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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Kindlin-1 protein-protein interactions and functional relevance to Kindler syndrome

Begum, Rumena January 2013 (has links)
Kindler syndrome (KS) is an autosomal recessive genodermatosis resulting from pathogenic mutations in the FERMT1 (KIND) gene. This gene encodes kindlin-1 (also known as fermitin family homologue 1), a focal adhesion protein involved in activation of the integrin family of extracellular matrix receptors. Most cases of KS show a marked reduction or complete absence of the kindlin-1 protein in keratinocytes, resulting in defective integrin activation and abnormal cell adhesion and migration. However, currently very little is known about the way in which different FERMT1 mutations found in patients impact upon keratinocyte behaviour. The aim of this thesis is to screen for novel binding partners of kindlin-1 to elucidate possible new functions for this protein in epidermal cells. The main approaches taken were to assess differentially expressed proteins in normal vs. KS patient keratinocytes and also to use recombinant wild type and mutant kindlin-1 for pulldown assays to identify novel binding partners. Mass spectrometry analysis revealed a number of downregulated proteins in KS keratinocytes including epidermal growth factor receptor (EGFR) and thrombospondin-1 (TSP-1). Immunoblotting confirmed a significant reduction in both of these proteins. Further investigation showed changes in localisation of both TSP-1 and EGFR, and also defective signalling and response following EGF stimulation in KS keratinocytes. Moreover, EGFR levels in KS keratinocytes were partially restored following treatment with lysosomal inhibitors, suggesting that kindlin-1 can regulate the recycling of this receptor. Mass spectrometry analysis also identified the potential interaction partners of kindlin-1 to be talin and integrin linked kinase (ILK). Biochemical analysis revealed that kindlin-1 interacts specifically with the talin head domain. This interaction was significantly reduced with a mutant form of kindlin-1 dentified in a KS patient that lacks part of the F3 subdomain. Taken together, these studies have identified novel proteins that are regulated by kindlin-1 and may be important regulators of keratinocyte adhesion and migration.

The characterisation of cellular and tissue chronic inflammation in recessive dystrophic epidermolysis bullosa

Proudfoot, Laura Erin January 2015 (has links)
Recessive dystrophic epidermolysis bullosa (RDEB) occurs as a result of loss of function mutations in COL7A1, resulting in reduced/absent collagen VII deposition in the anchoring fibril adhesion structures at the dermal-epidermal junction. The condition is typified by severe trauma-induced blistering and cutaneous erosions from infancy and chronic wounds that progress to early aggressive cutaneous squamous cell carcinomas (SCCs) which are the main cause of death in this patient cohort. Thus far, the RDEB chronic inflammatory environment has not been characterised in detail nor is there any theoretical basis for the targeting of candidate genes or inflammatory biomarkers to reduce chronic inflammation that might halt the inevitable malignant decline. The studies presented herein provide a detailed comparative analysis of RDEB wounded skin and control skin at the transcriptional and immunological levels. The findings presented in this thesis: 1) define baseline gene expression profiles and immunobiology of chronically inflamed RDEB skin and blood; 2) reveal matrix metalloproteinase (MMP) family genes germane to RDEB chronic inflammation; 3) provide a body of data and supportive evidence that targeting interleukin (IL)-17-associated signalling pathways may be therapeutically meaningful for treating RDEB patients with chronic wounds; and 4) generate new insights into the functional relevance of these targets in RDEB wounds and RDEB-SCC. Illumina whole-genome expression microarray was used to define the pattern of differential gene expression in RDEB wounded skin. MMP-11, -2 and -9 were revealed as significantly upregulated in RDEB chronic wounds, with augmented MMP-11 levels disclosed in the sera of an extended RDEB cohort. Detailed immunoprofiling of RDEB skin and blood via fluorescence-activated flow cytometry revealed a significant elevation in the pro-inflammatory and pro-tumourigenic cytokine IL-17A, further supported on serum multiplex analyses and correlating with immunohistochemical labelling of RDEB wound and RDEB-SCC cutaneous sections. IL-17A significantly enhanced RDEB and RDEB-SCC fibroblast migration and MMP inhibition alone was insufficient to inhibit this effect. An in vitro organotypic model system was developed to study the effects of IL-17A and MMP-11 on RDEB keratinocytes, although pre-treatment did not induce keratinocyte migration or curtail cell invasion in the RDEB-SCC co-cultures. Taken together, these data provide rationale for future work to examine the potential utility of anti-IL-17 biologic innovations as a therapy for individuals with RDEB, although more detailed functional pre-clinical studies are still needed.

Dissecting humoral immune responses in melanoma and the design of antibody immunotherapy

Karagiannis, Panagiotis January 2014 (has links)
Antibodies against melanoma antigens have been detected in patients but, despite known regulatory and activatory functions attributed to humoral immunity, the roles of B cells in solid tumours such as melanoma are inadequately understood. Insights into humoral responses and mechanisms of tumour-induced immune escape may in-form the design of more effective antibodies. The aims of this thesis are three-fold: a) to gain insights into regulatory mechanisms in tumour microenvironments that influence antibody expression; b) to examine whether humoral immune responses are associated with clinical outcomes with a view of defining biomarkers for melanoma; and c) to design antibody therapeutic strategies that may be less prone to tumour-induced immunomodulatory mechanisms. Th2-biased microenvironments favour production of IgG4 subclass antibodies, mainly through local expression of IL-10. Since IL-10 is expressed locally in melanoma tu-mours, B cell infiltration, IgG expression, cytokine production and IgG subclass distribution in melanoma tissues (n=57) were investigated and compared to samples from health volunteers (n=26). Consistent with Th2-biased inflammation, CD22+ and IgG4+ B cells infiltrated melanoma lesions. When cultured together ex vivo, B cells secreted increased VEGF and IgG4, while tumour cells enhanced IL-10 secre-tion. Two antibodies (IgG1, IgG4) against the tumour-associated antigen CSPG4 were engineered to examine the functional significance of IgG4 subclass. Despite ac-cumulation in tumours, anti-CSPG4 IgG4, in contrast to anti-CSPG4 IgG1, did not trigger effector cells to kill tumours in vitro and in vivo. IgG4 mediated IgG1 block-ade through the reduction of FcγRI activatory signalling, reducing immune effector cell capacity, and significantly impairing the potency of IgG1 in a humanised mouse model of cutaneous melanoma. Since IgG4 may impair anti-tumoural immunity, correlations between IgG4 serum levels and clinical outcomes were studied. Increased IgG4/IgGtotal ratios (G4-levels) in melanoma patient sera (n=173) were seen compared to those of healthy volun-teers (n=104). G4-levels were predictive of disease progression (ROC Curve analysis z=0.62; p=0.0065). Using 0.034 as a cut-off for G4-levels (Youden Index) higher ex-pression correlated with decreased progression-free survival (median 694 days; hazard ratio 2.559; 95% CI 1.555 to 4.211; p=0.0004) and overall survival (median 879 days; hazard ratio 1.871; 95% CI 1.0.45 to 3.349; P=0.035). These findings suggest that IgG4 may be further evaluated as a putative biomarker in sera of patients with melanoma. Tumour immune evasion may be overcome by employing antibodies less prone to Fcγ-mediated blockade, such as those of the IgE class. Two antibodies, anti-CSPG4 IgG1 and anti-CSPG4 IgE induced significant tumor cell death by differential mecha-nisms: antibody-dependent cell-mediated phagocytosis and antibody-dependent cell-mediated cytotoxicity, respectively, by human monocytes in vitro. Anti-CSPG4 IgE was however superior to IgG1 (p < 0.05) in restricting subcutaneous human melanoma tumour growth in a humanized mouse model. IgE efficacy was confirmed in an or-thotropic patient tumour in mice populated with autologous patient PBMCs. In summary, this thesis reports a novel pathway of tumour evasion through melanoma favouring production of IgG4 subclass antibodies; provides evidence that IgG4 can be considered as a putative biomarker in melanoma and demonstrates a possible strategy to overcome Fcγ-mediated blockade by designing an IgE antibody against a melanoma-associated antigen and demonstrating its superiority to IgG1.

Eczematoid dermatoses of the hands with special reference to mycotic infection

Rahim, G. F. January 1948 (has links)
No description available.

Observations on pemphigus

Raimes, A. January 1891 (has links)
No description available.

Functional and structural organisation of the visual system in human albinism

Alvarez Ferreira, I. A. January 2017 (has links)
Albinism is a developmental disorder which involves the misrouting of optic nerve projections, leading to an abnormally organised visual system. Despite the aberrant input, people with albinism have relatively normal vision and experience the world in much the same way as their peers. This thesis explores the functional and structural organisation of visual cortex in human albinism using magnetic resonance imaging (MRI) techniques. This thesis covers four main experiments. Experiment 1 deals with stimulus optimisation for population receptive field (pRF) mapping in healthy adults. pRF mapping is a functional MRI technique for estimating cortical receptive field characteristics non-invasively. In this experiment, a stimulus configuration optimized for short acquisition time requirements is presented and implemented in subsequent experiments. Experiment 2 combines the pRF approach for retinotopic localization with diffusion MRI tractography in healthy adults to show evidence for direct extrastriate connections of the human optic radiation. The optic radiation is the principal white matter pathway for relaying retinal input to visual cortex, and typically considered a projection to primary visual cortex. In this experiment, independent pathways of the optic radiation to visual areas V2 and V3 are identified, and functional-structural methodologies developed for Experiment 4. Experiment 3 investigates the functional organisation of visual cortex in participants with albinism. A pRF mapping approach was implemented, identifying abnormal retinotopic organisation and altered receptive field properties in extrastriate visual cortex. In addition, we explore evidence for and against a dual receptive field model of visual field representation in albinism. Experiment 4 examines the structural and functional connectivity of early visual system in human albinism. In particular, differences in white matter microstructure and inter- hemispheric visual map connectivity are found between participants with albinism and a cohort of healthy controls. This thesis highlights the capacity and limitations of developmental plasticity in human albinism.

Mouse models of inherited skin diseases

Fu, Dun Jack January 2014 (has links)
Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal-dominant keratin disorder. It is clinically characterised by diffuse hyperkeratosis of the palms and soles, demarcated by an erythematous border. Mutations altering the coding sequence of the keratin 9 (KRT9) gene, a palmoplantar-specific type I keratin, have been identified as the cause of EPPK. We hypothesise that effective, long-term treatment of EPPK will require silencing, or limiting the activity of, these causative mutant variants. To this end, a two-pronged strategy for disrupting mutant KRT9 allele with short interfering RNAs (siRNAs) was explored as a potential therapeutic approach. This led to the development and in vitro validation of potent mutation- and gene-specific siRNA inhibitors. Despite its importance in EPPK, little is known about the physical requirement for KRT9 or its functional role in the palmoplantar epidermis. Here, a K9-null mouse was generated to define the functional importance of KRT9 (Krt9 in mice) in the palmoplantar epidermis, and determine the extent to which silencing is therapeutically viable. Krt9-/- mice developed epidermal fragility phenotypes localised to the epidermal footpad regions, demonstrating that Krt9 is essential for the structural integrity of palmoplantar epidermis. However, one functional Krt9 allele was sufficient for the normal development of epidermis, strongly suggesting that our mutation-specific siRNAs would be viable in a therapeutic context. To further advance our candidate siRNA therapeutics into clinically applicable treatments, two additional novel mouse models were generated. A Krt9 luciferase reporter mouse model was developed to facilitate live animal epidermal imaging, and thus serve as a platform to identify and develop in vivo siRNA delivery methodologies. An EPPK phenotypic mouse model was also generated, which exhibited EPPK-like epidermal fragility phenotypes. Following the development of an optimal siRNA delivery system with the reporter gene mice, this phenotypic model will enable preclinical validation of its phenotype-resolution capabilities. These novel mouse models will further our understanding of KRT9 and how mutated variants give rise to EPPK, as well as, bring candidate siRNA therapeutics closer to clinical use.

Etude d'acquisition de connaissances sur l'acné nodulaire du dos : impact du microbiote cutané et de l’immunité innée dans la physiopathologie de l’acné sévère du dos / Knowledge acquisition study about nodular acne of the back

Dagnelie, Marie-Ange 17 October 2018 (has links)
L'acné est une dermatose inflammatoire multifactorielle affectant jusqu'à 85 % de la population mondiale ägée de 11 à 30 ans. Cutibacterium acnes est une bactérie jouant un rôle majeur dans la physiopathologie de cette maladie. Ces dernières années, le microbiote cutané et l'immunité innée ont commencé à faire leur apparition comme deux entités pouvant être impliquées dans l'acné. Ainsi, ce travail de Thèse visait à mieux comprendre l'impact du microbiote cutané et de l'immunité innée dans la physiopathologie de l'acné sévère du dos. L'étude clinique, déposée au Comité de Protection des Personnes (CPP) sous le numéro 21-15, a permis le recrutement de 24 patients atteints d'acné sévère du dos et 12 volontaires sains, sur lesquels plusieurs prélèvements ont été réalisés (protocole nºRD.03.SPR. 105704 et nºID-RCB 2015- A01139-40). Ce travail a d'abord eu pour but de faire une caractérisation moléculaire des isolats de C. acnes provenant des patients et des sujets sains. A l'issue de cette première partie, la prédominance importante du phylotype IA1 (CC18/A1) en contexte d'acné sévère du dos a orienté l'étude sur une nouvelle question. En effet, la Thèse a ensuite visé à décrypter l'impact de la diversité des phylotypes de C. acnes sur le niveau d'activation de l'immunité innée en contexte d'acné sévère. li s'agissait de déterminer si cette perte de diversité des phylotypes observée en contexte d'acné sévère était une cause ou une conséquence de la maladie. Un système de cocultures in vitro entre bactéries et explants de peau humaine saine a été mis au point et l'évaluation de la réponse inflammatoire par immunohistochimie et ELISA à la suite de ces cocultures a permis de démontrer que la perte de diversité des phylotypes était une cause très probable de l'inflammation cutanée observée en contexte d'acné sévère. En parallèle de ce travail, une caractérisation du niveau d'activation de l'immunité innée de la peau cliniquement saine de patients atteints d'acné sévère en comparaison à des sujets sains a été réalisée, en ciblant les marqueurs TGF-ß, TLR-2, IL-1 ß, IL-1 O, IL-17, et ß-défensine-2. L'étude de ces marqueurs a également été réalisée dans deux types de lésions inflammatoires d'acné (papule et nodule) en comparaison à de la peau cliniquement saine. A l'issue de ce travail, nous avons mis en évidence une activation anormale du système immunitaire innée, notamment via la surexpression du TLR-2 et de la ß-défensine-2 dans la peau des patients atteints d'acné sévère comparée aux individus sains. Ce travail de Thèse ouvre la voie à de nouveaux paradigmes pour expliquer la physiopathologie de l'acné sévère, notamment par le déséquilibre relatif observé entre les sousgroupes de C. acnes, qui, de pair avec la suractivation du TLR- 2 et de la ß-défensine-2, expliquerait l'inflammation cutanée importante observée dans cette dermatose et l'apparition de nodules inflammatoires. Ce travail ouvre également la voie au développement de nouvelles approches thérapeutiques, basées sur les pré et pro-biotiques cutanés pour restaurer une flore microbienne équilibrée, ou encore des stratégies basées sur la modulation de l'immunité innée chez les patients souffrants d'acné sévère. / Acne is a multifactorial inflammatory skin disease affecting up to 85% of the world's population between 11 to 30 years-old. Cutibacterium acnes is a bacterium that plays a major role in acne physiopathology. Recently, skin microbiota and innate immunity have begun to appear as two entities that may be involved in this skin inflammatory disease. Thus, this Thesis aimed to better understand the impact of skin microbiota and innate immunity in the physiopathology of severe back acne. The clinical study, filed with the Committee for the Protection of Persons (CPP) under the number 21-15, allowed the recruitment of 24 patients with severe back acne and 12 healthy volunteers, from whom several samples were peñormed (protocol nºRD.03.SPR.105704 and NºID-RCB 2015-A01139-40). The aim of this work was first to make a molecular characterization of C. acnes isolates from patients and healthy subjects. At the end of this first part, the important predominance of the IA1 (CC18/A1) phylotype in the context of severe back acne guided the study to a new question. Indeed, the Thesis then aimed to decipher how far the diversity of C. acnes phylotypes could impact on the activation level of innate immunity in the context of severe acne. The question was whether this loss of phylotype diversity observed in the context of severe acne was a cause or consequence of the disease. To answer this new question, an in vitro coculture system between bacteria and healthy human skin has been developed. The evaluation of the skin inflammatory response by immunohistochemistry and ELISA after different coculture conditions showed that the loss phylotype diversity was a possible cause of cutaneous inflammation observed in acne context. ln parallel with this work, a characterization of the activation level of the innate immunity of non lesiona! skin from severe acne patients comparing with healthy subjects was carried out, targeting the TGF-ß, TLR- 2, IL-1ß, IL-10, IL-17, and ß-defensin-2 markers. These markers study was also peñormed in two types of inflammatory lesions of acne (papule and nodule) in comparison to non lesiona! skin. At the end of this work, we were able to demonstrate an abnormal activation of the innate immune system, notably via the overexpression of TLR-2 and ß-defensin-2 in the skin of severe acne patients comparing with healthy individuals. This Thesis work paves the way for new paradigms to explain severe acne physiopathology, including the relative imbalance observed between C. acnes subgroups, which, together with TLR-2 and ß-defensin-2 overactivations, would explain the important cutaneous inflammation observed in this dermatosis and the appearance of inflammatory nodules. Besides, this work paves the way for the development of new therapeutic approaches, based on skin pre- and pro-biotics to restore a balanced microbial flora, and also for strategies based on the modulation of innate immunity in patients suffering from severe acne.

Histopathogenesis of eczema

McCallum, D. I. January 1955 (has links)
No description available.

The trance system in langerhans cell and keratinocyte homeostasis

Barbaroux, Jean-Baptiste Olivier Stephen January 2008 (has links)
No description available.

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