10 and -11 were increased in OLP. Expressions of the differentiation involved factor ELF-3 mRNA as well as protein were decreased in OLP. Conclusion: The factors studied are involved in differentiation, malignant transformation and inflammation. Some of the results in these studies indicate a similar expression pattern for OLP and SCCHN. Several of the factors studied are involved in differentiation and their deregulation suggests a disturbed differentiation pattern and this could indicate a premalignant character of OLP but malignant transformation of OLP lesions are relative rare. A lot of these factors are also involved in inflammatory processes and connected to autoimmune diseases and their deregulation in OLP could also support an autoimmune cause of the disease. Based on our studies a suggestion is that the disturbed differentiation pattern triggers the intense immune response directed against the epithelial cells seen in OLP.