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1
Schoonen, Wilma Marieke. "Pharmacoepidemiology of autoimmune diseases." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2007. http://researchonline.lshtm.ac.uk/4646551/.
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The current system in place to study safety of medicines after introduction on the market relies on spontaneous reporting. Adverse events occurring long after initiation or cessation of drug use are likely to be missed by this system. In this thesis we explore methods to identify signals of long-term, unexpected adverse events and methods to evaluate these signals. We utilised data from the UK General Practice Research Database (GPRD), a large primary care database. A systematic review investigating the validity of medical diagnoses recorded in this database illustrated that the GPRD is a powerful tool to study morbidity in primary care. However, intimate knowledge of the complexities of the database is needed to ensure the best use is made of the database. Pre-existing hypotheses of drug-induced systemic lupus erythematosus (SLE) were evaluated using the GPRD. Associations between risk of SLE and exposure to hydralazine, minocycline, and carbamazepine were confirmed using both a matched case-control design and the self controlled case series method. Spontaneous reports of drug-induced SLE recorded in the UK Yellow Card database indicated that symptoms of SLE often resolve after withdrawal of the suspected drug. Using the Smile Plot method to generate signals of drug-induced SLE, we were not able to identify known signals of drug-induced lupus. However, we did identify factors strongly associated with treatment of early symptoms of disease. These findings indicated a high specificity of the Smile Plot method. To improve sensitivity, better hierarchical coding systems for drugs are needed to ensure appropriate grouping. Lastly, we utilised the GPRD to provide an example of a systematically performed drug safety study. In a small subset of data, we generated hypotheses of drug-induced Hashimoto's disease. Associations were subsequently evaluated in a larger subset of data. No drugs were clearly associated with risk of Hashimoto's disease.
2
Mustafa, Elwaleed Ibrahim. "Experimental autoimmune sialadenitis : studies of immunopathogenesis, cellular signaling and MHC genetics /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4791-0/.
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Madsen, Rasmus Kirkegaard. "Metabolic variation in autoimmune diseases." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-59475.
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The human being and other animals contain immensely complex biochemical processes that govern their function on a cellular level. It is estimated that several thousand small molecules (metabolites) are produced by various biochemical pathways in humans. Pathological processes can introduce perturbations in these biochemical pathways which can lead to changes in the amounts of some metabolites.Developments in analytical chemistry have made it possible measure a large number metabolites in a single blood sample, which gives a metabolic profile. In this thesis I have worked on establishing and understanding metabolic profiles from patients with rheumatoid arthritis (RA) and from animal models of the autoimmune diseases diabetes mellitus type 1 (T1D) and RA.Using multivariate statistical methods it is possible to identify differences between metabolic profiles of different groups. As an example we identified differences between patients with RA and healthy volunteers. This can be used to elucidate the biochemical processes that are active in a given pathological condition.Metabolite concentrations are affected by a many other things than the presence or absence of a disease. Both genomic and environmental factors are known to influence metabolic profiles. A main focus of my work has therefore been on finding strategies for ensuring that the results obtained when comparing metabolic profiles were valid and relevant. This strategy has included repetition of experiments and repeated measurement of individuals’ metabolic profiles in order to understand the sources of variation.Finding the most stable and reproducible metabolic effects has allowed us to better understand the biochemical processes seen in the metabolic profiles. This makes it possible to relate the metabolic profile differences to pathological processes and to genes and proteins involved in these.The hope is that metabolic profiling in the future can be an important tool for finding biomarkers useful for disease diagnosis, for identifying new targets for drug design and for mapping functional changes of genomic mutations. This has the potential to revolutionize our understanding of disease pathology and thus improving health care.
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Gambelunghe, Giovanni. "Immunogenetic studies in autoimmune endocrine diseases /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-691-x/.
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Graaff, Wiebo Leendert van der. "T cell differentiation in autoimmune diseases." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/70775.
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Leeuw, Karina de. "Premature atherosclerosis in systemic autoimmune diseases." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2008. http://irs.ub.rug.nl/ppn/.
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Pliushchyk, D. "Autoimmune diseases. How to prevent them?" Thesis, Sumy State University, 2016. http://essuir.sumdu.edu.ua/handle/123456789/45958.
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An autoimmune disease is a disease in which the immune system mistakenly attacks the body‘s own cells and tissues.
Different body parts like digestive system, joints, nerves, blood vessels, red blood cells, connective tissues, skin and endocrine system can be affected. It‘s found that autoimmune diseases and conditions predominantly affect people during the childhood. Autoimmune disease and condition symptoms vary from individual to individual.
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Ning, Shunbin. "Interferon Regulatory Factors and Autoimmune Diseases." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/6542.
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Narayanan, Harish Anandha. "Molecular Understanding of Selected Autoimmune Diseases." Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/146614.
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Pathogens that affect the immune system, or defects in the immune system contribute to numerous autoimmune diseases. In this paper, we are going to review, analyze and understand recent findings in literature. The papers that are to be reviewed explore the observation of loss of regulatory T cells in individuals with multiple sclerosis, the importance of CD4+ during HIV infection, the role of CCR6 in the immune system and the importance of Pan-DR-Binding Hsp60 self-epitopes in rheumatoid arthritis. So this literary review is limited to understanding major defects in specific parts of the immune system and its role in causing the specific autoimmune disease. The reason for this focus is to highlight the importance of the immune system in the functioning of many processes in our body and more specifically the importance of T cells and its regulators in maintaining the immune system.
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BORTOLOTTI, Daria. "HLA-G MOLECULES IN INFECTION AND AUTOIMMUNE DISEASES." Doctoral thesis, Università degli studi di Ferrara, 2015. http://hdl.handle.net/11392/2389029.
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Ieronymaki, Matthaia. "Immunological and Conformational characterization of synthetic peptide probes for autoimmune diseases." Thesis, Cergy-Pontoise, 2016. http://www.theses.fr/2016CERG0831/document.
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Les maladies auto-immunes sont des maladies chroniques et hétérogènes caractérisées par des réactions du système immunitaire acquis contre les propres tissus sains de l'organisme. Ces maladies affectent presque 5% de la population mondiale et en particulier les jeunes adultes. La complexité de leur spectre est énorme et même si leur étiologie est encore incertaine, il a été démontré que des facteurs génétiques et environnementaux sont impliqués dans le déclenchement du mécanisme pathologique. Cependant, il est nécessaire d'utiliser des outils diagnostiques et / ou pronostiques fiables pour le diagnostic précoce avant que des dommages cellulaires irréversibles ne se produisent et pour surveiller la progression de la maladie.De nombreuses études ont mis en évidence la présence de différents auto-anticorps dans le sérum de patients atteints de maladies auto-immunes. Les auto-anticorps qui sont spécifiques d’une maladie peuvent être utilisés en tant que biomarqueurs (BM) pour son diagnostic alors que les auto-anticorps qui diffèrent en fonction de l'état de la maladie peuvent être utilisés dans le suivi des patients. En fait, dans le cas de l'auto-immunité, un BM facilement détectable et fiable peut être représenté par le titre d'un auto-anticorps spécifique.Dans ce contexte, nous nous intéressons à deux maladies différentes, la sclérose en plaques (SEP) et la gammapathie monoclonale, en utilisant l'approche chimique inverse via le criblage de librairies de peptides par des sérums de patients.En particulier, l'importance des anticorps anti-myéline, et surtout, des anticorps anti-MOG (myéline oligodendrocyte glycoprotéine) est toujours l’objet de débats, soulignant la question très controversée d'un rôle pathogène putatif d'anticorps anti-MOG dans la SEP. Dans cette thèse, nous avons étudié le rôle de MOG comme auto-Ag putatif dans la SEP en utilisant le modèle expérimental d’encéphalomyélite auto-immune (EAE). Ainsi, afin d'évaluer la présence d'un mécanisme d’« epitope spreading » des cellules B, à savoir l'apparition d'une réponse dirigée vers des épitopes distincts de l'agent pathogène induisant la réponse immunitaire, nous avons synthétisé et testé en tant que sondes antigéniques cinq peptides synthétiques qui couvrent la séquence 1-117 de MOG.La seconde étude a porté sur la sélection d'un peptide mimant l'épitope minimal reconnu par l'anticorps monoclonal commercial anti- natural killer cell-1 humain (anti-HNK-1) en utilisant la résonance plasmonique de surface (SPR). L’épitope HNK-1 est considéré comme le déterminant antigénique de la glycoprotéine associée à la myéline (MAG), un composant quantitativement mineur des gaines de myéline. On observe que les patients atteints de troubles neurologiques auto-immuns, tels que la gammapathie monoclonale à IgM et la polyneuropathie démyélinisante, développent souvent des anticorps anti-MAG ciblant spécifiquement l’épitope HNK-1. Par conséquent, l'identification et la caractérisation de ces anticorps est pertinente. Le peptide choisi suite à notre étude pourrait ensuite être utilisé chez des patients atteints de troubles neurologiques pour le développement d'un outil de diagnostic fiable ou de surveillance de l'activité de la maladie par l'identification d'anticorps anti-HNK-1 dans le sérum des patientsAutoimmune diseases (ADs) refer to chronic and heterogeneous diseases with acquired immune system’s reactions against the body’s own healthy tissues. ADs affect more than 5% of the population worldwide and especially young adults. The complexity of their spectrum is enormous and even if their etiology is still unclear, it was demonstrated that both genetic and environmental factors are involved in triggering the pathological mechanism. Hence, a reliable diagnostic and/or prognostic tool for an early diagnosis of ADs before irreversible cellular damage occurs and for monitoring their progression is demanded.Numerous studies have revealed the presence of different autoantibodies (auto-Abs) in sera of patients suffering from ADs. Autoantibodies that are specific for a disease can be used as biomarkers (BMs) for its diagnosis while autoantibodies that differ depending on the disease state can be used in the follow up of the patients. Actually, in the case of autoimmunity, an easily detectable and reliable BM may be represented by the titer of a specific auto-Ab.In this context, we aimed to identify target(s) of the response for two different ADs, multiple sclerosis (MS) and monoclonal gammopathy, using the chemical reverse approach, which involves the screening of focused antigen (Ag) libraries with patients’ serum.In particular, the significance of anti-myelin antibodies, and especially, anti- Myelin Oligodendrocyte Glycoprotein (anti-MOG) antibodies is still matter of debate, underscoring the highly controversial issue of a putative pathogenetic role of anti-MOG antibodies in MS. In this thesis we investigated the role of MOG as putative auto-Ag in MS using the experimental autoimmune encephalomyelitis (EAE) model. Moreover, in order to assess the presence of a B-cell epitope spreading mechanism, i.e. the occurrence of a response directed toward epitopes distinct from the disease-inducing agent, we synthesized and tested as antigenic probes also five synthetic peptides covering the 1-117 sequence of MOG.The second issue focused on the selection of a peptide mimicking the minimal epitope recognized by the commercial available monoclonal antibody anti-human natural killer cell-1 (anti-HNK-1) using Surface Plasmon Resonance (SPR) technique. HNK-1 epitope, is considered as the antigenic determinant of myelin-associated glycoprotein (MAG), a quantitatively minor component of myelin sheaths. It is observed that patients affected by autoimmune neurological disorders, such as IgM monoclonal gammopathy and demyelinating polyneuropathy, often develop anti-MAG antibodies specifically targeting the HNK-1 epitope. Accordingly, identification and characterisation of these antibodies is relevant. The selected peptide could be subsequently used in earlier stage patients for the development of a novel and reliable diagnostic tool for anti-HNK-1 antibody identification in sera of patients affected by autoimmune neurological disorders monitoring disease activity
12
Ye, Ping. "Autoimmunity in chronic periodontitis." Thesis, The University of Sydney, 2003. http://hdl.handle.net/2123/4256.
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Profound perturbation of epithelial structure is a characteristic feature of the immunopatholoical response to bacterial antigens considered to be central in the pathogenesis of the destructive lesion of periodontitis. The pathological basis for the disturbance of epithelial structure is not understood. It was demonstrated that the structural integrity and functional differentiation of the lining epithelium is compromised in relation to inflammatory changes associated with destructive periodontitis. In the pathological lining epithelium of the periodontal pocket there was a marked reduction of epithelial cadherin important in intercellular adhesion, of involucrin, a marker of terminal differentiation, and of the gap junction connexions that form intercellular communication channels. These changes were associated with alterations of filamentous actin expression, collectively indicating profound perturbation of epithelial structure. The data reported support the concept that the ability of the pathological lining epithelium to function as an effective barrier against the ingress of microbial products into the tissues is severely compromised (Ye et al., 2000). In addition, a recent study (Ye et al., 2003) by Western analysis of serum IgG from all 22 patients with chronic periodontitis tested indicated recognition of multiple epithelial components in individual patterns. In contrast, subjects with a healthy periodontium displayed only trace recognition of epithelial antigens. Levels of epithelial-reactive antibodies were significantly correlated with attachment loss as an indication of disease activity. To investigate a possible relationship between the bacterial flora adjacent to the diseased sites and the presence of epithelial-reactive antibodies, subgingival plague samples were taken from deep periodontal pockets and cultured anaerobically. Gram positive bacteria containing antigens potentially cross-reactive with epithelial cells were reproducibly isolated by probing membrane colony lifts with affinity-isolated (epitheial-specific) antibodies. The bacteria were identified as streptococci (S. mitis, S. constellatus and two S. intermedius strains) and Actinomyces (A. georgiae, and A. sp. oral clone) by 16S rDNA sequence homology. Recognition by affinity-isolated antibodies of antigens from the captured organisms was confirmed by Western analysis. Conversely, absorption of affinity-isolated antibodies with bacterial species specifically reduced subsequent recognition of epithelial antigens. To identify the auto-antigens, a human keratinocyte cDNA expression library in Lambda phage was probed using a pooled sera. Groups of responders were detected for CD24 (a recently described adhesion molecule also known as P-selectin ligand), antioxidant protein 2 (a newly recognised member of the thiol-dependment anti-oxidant proteins), lavtate dehydrogenase A, the transcription factor NFAT5, and for three genes encoding novel proteins. Six identified bacteria, especially S intermedius were demonstrated to absorb antibodies reaching with identified auto-antigens in patterns varying between individuals. This evidence indicated that during the course of periodontits, subjects develop increased levels of antibodies to common oral bacteria amongst which are included tissue cross-reactive antigens. Periodontitis could therefore present a risk for the subsequent initiation or exacerbation of a broad spectrum of disease processes including autoimmune, inflammatory, proliferative and degenerative disorders.
13
Ye, Ping. "Autoimmunity in chronic periodontitis." University of Sydney, 2003. http://hdl.handle.net/2123/4256.
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Doctor of PhilosophyProfound perturbation of epithelial structure is a characteristic feature of the immunopatholoical response to bacterial antigens considered to be central in the pathogenesis of the destructive lesion of periodontitis. The pathological basis for the disturbance of epithelial structure is not understood. It was demonstrated that the structural integrity and functional differentiation of the lining epithelium is compromised in relation to inflammatory changes associated with destructive periodontitis. In the pathological lining epithelium of the periodontal pocket there was a marked reduction of epithelial cadherin important in intercellular adhesion, of involucrin, a marker of terminal differentiation, and of the gap junction connexions that form intercellular communication channels. These changes were associated with alterations of filamentous actin expression, collectively indicating profound perturbation of epithelial structure. The data reported support the concept that the ability of the pathological lining epithelium to function as an effective barrier against the ingress of microbial products into the tissues is severely compromised (Ye et al., 2000). In addition, a recent study (Ye et al., 2003) by Western analysis of serum IgG from all 22 patients with chronic periodontitis tested indicated recognition of multiple epithelial components in individual patterns. In contrast, subjects with a healthy periodontium displayed only trace recognition of epithelial antigens. Levels of epithelial-reactive antibodies were significantly correlated with attachment loss as an indication of disease activity. To investigate a possible relationship between the bacterial flora adjacent to the diseased sites and the presence of epithelial-reactive antibodies, subgingival plague samples were taken from deep periodontal pockets and cultured anaerobically. Gram positive bacteria containing antigens potentially cross-reactive with epithelial cells were reproducibly isolated by probing membrane colony lifts with affinity-isolated (epitheial-specific) antibodies. The bacteria were identified as streptococci (S. mitis, S. constellatus and two S. intermedius strains) and Actinomyces (A. georgiae, and A. sp. oral clone) by 16S rDNA sequence homology. Recognition by affinity-isolated antibodies of antigens from the captured organisms was confirmed by Western analysis. Conversely, absorption of affinity-isolated antibodies with bacterial species specifically reduced subsequent recognition of epithelial antigens. To identify the auto-antigens, a human keratinocyte cDNA expression library in Lambda phage was probed using a pooled sera. Groups of responders were detected for CD24 (a recently described adhesion molecule also known as P-selectin ligand), antioxidant protein 2 (a newly recognised member of the thiol-dependment anti-oxidant proteins), lavtate dehydrogenase A, the transcription factor NFAT5, and for three genes encoding novel proteins. Six identified bacteria, especially S intermedius were demonstrated to absorb antibodies reaching with identified auto-antigens in patterns varying between individuals. This evidence indicated that during the course of periodontits, subjects develop increased levels of antibodies to common oral bacteria amongst which are included tissue cross-reactive antigens. Periodontitis could therefore present a risk for the subsequent initiation or exacerbation of a broad spectrum of disease processes including autoimmune, inflammatory, proliferative and degenerative disorders.
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Wang, Chuan. "DNA Sequence Variants in Human Autoimmune Diseases." Doctoral thesis, Uppsala universitet, Molekylär medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-179189.
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Human autoimmune diseases are hallmarked by inappropriate loss-of-tolerance and self-attacking response of the immune system. Studies included in this thesis are focusing on the implication and functional impact of genetic factors in three autoimmune diseases rheumatoid arthritis (RA), asthma, and systemic lupus erythematosus (SLE). Using genetic association studies, we found in study I and II that sequence variants of the interferon regulatory factor 5 (IRF5) gene were associated with RA and asthma, and the associations were more pronounced in certain disease subtypes. Distinct association patterns or risk alleles of the IRF5 gene variants were revealed in different diseases, indicating that IRF5 contributes to disease manifestations in a dose-dependent manner. In study III, we found that seven out of eight genetic risk loci for SLE, which were originally identified in East Asian populations, also conferred disease risk with the same risk alleles and comparable magnitudes of effect sizes in Caucasians. Remarkable differences in risk allele frequencies were observed for all associated loci across ethnicities, which seems to be the major source of genetic heterogeneity for SLE. In study IV we explored an exhaustive spectrum of sequence variants in the genes inhibitor of kappa light polypeptide gene enhancer in B-cells kinase epsilon (IKBKE) and interferon induced with helicase C domain 1 (IFIH1) by gene resequencing, and identified nine variants in IKBKE and three variants in IFIH1 as genetic risk factors for SLE. One of the associated variants may influence splicing of IKBKE mRNA. In study V we provided genome-wide transcriptional regulatory profiles for IRF5 and signal transducer and activator of transcription 4 (STAT4) using chromatin immunoprecipitation-sequencing (ChIP-seq). The target genes of IRF5 and STAT4 were found to play active roles in pathways related with inflammatory response, and their expression patterns were characteristic for SLE patients. We also identified potential cooperative transcription factors for IRF5 and STAT4, and disease-associated sequence variants which may affect the regulatory function of IRF5 and STAT4. In conclusion, this thesis illuminates the contribution of several genetic risk factors to susceptibility of human autoimmune diseases, which facilitates our understanding of the genetic basis of their pathogenesis.
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Emonts, M. "Polymorphisms in immune response genes in infectious diseases and autoimmune diseases." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/14316.
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Hall, Richard James, and n/a. "Chromosome 18 and autoimmune disease." University of Otago. Department of Biochemistry, 2005. http://adt.otago.ac.nz./public/adt-NZDU20070221.141018.
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The autoimmune diseases embody a diverse range of common human conditions that are caused by a loss of self-tolerance in the host immune system to a specific organ or tissue type. Approximately 5% of the general population are affected by autoimmune diseases which include type 1 diabetes (T1D), rheumatoid arthritis (RA) and Graves disease (GD). The majority of the autoimmune diseases are multifactorial in origin, brought about by a combination of both environmental and genetic factors. Numerous susceptibility loci have been identified for each autoimmune disease and a number of these loci have been shown to be shared amongst the autoimmune diseases. The fine-mapping of susceptibility loci to the underlying disease genes remains the current challenge facing complex disease genetics. This project aimed to further characterise the autoimmune disease susceptibility locus IDDM6 on chromosome 18q12-21. This was achieved by using a comparative mapping approach that incorporates the study of genetic association in human autoimmune disease alongside the consomic mapping of the orthologous region in the non-obese diabetic (NOD) mouse model of autoimmunity.
Deleted in colorectal carcinomas (DCC) provided a strong candidate gene at IDDM6 and the resident R201G polymorphism was identified as a functional candidate A potential mechanism for the R201G polymorphism involvement in T1D aetiology was identified where the polymorphism may affect the ability of DCC to induce apoptosis in vitro. However, no evidence for R201G association could be detected in autoimmune disease case-control datasets from the New Zealand (NZ) population (T1D n = 428, RA n = 730, autoimmune thyroid disease n = 192 (AITD); versus n = 1246 healthy controls). In addition, no evidence for R201G involvement in T1D could be provided in a transmission disequilibrium test (TDT) incorporating 382 affected sib-pair families (54.2% transmission; P = 0.15). Significant association of R201G with GD was detected in a United Kingdom (UK) dataset (P = 0.002) from the Newcastle population (423 cases vs. 393 controls) but this was not replicated in an additional dataset from the UK Birmingham population (731 cases vs 668 controls; P = 0.81). It was concluded that the R201G polymorphism may encode susceptibility to GD but is unlikely to be the sole aetiological variant that accounts for the linkage previously observed at IDDM6 in autoimmune disease. To further investigate DCC as a positional candidate at IDDM6, five SNPs were selected from a 100 kb window surrounding a DCC-resident microsatellite that had previously been associated with T1D, called "88,21". The five SNPs were genotyped in the NZ T1D dataset, and the ascertainment of estimated haplotypes in this dataset revealed association of a rare haplotype with T1D, called haplotype H (3.31% cases vs 1.17% controls; P = 0.0044), in addition to global association of all haplotypes (P = 0.018). Haplotype H was also associated in an independent case-control dataset from the UK comprised of 400 T1D subjects and 443 healthy controls (P = 0.038). Maximum support for association of haplotype H was extended when both the UK and NZ T1D datasets were combined (P = 0.0017). Association of haplotype H could not be verified in a family-based test for association using the 382 UK T1D families (P = 0.40). However, the inclusion of the DCC SNPs in a TDT analysis of the published DCC-resident microsatellites "88,21" and "55,26", that had been used to identify IDDM6, extends support for the previously-associated 2-10 haplotype (2-10 refers to the published allele nomenclature at "88,21" and "55,26" respectively; 2-10-haplotype A; 59.6% T; P = 0.0058). There was no evidence for association of the five SNPs with RA or AITD when using either individual SNP analyses or estimated haplotypes in the NZ datasets. A similar lack of association was reported for the UK Newcastle GD dataset. Taken together, these data further support DCC, or a nearby gene, as conferring susceptibility to T1D.
The human genetic data that supports IDDM6 involvement in autoimmune disease is further strengthened by consomic mapping of the orthologous region in mouse, using the non-obese diabetic mouse (NOD) model of autoimmune disease. In this thesis, the first evidence for a diabetes and thyroiditis susceptibility locus on mouse chromosome 18 is presented, which have been designated Idd21 and Sat1 respectively. This was achieved by using a chromosome-replacement strain with chromosome 18 derived from the diabetes-resistant Biozzi ABH strain on a diabetes-susceptible NOD genome, called NOD.ABH[Chr�⁸]. Mouse chromosome 18 contains orthology to both IDDM6 and the rat diabetes-susceptibility locus Iddm3. The NOD.ABH[Chr�⁸] mice showed a dramatic and significant reduction in diabetes incidence (30% of females were affected by 7 months of age versus 85% in NOD; P <0.0001) and that of thyroiditis (15.5% at 12 months compared to 37.4% in NOD; P <0.002).
The comparative mapping of the chromosome 18 autoimmune susceptibility locus IDDM6 in human and mouse presented in this thesis provides further support for this locus. This research also clearly defines the next steps required to fine-map IDDM6 to the underlying disease genes, especially in regard to the DCC gene.
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Halonen, Maria. "Monogenic model for autoimmune diseases : molecular basis of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/halonen/.
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Prokunina, Ludmila. "Strategies for Identification of Susceptibility Genes in Complex Autoimmune Diseases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4138.
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Adikari, Sanjaya Bandara. "Cytokine-modulated dendritic cell immunotherapy in autoimmune diseases /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-149-0/.
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Kazbay, Kasim. "Leu 1+B cells in autoimmune human diseases." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55681.
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Gupta, Yask [Verfasser]. "Systems genetics in polygenic autoimmune diseases / Yask Gupta." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2016. http://d-nb.info/1117169758/34.
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Motwani, Mona. "Cytosolic DNA sensing in autoimmune and autoinflammatory diseases." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1074.
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Cytosolic DNA sensing plays a key role in autoimmune and autoinflammatory diseases. STING is a cytosolic adaptor protein which upon activation leads to induction of type I interferons and inflammatory cytokines. Recently, gain-of-function mutations in STING have been identified in patients with an autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI). We compared two independent SAVI mutant mouse models and revealed a hierarchy of immune abnormalities which were dependent on SAVI mutation in lymphocytes. We also showed that bone marrow from the V154M mutant mice transfers disease to the wild-type host, whereas the N153S does not, indicating mutation-specific disease outcomes. Collectively, these mutant mice recapitulate disease features seen in SAVI patients and highlight mutation-specific functions of STING.
Other autoimmune mouse models such as DNAseII and DNAseIII-deficient mice, that fail to degrade DNA result in activation of the cGAS STING pathway. Deficiency of this pathway in these mouse models ameliorates lethality. By contrast, we previously reported that STING potently suppresses inflammation in a pristane-induced model of autoimmunity. In this model, we show that both cGAS- and STING-deficient mice exhibit exacerbated disease phenotypes compared to controls. We report that STING constrained TLR activation, and thereby limited autoimmune manifestations. Consistent with this premise, cGAS or STING deficient mice that lack a common TLR chaperone UNC93b develop less severe systemic autoimmunity than cGAS or STING deficient mice that are UNC93b sufficient. Overall, this study demonstrates that STING activation constrains systemic autoimmune disease and has important implications for cGAS STING-directed therapies.
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Massey, Jonathan Peter. "Mapping the genes for complex canine autoimmune diseases." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/mapping-the-genes-for-complex-canine-autoimmune-diseases(5ea87f15-cfd6-4764-87b4-287cff05ed96).html.
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The aetiology of autoimmune disease is a complex interplay between genetics, environment and immunological regulation. Our understanding of the genetic aspects of autoimmunity has increased with recent findings from Genome Wide Association Studies (GWAS). There is now a movement towards meta-analyses of GWA studies in order to increase the number of genetic loci detected. There are also efforts to detect common genetic risk factors amongst groups of diseases that potentially share common aetiopathogenic pathways. Animal models have formed the basis of many genetic discoveries and the domestic dog presents a spontaneous model for many diseases, including autoimmunity. Through man’s efforts to create specific breeds, the dog has acquired a genomic architecture consisting of long haplotype blocks and extensive linkage disequilibrium. This means that a GWAS can be conducted in dog breeds with fewer samples and fewer markers than an equivalent study in humans, reducing costs, cohort collection times, and data handling/storage considerations. Successful canine GWA studies are now starting to be published. Building upon this success, the findings from GWA studies in three canine autoimmune diseases (across six different breeds), with equivalent human pathologies, are presented. Dogs with diabetes mellitus (similar to latent autoimmune diabetes of adulthood in man), lymphocytic thyroiditis (similar to Hashimoto’s thyroiditis), and anal furunculosis (similar to perianal Crohn’s disease) were compared to control dogs to identify genetic susceptibility loci underlying disease. Follow-up genotyping of the top hits from the GWAS analyses were conducted to replicate findings and to better characterise the diseases across a number of dog breeds. Typing of MHC class II genes, important in the immune response, was also undertaken in canine diabetes mellitus and canine lymphocytic thyroiditis. In anal furunculosis, high-throughput, next-generation sequencing was utilised to identify novel mutations and fine-map associations at discovered loci. Several genes were identified in all of these canine autoimmune diseases, many with good candidate function. Some of these genes indicated common genetic susceptibility loci and pathways between canine autoimmune diseases. Breed-specific genetic effects underlying canine diabetes mellitus and canine lymphocytic thyroiditis were identified, which has implications for disease diagnosis and clinical management. Novel loci for investigation in the corresponding human disease studies have been identified and future work will begin to genetically link the conditions in dog and man.
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Lee, Youjin. "Pathogenic Potential ofCD4 T Cells in Autoimmune Diseases." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17465319.
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The molecular mechanisms governing T helper (Th) cell differentiation and function have revealed a complex network of transcriptional and protein regulators. Cytokines not only initiate the differentiation of CD4 T helper into subsets, but also influence the identity, plasticity and effector function of a T cell. Th17 cells, named for producing interleukin 17 (IL-17) as their signature cytokine, secrete a cohort of other cytokines including IL-22, IL-21, IL-10, IL-9, IFNγ, and GM-CSF. In recent years, Th17 cells have emerged as a key player in host defense against both extracellular pathogens and fungal infections. Th17 cells have also been implicated as one of the main drivers in the pathogenesis of autoimmune diseases such as multiple sclerosis, which are likely mediated in part by the cytokines that Th17 cells produce.
Here in this thesis, we explore the pathogenic regulation of CD4 T cells in the context of the autoimmune diseases, multiple sclerosis and inflammatory bowel disease. We attempt to understand the mechanisms by which Th17 cells promote pathogenic inflammation by utilizing high throughput whole genome mRNA sequencing as well as next generation single cell RNA sequencing to uncover novel regulators that drive effector function. Advances in high throughput genomic sequencing allowed us to uncover an unexpected heterogeneity and diversity in Th17 cell populations. The four studies outlined in this thesis reconcile many confounding questions in the areas of autoimmune pathogenicity and reveal key regulators that define the various functional states of Th17 cells.Medical Sciences
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Minas, Konstantinos. "New approaches to autoimmune therapy through gene analysis." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources. Restricted no access until May 19, 2011. Online version available for University member only until May 19, 2012, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25620.
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Lövgren, Tanja. "Endogenous Type I Interferon Inducers in Systemic Autoimmune Diseases." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7181.
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Patients with systemic lupus erythematosus (SLE) have elevated levels of interferon (IFN)-α in blood and IFN-α-producing cells in tissues. In the present thesis, we investigate the mechanisms behind the upregulated IFN-α-production in SLE and also show that the IFN-α system is activated in primary Sjögren’s syndrome (pSS), with IFN-α-producing cells in the major affected organ, the salivary glands. The IFN-α is a type I IFN, a family of cytokines counteracting especially viral infections, by acting directly on infected cells, and via many immunomodulatory effects. The latter may also contribute to autoimmune processes.
The type I IFNs are usually produced upon recognition of microbial structures. In SLE, however, DNA-containing immune complexes (ICs) that induce IFN-α production are found. Many autoantibodies in SLE and pSS are directed to nucleic acids or to DNA/RNA-binding proteins. We show that also RNA in complex with autoantibodies from SLE or pSS patients (RNA-IC) induces IFN-α-production. The RNA could be either in the form of RNA-containing material released from apoptotic or necrotic cells or as a pure RNA-containing autoantigen, the U1 small nuclear ribonucleoprotein particle.
The IFN-α-production induced by RNA-IC occurred in plasmacytoid dendritic cells (PDCs), also termed natural IFN-producing cells (NIPCs), via binding to Fcγ-receptor IIa, endocytosis and triggering of Toll-like receptors (TLRs), probably TLR7 and TLR9. The RNA-IC may also have other effects, and we found that they induce prostaglandin E2 (PGE2) production in monocytes and tumor necrosis factor (TNF)-α in both monocytes and NIPC/PDC. The PGE2 downregulated the IFN-α induction in NIPC/PDC, and the IFN-α induction was increased in monocyte-depleted cell cultures.
The findings presented in this thesis aids in the understanding of the mechanisms behind the activated IFN-α system in SLE and other autoimmune diseases, and shows that also pSS is one of these diseases.
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Lövgren, Tanja. "Endogenous type I interferon inducers in systemic autoimmune diseases /." Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7181.
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Dahlman, Ingrid. "Genetic dissection of experimental autoimmune neuroinflammatory diseases in rats /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3768-0/.
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Almeida, Rita Alexandra Silva de. "Autoimmune blistering diseases: bullous Pemphigold, Pemphigus vulgaris and follaceus." Master's thesis, Universidade de Aveiro, 2016. http://hdl.handle.net/10773/22358.
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Mestrado em Biologia Molecular e CelularBullous pemphigoid and pemphigus belong to a group of autoimmune blistering diseases that attacks the body healthy tissue, causing blisters and erosions on the skin. Bullous pemphigoid is characterized by an attack to the basal keratinocytes, making them to lose adhesion to the basement membrane zone, whereas in pemphigus happens that keratinocytes in epidermis and mucous membranes lose cell-to-cell adhesion. A single mouse click on the topic pemphigus in PubMed reveals more than 9 000 articles providing one or the other information about this group of autoimmune blistering disease. This could only demonstrate the enormous scientific and clinical interest in unraveling the mysteries that still surrounds these diseases, which began over 60 years ago with the differentiation of bullous pemphigoid from pemphigus. BP is the most common ABD affecting mainly the elderly. It has a high mortality rate, mainly due to therapy and some other complications disease-associated. Lesions are caused by autoantibodies that fix the complement and thus mediate an inflammatory process. Pemphigus has an increased incidence in women. PV has a mean age of onset between 60 and 70 years old in European countries and between the ages of 30 and 50 in the remaining countries of the world. PF has it between 30 to 45 years old. Moreover, the mortality rates of BP patients are two times higher and of pemphigus patients three times higher, than general population. Much information points out a clear genetic predisposition for disease, combined with triggering factors. Regarding the diagnosis, the physical evaluation is a milestone, where the skin, mucous membranes and the nails are examined. Also, patients are submitted to meticulous questions about symptoms where the medical history is not left out. Some quantitative and qualitative histologic examination is always performed, like ELISA. Nowadays, corticosteroids are still the main therapy; however, novel therapeutic targets have been developed. The therapeutic management comprised a series of drugs, like corticosteroids, mycophenolate mofetil, rituximab or innovative approaches associated to biotechnology. Using two associated drugs really improved patients’ prognosis. However, these medications could lead to the arising of other disorders, namely respiratory ones, as they debilitate the immune system. The contraction of such disease in a hospital environment often occurs due to one or more strains, which makes it difficult to choose a suitable therapy. Infections with bacterial origin, viruses, etc., also associate themselves to the diseases, sometimes. There have been documented cases of patients with pemphigus or BP associated with other disorders, such as neoplasia, neurologic disorders, other immune disorders. This brief review will focus on three autoimmune diseases – BP, PV and PF.
Penfigóide bolhoso e pênfigo pertencem a um grupo de doenças bolhosas auto-imunes que afectam tecidos saudáveis do corpo, causando formação de bolhas e lesões na pele. Penfigóide bolhoso é caracterizado pelo ataque aos queratinócitos basais, fazendo com que estes percam a capacidade de aderência à zona da membrana basal, enquanto no pênfigo os queratinócitos na epiderme e membranas mucosas perdem adesão celular. Um único click no tópico “pemphigus” na PubMed revela mais de 9 000 artigos que providenciam informação acerca deste grupo de doenças bolhosas auto-imunes. Isto demonstra o enorme interesse clínico e científico em desvendar os mistérios que ainda cercam estas doenças, que começou há mais de 60 anos com a diferenciação de penfigóide bolhoso de pênfigo. Penfigóide bolhoso é a doença bolhosa auto-imune mais comum e afecta maioritariamente os idosos. Tem uma taxa de mortalidade elevada sobretudo devido a terapia associada e outras complicações que surgem associadas à doença. As lesões são causadas por autoanticorpos que fixam o complemento, mediando um processo inflamatório. Pênfigo tem uma incidência superior nas mulheres. A idade média de início de pênfigo vulgar é entre os 60 e os 70 anos nos países Europeus e entre 30 e 50 nos restantes zonas do globo. Pênfigo foliáceo tem uma idade média de iniciação entre 30 a 45 anos. Além disso, as taxas de mortalidade de penfigóide bolhoso são cerca de duas vezes superior e de pênfigo cerca de três vezes superior, comparando com a população geral. Muita informação aponta para uma clara predisposição genética da doença, combinada com factores que podem desencadear a doença. No que respeita o diagnóstico, a avaliação física é um marco importante, onde a pele é examinada, tal como as membranas mucosas e as unhas. Os pacientes também são submetidos a questões meticulosas sobre os sintomas, onde o historial médico não é deixado de fora. Examinação histológica quantitativa e qualitativa é sempre feita, por exemplo ELISA. Hoje em dia os corticosteróides continuam a ser a terapia principal, contudo, novas estratégias terapêuticas têm vindo a ser desenvolvidas. A gestão terapêutica compreende uma serie de medicação, como os corticosteróides, micofenolato, rituximab ou abordagens inovadoras associadas a biotecnologia. O uso de compostos associados melhora o prognóstico do doente. Contudo, estas medicações podem levar ao aparecimento de complicações devido a alterações no sistema imunitário, tais como complicações respiratórias. Quando este tipo de complicações aparecem em ambiente hospitalar são, normalmente, devido a uma ou varias estirpes, o que dificulta o tratamento. Infecções com origem bacteriana, vírus, etc., são elas próprias associadas a penfigóide bolhoso e pênfigo. Tem vindo a ser documentados casos de ambas doenças associadas a outras complicações, como cancros, outras doenças do foro imunitário, neurológicas, etc. Esta breve revisão aborda as três doenças bolhosas auto-imunes – penfigóide bolhoso, pênfigo vulgar e pênfigo foliáceo.
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Dumoitier, Nicolas. "Analysis of B lymphocytes in systemic autoimmune vascular diseases." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC304.
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Différents mécanismes de tolérance centraux et périphériques permettent la sélection négative des lymphocytes B auto-réactifs tout en préservant la sélection positive et la différenciation en plasmocytes producteurs d’anticorps de haute affinité. Ces mécanismes de tolérance sont altérés dans les pathologies auto-immunes et ces altérations conduisent à la production d’auto-anticorps. Ainsi, un ciblage thérapeutique des lymphocytes B autoréactifs, notamment avec les anticorps monoclonaux anti-CD20, donne des résultats prometteurs dans différentes pathologies auto-immunes. Si ces traitements ont démontré leur efficacité dans les vascularites associées aux anticorps anti-protéines cytoplasmiques des polynucléaires neutrophiles (ANCA) (VAA), d’autres maladies auto-immunes à composante vasculaire, dont la sclérodermie systémique (ScS) ou l’hypertension artérielle pulmonaire idiopathique (iHTAP), restent insensibles à ce ciblage. D’autre part, la caractérisation des sous-populations lymphocytaires B pathologiques porte essentiellement sur la détection des cellules exprimant ces auto-anticorps. Ce projet a ainsi eu pour objectif une caractérisation phénotypique et fonctionnelle comparative des sous-populations lymphocytaires B impliquées dans ces différentes pathologies auto-immunes vasculaires.Les patients atteints de granulomatose avec polyangéite présentent une activation importante de l’immunité innée mais aussi une production augmentée d’IL6 par les lymphocytes B en lien avec une activation importante des lymphocytes T. Des modifications phénotypiques des lymphocytes B sont observées chez les patients atteints de VAA, notamment la polyangéite microscopique suggérant pour cette vascularite une composante auto-immune. Ainsi, le CD69, le CD95 et le récepteur à l’IL-6 permettent de discriminer les différentes formes de la maladie. Dans la ScS et plus particulièrement dans les formes les plus sévères, diffuses, et dans l’HTAP associée, une activation basale des lymphocytes B est observée avec une sécrétion importante d’IL-6 et de TGF-ß. Ce dernier contribue, in vitro, à la prolifération des fibroblastes et à la sécrétion de collagène, responsables des mécanismes fibrosants observés dans la pathologie. Enfin, les basophiles présents dans la ScS semblent également activés et participer à l’activation des lymphocytes B et des fibroblastes malades. Ces résultats montrent que le lymphocyte B, en plus de son rôle dans la production d’anticorps, peut intervenir en physiopathologie par la sécrétion de cytokines pro-inflammatoires ou pro-fibrosantes comme l’IL-6 et le TGF-ß, toutes deux impliquées dans les processus d’activation vasculaireTolerance mechanisms allow the negative selection of auto-reactive B lymphocytes while protecting the positive selection and differentiation of plasmocytes that produce high affinity antibodies. Tolerance mechanisms are altered in various auto-immune diseases and allow the production of auto-antibodies. Indeed, therapeutic targeting of autoreactive B lymphocytes, notably using anti-CD20 monoclonal antibodies, gives promising results in several auto-immune pathologies. While these treatments show a relative efficacy in anti-neutrophil cytoplasmic antibodies associated vasculitis (ANCA) (AAV), other autoimmune diseases with vascular components, among which systemic sclerosis (SSc) or idiopathic high blood pressure (iPAH), remain resistant to the targeting. Previous studies have essentially addressed the characterization of auto-antibodies producing B cells sub-populations. Therefore, this thesis project aimed at delineating phenotypic and functional characterization of the lymphocytic B cells sub-populations involved in these various vascular autoimmune diseases.Patients affected by Granulomatosis with polyangiitis presented with important activation of innate immune system altogether with an increased production of IL6 by B lymphocytes correlated with T lymphocytes activation. Phenotypic alterations of B lymphocytes were observed for AAV patients, notably with MPA, suggesting an autoimmune component. Expression of CD69, CD95 and IL-6- receptor allowed discrimination between the various forms of the disease. In SSc, with particular emphasis in the most severe, diffuse forms, and in the associated PAH, a basal activation of the B cells was observed, allowing an important secretion of IL-6 and TGF-ß1. The latter contributed to the proliferation of fibroblasts and to the secretion of collagen, responsible for fibrosis induction as observed in the pathology. Finally, presence of activated basophils in SSc also participates in the activation of B cells and fibroblasts. These results place B lymphocytes, besides their role in antibody production, as important pathophysiological players through the secretion of pro-inflammatory and pro-fibrotic cytokines such as IL-6 and TGF-ß which are both implicated in endothelial cells activation in autoimmune vascular diseases
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TROTTA, ROSA. "A novel biomarker for cancer and autoimmune diseases: IGFBP6." Doctoral thesis, Università degli Studi di Foggia, 2019. http://hdl.handle.net/11369/382356.
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La temperatura corporea costituisce un importante meccanismo di difesa ed è il risultato di una complessa interazione che coinvolge numerosi fattori. Nell'uomo sano, la temperatura corporea è finemente regolata; deviazioni di 0.5°C oltre il limite superiore possono indicare una condizione patologica. Numerosi agenti possono indurre ipertermia, tra cui, insufficienza cardiaca acuta/cardiomiopatia acuta da stress [1] e infarto miocardico acuto [2] sindrome neurolettica maligna [3], endocrinopatie [4, 5], disturbi del sistema nervoso centrale (SNC) [6] e patologie oncologiche [7]. Le temperature febbrili aumentano l'efficacia della risposta immunitaria durante le infezioni stimolando il sistema immunitario innato e adattativo. Questo studio ha come obiettivo quello di dimostrare come l'ipertermia possa indurre modifiche del profilo di espressione genica e di evidenziare nuovi marker precoci di prognosi/diagnosi in patologie autoimmuni e/o tumorali. Nelle cellule dendritiche, alcuni tra i geni up-regolati codificano per proteine secrete, come IGFBP6 [8]. In condizioni ipertermiche, questa proteina induce chemiotassi dei monociti, dei linfociti T, ma non dei linfociti B. Inoltre, IGFBP6 è un agonista selettivo nei neutrofili poiché aumenta sia il burst ossidativo che la degranulazione e agisce come fattore chemotattico.Body temperature is an important defense mechanism and is the result of a complex interaction of many factors. In healthy human, the body temperature is regulated very carefully; deviations of 0.5°C above the upper limit of normal are considered to be significant indications of disease. Numerous elements may induce febrile conditions, including acute heart failure/stress cardiomyopathy [1] and acute myocardial infarction [2] neuroleptic malignant syndrome [3], endocrinopathies [4, 5], central nervous system (CNS) disorders [6] and oncological diseases [7]. Febrile temperatures increase the effectiveness of the immune response during infections by stimulating both the innate and adaptive arms of the immune system. The aim of this study is to demonstrate how hyperthermia can induce changes in the gene expression profile and highlight new early markers of prognosis/diagnosis in autoimmune and/or tumor pathologies. Among the up-regulated genes in dendritic cells, some encode secreted proteins, such as IGFBP6 [8]. This protein may have a functional role in the hyperthermic conditions as chemoattractant factor in monocytes and T cells, but not in B cells. Moreover, IGFBP6 is a selective neutrophil agonist, increasing oxidative burst and degranulation, as well as functioning as a chemotactic factor.
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Ekström, Smedby Karin. "Ultraviolet light, autoimmune disorders and the etiology of malignant lymphomas /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-313-2/.
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Gebre-Medhin, Gennet. "Clinical and experimental studies of organ-specific autoimmune diseases : With special reference to Addison's disease and autoimmune hepatitis : by Gennet Gebre-Medhin." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5043-1/.
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Mulcahy, Anthony Francis. "The molecular cloning and characterisation of autoantigens." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242453.
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Burfoot, Mark S. "Cloning of genes in the human major histocompatibility complex class III region by use of novel techniques." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308669.
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Duffy, Emeir. "An investigation of the influence of dietary supplementation of n-3 fish oil and/or copper on systemic lupus erythematosus." Thesis, University of Ulster, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273795.
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Caso-Pelaez, Enrique. "Analysis of the T cell receptor repertoire in autoimmune thyroid disease." Thesis, King's College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309142.
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O'Neill, Emma J. "An investigation of the role of interleukin-10 in the function of regulatory T cells induced by intranasal peptide administration within the context of experimental autoimmune encephalomyelitis." Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274646.
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Chang, Thashi. "Autoimmune mechanisms underlying the stiff person syndrome." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670147.
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Atta, Mustafa S. "Investigation of the humoral and cellular features of autoimmune diseases." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281586.
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Bluvas, Peter J. (Peter Jan) 1979. "Identification of viral and bacterial triggers for human autoimmune diseases." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/87184.
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Thesis (M.Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2002.Includes bibliographical references (leaf 31).
by Peter J. Bluvas, Jr.
M.Eng.
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Imgenberg-Kreuz, Juliana. "Epigenetic and Gene Expression Signatures in Systemic Inflammatory Autoimmune Diseases." Doctoral thesis, Uppsala universitet, Molekylär medicin, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-310388.
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Autoimmune diseases are clinical manifestations of a loss-of-tolerance of the immune system against the body’s own substances and healthy tissues. Primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE) are two chronic inflammatory autoimmune diseases characterized by autoantibody production and an activated type I interferon system. Although the precise mechanisms leading to autoimmune processes are not well defined, recent studies suggest that aberrant DNA methylation and gene expression patterns may play a central role in the pathogenesis of these disorders. The aim of this thesis was to investigate DNA methylation and gene expression in pSS and SLE on a genome-wide scale to advance our understanding of how these factors contribute to the diseases and to identify potential biomarkers and novel treatment targets. In study I, differential DNA methylation was analyzed in multiple tissues from pSS patients and healthy controls. We identified thousands of CpG sites with perturbed methylation; the most prominent finding was a profound hypomethylation at regulatory regions of type I interferon induced genes in pSS. In study II, a cases-case study comparing DNA methylation in pSS patients with high fatigue to patients with low fatigue, we found methylation patterns associated to the degree of fatigue. In study III, RNA-sequencing was applied to investigate the transcriptome of B cells in pSS in comparison to controls. Increased expression of type I and type II interferon regulated genes in pSS was observed, indicating ongoing immune activation in B cells. In study IV, the impact of DNA methylation on disease susceptibility and phenotypic variability in SLE was investigated. We identified DNA methylation patterns associated to disease susceptibility, SLE manifestations and different treatments. In addition, we mapped methylation quantitative trait loci and observed evidence for genetic regulation of DNA methylation in SLE. In conclusion, the results presented in this thesis provide new insights into the molecular mechanisms underlying autoimmunity in pSS and SLE. The studies confirm the central role of the interferon system in pSS and SLE and further suggest novel genes and mechanisms to be involved in the pathogenesis these autoimmune diseases.
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Hu, Xinli. "Discovery and Functional Interpretation of Genetic Risk in Autoimmune Diseases." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467297.
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Autoimmune diseases are chronic and debilitating conditions arising from abnormal immune responses directed against normal body tissues; they collectively affect the lives of 5-10% of the world population. These diseases often show familial clustering, suggesting strong genetic heritability. For many of autoimmune diseases, variation in the human leukocyte antigen (HLA) genes is the primary modulator of genetic risk. Recently, genome-wide association studies (GWAS) identified hundreds of genomic regions outside the HLA that harbor additional risk-conferring variants. The ultimate goal is to identify the precise causal variants and understand the mechanisms by which they lead to autoimmunity, which is challenged by complexities of the genome and the immune system.
In this work, my colleagues and I developed and applied experimental and computational tools to reveal critical clues from multiple genetic and biological data types. First, we devised a statistical algorithm to identify the critical cell types involved in different autoimmune diseases. Two strongly heritable and common diseases, rheumatoid arthritis (RA) and type 1 diabetes (T1D), both involve the adaptive immune system, specifically the CD4+ T cells. We then conducted focused studies in CD4+ T cells using high-throughput genomic and proteomic technologies, and showed that immunological phenotypes and functions varied with genetic differences across individuals. To facilitate this study, we developed an automated computational tool to efficiently and reliably analyze the large-scale data. Finally, the HLA genes, which encode a family of highly variable antigen-recognition proteins, are the longest-known and strongest modulators of genetic risk in T1D. However, the extraordinary level of polymorphism and complex structure in the HLA region largely hindered precise localization and functional investigation of the causal mutations. We used dense-genotyping and robust statistical analyses to pinpoint the amino acid residue changes at a few key amino acid positions that explained the majority of disease risk within the HLA.
The work presented in this dissertation revealed the specific immune cell populations, genetic variants, and cellular functions that affect RA, T1D, and other autoimmune diseases. Furthermore, it offers a rational framework, as well as powerful open-source computational tools, that can be applied in future functional genomic studies.Medical Sciences
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Maves, Lindsay. "The Role of T-lymphocyte Repertoire Selection in Autoimmune Diseases." Connect to full text in OhioLINK ETD Center, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=toledo1249324194.
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Thesis (M.S.)--University of Toledo, 2009.Typescript. "Submitted as partial fulfillment of the requirements for The Master of Science in Biology." "A thesis entitled"--at head of title. Bibliography: leaves 88-97.
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BUTTINI, SARA. "Genetic variations in autoimmune demyelinating diseases of the nervous system." Doctoral thesis, Università del Piemonte Orientale, 2014. http://hdl.handle.net/11579/45570.
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Yang, Min, and 杨敏. "Role of regulatory B cells in autoimmune disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48079832.
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Although B cells are well-known for their functions in antibody production and antigen presentation, certain B cell subsets have been recently identified as regulatory B cells to modulate immune responses through cytokine production. However, the microenvironmental factors involved in the induction of regulatory B cells remain largely uncharacterized. B cell-activating factor (BAFF), a member of TNF family cytokines produced by myeloid cells, is a key regulator for B cell maturation and function. However, it remains unknown whether BAFF plays a role in modulating the generation of regulatory B cells and how regulatory B cells suppress autoimmune pathogenesis. In this study, treatment with BAFF significantly increased IL-10-producing B cells in culture of mouse splenic B cells, an effect specifically abrogated by neutralization with TACI-Fc. BAFF-induced IL-10-producing B cells showed a distinct CD1dhiCD5+(B10) phenotype. Phenotypic analysis further indicated that these BAFF-induced B10 cells were marginal-zone (MZ)-like B cells. Interestingly, BAFF treatment in vivo also increased the number of IL-10-producingB cells in splenic MZ regions. Moreover, chromatin immunoprecipitation analysis revealed that BAFF activated the transcription factor AP-1 for binding to IL-10 promoter, demonstrating a novel function for BAFF in inducing IL-10 production. Furthermore, those BAFF-induced B10 cells exhibited significant suppressive effects on CD4+T cell proliferation and Th1 cytokine production in culture.
To explore whether these BAFF-induced B10 cells possess a regulatory function in suppressing autoimmune progression in vivo, collagen-induced arthritis (CIA) mouse model was employed. In vitro-expanded B10 cells and other control B cells were intravenously transferred into DBA/1J mice on the day of 2ndcollagen II (CII)-immunization. After adoptive transfer of BAFF-induced B10 cells, CII-immunized mice exhibited a delayed onset of arthritis and substantially reduced severity of clinical symptoms. The pathogenesis of IL-17-producing CD4+T cells (Th17) in the development of arthritis has been well-recognized, which has led me to test the hypothesis whether B10 cells ameliorate the development of arthritis via modulating Th17 cells. During the progression of CIA, IL-10-producing B cells were decreasedwhereasTh17 cells were significantly increased at the acute phase of CIA. Upon transfer of BAFF-induced B10 cells, a substantially reduction ofTh17 cells in both lymphoid organs and inflamed joints were detected. To verify whether B10 cells inhibit Th17 cell generation in culture, CFSE-labeled na?ve CD4+T cells were cocultured with B10 cells in Th17 cell polarization medium. It was found that B10 cells suppressed Th17 cell differentiation via reducing STAT3 phosphorylation and RORt expression. Although adoptive transfer of Th17 cells triggered the development of CIA in IL-17-/-DBA mice, cotransfer of B10 cells with Th17 cells profoundly delayed the onset of delayed the onset of arthritisand remarkably reduced the infiltration of Th17 cells in synovial fluid.
Taken together, I have identified a novel function of BAFF in the induction of IL-10-producing regulatory B cells. My findings that adoptive transfer of BAFF-expanded B10 cells can effectively suppress the development of experimental arthritisin mice via the inhibition of Th17 cell generation may contribute to the development of new therapeutic strategies in treating human rheumatoid arthritis.published_or_final_version
Pathology
Doctoral
Doctor of Philosophy
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Deng, Jun, and 鄧軍. "Leptin modulates T cells responses in autoimmune arthritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208601.
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Leptin, a protein hormone encoded by obese (ob) gene, is mainly produced by adipocytes. Leptin plays an important role in regulating neuroendocrine function and energy metabolism. As a cytokine, leptin is involved in modulating the hematopoiesis and lymphopoiesis. Although leptin has been found to promote T cells activation, it is largely unclear whether and how leptin regulates T cell differentiation and function.
Leptin has been associated with disease severity in rheumatoid arthritis (RA). Elevated leptin levels have been detected in the sera and synovial fluid of active RA patients. Th17 cells play key roles in synovitis and joint damage during arthritis development. However, the role of leptin on Th17 cells has not been investigated so far. In culture, leptin promoted Th17 cells differentiationfrom naïve 〖CD4〗^+ T cells via upregulating ROR-γt expression. Moreover, Th17 cells and IL-17 levels were significantly increased in leptin-treated naïve CD4+ T cells. Moreover, this study found that synoviocytes and chondrocytes produced large amounts of leptin especially during acute and chronic stages of mice with collagen-induced arthritis (CIA). Furthermore, leptin levels, Th17 cells in the joint and IL-17 levels in the synovial fluid were closely related to disease activity. Leptin intraarticular injection led to earlier onset of disease, higher clinical score, and more severe joint destruction compared with PBS-treated control mice. Importantly, leptin-injected mice had higher percentages of Th17 cells and cell numbers, elevated IL-17 levels in the synovial fluid, and increased infiltration of Th17 cells in the inflamed joint tissues compared with PBS-treated mice.
T follicular helper (Tfh) cells are indispensible for pathogenic autoantibodies production. However, whether leptin receptor (ObR) signaling has a role on Tfh cells and its implication in CIA remain elusive. Upon a T cell-dependent antigen TNP-KLH immunization, germinal center (GC) response, plasma cells (PCs) and memory B cells formation were impaired in db/db mice compared with wild-type (WT) controls. In coculture of Tfh cells from db/db and WT mice with WT GC B cells, anti-TNP IgGs titers in supernatants of db/db Tfh cells were significantly reduced. Intravenously transfer of naïve CD4+ T cells from db/db and WT mice to BoyJ recipient mice, donor CD4+ T cells from db/db mice showed impaired Tfh cells generation in spleens of BoyJ recipient mice compared with mice received with WT CD4+ T cells. These data indicated that ObR-mediated signaling intrinsically modulate Tfh cells generation. In culture, leptin promoted Tfh cells differentiation via inducing Bcl6 expression, and increased IL-21 production in Tfh cells in a dose-dependent manner. Leptin significantly enhanced the phosphorylation of STAT3, upregulated Bcl6 expression, and increased p-STAT3 binding to the Il21 promoter in CD4+ T cells with leptin receptor b (Ob-Rb) overexpression. Upon CIA induction, db/db mice exhibited ameliorated disease severity with impaired Tfh cells response. However, WT Tfh cells transfer to db/db mice restored GC responses, PCs formation, antibody production, and exacerbated synovium inflammation and joint damage in db/db recipient mice.
Together, these findings demonstrate that leptin modulates arthritis development via enhancement of Th17 and Tfh cells responses.published_or_final_version
Pathology
Doctoral
Doctor of Philosophy
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