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1
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/.
Повний текст джерела
2
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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3
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.
Повний текст джерелаАнотація:
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.
4
Dumoitier, Nicolas. "Analysis of B lymphocytes in systemic autoimmune vascular diseases." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC304.
Повний текст джерелаАнотація:
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
5
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.
Повний текст джерелаАнотація:
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.
6
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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7
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.
Повний текст джерелаАнотація:
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.
8
McCormick, Natalie. "The health resource utilization and economic burden of systemic autoimmune rheumatic diseases." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42149.
Повний текст джерелаАнотація:
Background: SARDs (Systemic Autoimmune Rheumatic Diseases) are a group of rare, chronic conditions (systemic vasculitis, systemic lupus erythematosus, scleroderma, Sjogren's disease, and poly/dermatomyositis) associated with high health resource consumption. However, estimates of their healthcare burden are sparse, with most determined at tertiary centres over short periods. Studying them separately has also limited research progress. Here we grouped the SARDs, for the first time ever, to quantify their collective, longitudinal (twelve-year) burden at the population-level.
Methods: A population-based cohort of SARDs cases was identified from the administrative database of BC’s single-payer health system (PopDataBC). A detailed algorithm, with time and specialist parameters, was used to enhance diagnostic specificity. From PopDataBC, all provincially-funded health services, and all prescriptions (regardless of funding source), consumed from 1996 -2007 were captured. Costs for outpatient services and prescriptions were summed directly from paid claims; case-mix methodology was used for most hospitalizations. To quantify their net burden, costs were summed for claims attributable (under broad and narrow definitions) to SARDs. Costs are reported in 2007 Canadian dollars.
Results: 18,741 SARDs cases were identified, contributing 82,140 patient-years(PY). After inflation adjustments, the annual mean per-PY direct medical costs of SARDs averaged $6,954/PY, with $1,882/PY(27%) from outpatient, $3,551/PY(51%) from hospital, and $1,521/PY(22%) from prescriptions. Over twelve years, annual costs decreased by 32%, from $8,901/PY in 1996 to $6,087/PY in 2007. Outpatient costs and encounters decreased by 26% ($2,205-$1,641/PY) and 19% (34-27/PY), respectively. Mean annual hospital costs decreased by half ($5,579-$2,776/PY), and admissions by 46% (0.89-0.48/PY). Despite these decreases, the annual mean number of dispensed prescriptions increased by 49% (23-34/PY), and their costs by 50% ($1,117-$1,670/PY). The annual net per-PY costs of SARDs, mainly from hospitalizations(18-43% of costs) and prescriptions(48-76%), averaged $2,011-$3,202/PY.
Conclusions: SARDs impart a substantial healthcare burden at the population level, and in 2007 were directly responsible for ≥44% of cases’ gross mean annual healthcare costs ($6,087/PY). Most costs have decreased over twelve years; however, medication costs are rising (by 4% annually, on-average), which suggests comorbidity burdens are too. As demand grows for expensive but potentially-better SARDs therapies, research to assess their impact on long-term comorbidity risk is needed.
9
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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10
Esfandiari, Ehsanollah. "Role of Th1 and Th2 cytokines in the pathogenesis of systemic autoimmune diseases." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366255.
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11
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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12
BANKS, THERESA ANNE. "IDENTIFICATION AND SEQUENCE OF THE IMMUNOGLOBULIN HEAVY CHAIN VARIABLE REGION GENE INVOLVED IN CODING FOR AN ANTI-DNA AUTOANTIBODY." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/183939.
Повний текст джерелаАнотація:
The major pathologic feature of the human autoimmune disease Systemic Lupus Erythematosus (SLE) and its murine counterpart, murine lupus, is the production of autoantibodies to nucleic acid antigens. In this study, a panel of six murine monoclonal anti-DNA autoantibodies was characterized at both the cellular and molecular levels in order to determine their possible role in the etiology of autoimmune disease. At the cellular level the autoantibodies were found to be highly cross-reactive, binding to three different antigenic forms of DNA as well as to the cell surface of various lymphoid cell lines. Furthermore, the fact that this autoantibody binding could be abrogated by pretreating the cells with either Proteinase K or DNase supports the hypothesis that a DNA binding protein may exist on the cell surface and that DNA bound to this receptor may serve as the target for the anti-DNA autoantibody. At the molecular level, the immunoglobulin (Ig) gene segments (V(H), D, J(H)) used to encode the variable region of the heavy chain of an anti-DNA autoantibody were sequenced. All three gene segments could be identified as members of established Ig gene segment families. In fact, the heavy chain of an antibody directed against the hapten L-glutamine₆₀-L-alanine₃₀-L-tyrosine₁₀ polymer (GAT) was found to utilize the same combination of V(H), D, and J(H) gene segments as the anti-DNA autoantibody. These results clearly indicate that autoantibodies are encoded by gene segments from the same Ig gene families used to encode antibodies to exogenous antigens. However, the discovery that this anti-DNA autoantibody is encoded by the same V(H) gene segment which encodes another anti-DNA autoantibody, derived from a different autoimmune mouse strain, supports the idea that certain V(H) gene segments may, in fact, be preferentially used to encode autoantibodies.
13
Hassan, Adla Bakri. "Mixed connective tissue disease, myositis and systemic lupus erythematosus : immunological and genetic studies in three related rheumatic autoimmune diseases /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-388-0.
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14
Singh, Akriti. "Investigating the role of TLR7 in the activation of autoreactive B cells in systemic lupus erythematosus /." Connect to online version, 2008. http://ada.mtholyoke.edu/setr/webscr/pdfs/www/2008/266.pdf.
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15
Ceribelli, A. "PROTEIN AND RNA IMMUNOPRECIPITATION FOR THE IDENTIFICATION OF SPECIFIC SERUM AUTOANTIBODIES IN SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES." Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/365538.
Повний текст джерелаАнотація:
Serum autoantibodies play a key role in systemic autoimmune rheumatic diseases for diagnostic, classification and prognostic purposes. Research of new autoantibodies has been very active in the last decade in rare connective tissue diseases such as systemic sclerosis and poly/dermatomyositis, with new biomarkers entering the clinical practice. Immunoprecipitation of protein and/or RNA components of the target autoantigens constitutes the gold standard method for the discovery of new autoantibodies in a screening setting but is considered time- and labor-intensive and, accordingly, is performed only in a few laboratories worldwide. As a result, alternative techniques such as ELISA and immunoblotting are often preferred for large-scale testing, despite the lack of standardization.
The aims of the present project are (1) to set up protein- and RNA- immunoprecipitation in our laboratory and (2) to describe serum autoantibodies identified in our series of patients affected by systemic autoimmune rheumatic diseases. During the PhD program we were able to perform correctly protein-and RNA-immunoprecipitation in our laboratory as demonstrated by positive reference sera, and then by the identification of known but also new and rare autoantibodies, as represented by two new patterns immunoprecipitated in systemic sclerosis, corresponding to serum anti-hnRNP-L and anti-mitochondrial antibodies. In psoriatic arthritis we also analyzed the concentration of circulating levels of LL37, a recently established target of autoimmune response at the skin level, and we identified an increased production in a subset of patients. In conclusion, performing protein- and RNA-immunoprecipitation as a screening method in our laboratory allows a more complete and specific autoantibody analysis that cannot be performed by the commercial techniques available nowadays, and further analysis of the role of LL37 in psoriatic arthritis patients may help in the identification of a new biomarker in this condition.
16
Coley, Rose Michelle. "The Association of Cancer Development in Patients with Systemic Lupus Erythematosus." ScholarWorks, 2016. https://scholarworks.waldenu.edu/dissertations/2148.
Повний текст джерелаАнотація:
The Association of Cancer Development in Patients with Systemic Lupus Erythematosus by
Rose Michelle Coley
MPH, Walden University, 2011
BS, University of Mount Olive, 2008
Dissertation Submitted in Partial Fulfillment
of the Requirements for the Degree of
Doctor of Philosophy
Public Health
Walden University
March 2016
Both cancer and autoimmune diseases have been associated with numerous factors that may independently lead to the development of either disease. When these factors overlap the difficulty in assessing association is compounded. The numerous factors that are thought to cause systemic lupus erythematosus (SLE), which leads to the development of cancer, makes the study of an association between the 2 diseases challenging. The purpose of this study was to examine whether the risk of cancer development increased in SLE patients compared to the risk in non-SLE patients. Researchers have not shown consistent relationships of cancer development in patients with SLE; however, consideration of the various factors that contribute to the diseases is necessary to measure an association between the 2 diseases. This study used the Clinical Practice Research database (CPRD), a large, population-based database to test the relationship between SLE and cancer. A matched retrospective cohort study among SLE (n=3025) and non-SLE (n=180555) patients was conducted using the propensity score methodology to help balance the differences between the comparison groups. The propensity score methodology created a similar distribution of observed baseline covariates between the 2 groups. With adjustment for age, the predictor variable of SLE indicates that a patient with SLE is still 2.7 times more likely to develop cancer than is a non-SLE patient. The study outcomes could promote positive social change by reinforcing current recommendations for cancer screenings in persons with SLE, which could enhance the ability to detect cancer early enough to decrease mortality because of cancer in persons with SLE.
17
Kristjansdottir, Gudlaug Thora. "Genetic Variation and Expression of the IRF5 Gene in Autoimmune Diseases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-99098.
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18
Kristjánsdóttir, Helga. "The PD-1 pathway and the complement system in systemic lupus erythematosus." Doctoral thesis, Uppsala universitet, Medicinsk genetik, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107198.
Повний текст джерелаАнотація:
Autoimmune diseases occur in up to 3-5% of the general population and represent a diverse collection of diseases with regards to clinical manifestations. The unifying factor of autoimmune diseases is tissue and organ damage as a result of an immune response mounted against self-antigens. Systemic lupus erythematosus (SLE) is considered a prototype of human systemic autoimmune diseases. The etiology of SLE is as yet largely unknown, but both epidemiological and genetic data suggest an interplay between numerous and varying genetic and environmental factors. There is compelling evidence for a strong genetic component in SLE. The disease has a high λsibs value and familial clustering is apparent. Multiple susceptibility loci have been identified, some of which are syntenic between humans and mice and some of which overlap with other autoimmune diseases. This thesis is based on analysis of Icelandic multicase SLE families and Swedish SLE patients. Paper I is a study of the association of C4A protein deficiency (C4AQ0) with SLE in the multicase families and shows a significantly increased frequency of C4AQ0 in the families. The genetic basis for C4AQ0 varies and C4AQ0 is found on different MHC haplotypes, pointing to C4AQ0 as an independent risk factor for SLE. Paper II describes the association of low MBL serum levels with SLE in the families and identifies low MBL as risk factor for SLE in families that carry the defect. Low MBL was furthermore found to mediate an additive risk when found in combination with C4AQ0. In paper III cellular expression the PD-1 co-inhibitory receptor on T cells was studied. A polymorphism in the PDCD1 gene, PD-1.3A was previously associated with SLE in the multicase families. The polymorphism is thought to disrupt expression of the gene and may lead to decreased expression of the PD-1 receptor. The study demonstrates lower PD-1 expression in SLE patients and relatives in correlation to the PD-1.3A genotype. Paper IV is a compiled analysis of the SLE families, including PD-1.3A, C4AQ0, low MBL, autoimmune diseases and autoantibody profiles. The study demonstrates clustering of different autoimmune diseases and autoantibodies in families that are heterogenic with regards to the genetic susceptibility factors, PD-1.3A, C4AQ0 and low MBL.
19
Pfeifer, Maria A. "Self-help Support Groups: Choices in Participation Among Women Facing Systemic Lupus Erythematosus (SLE)." PDXScholar, 2005. https://pdxscholar.library.pdx.edu/open_access_etds/4793.
Повний текст джерелаАнотація:
This research study explored the experiences of 19 women who had been diagnosed with, or were still seeking the diagnosis of SLE (lupus) and their decisions regarding support group participation. The aim of this study was to evaluate the variety of factors influencing their choices in types and sources of support, their coping strategies and the reasons behind their decisions to either choose or not choose lupus support groups as a viable support resource. Those women identified as support groups attendees recalled a more emotion-focused response to their diagnosis and showed stronger reliance on seeking emotional forms of support. Conversely, those women who chose not to participate in groups (non-attendees) utilized more problem-focused strategies when they received their news of the illness and indicated more reliance on instrumental forms of support. Additionally, the women who do not attend support groups did not seem to have more social support from outside sources, but did show a tendency to utilize relationship-focused coping more than other forms of coping strategies overall. Both groups showed a heavy reliance on their medical providers for both emotional and instrumental forms of support suggesting this source as an important factor in individual choices in coping strategies and support sources. The decisions to attend or not attend differed only in the strategies they relied on and specific group structure, timing and locations. The results of this study supports earlier research in the types and sources of social support used in adapting to a chronic illness. This study also encourages incorporating individual support services through medical providers and the development of programs that acknowledge individual coping and support needs.
20
Sigurdsson, Snaevar. "Large-Scale Genotyping for Analysis of the Type I Interferon System in Autoimmune Diseases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6792.
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21
Havarinasab, Said. "Effect of thimerosal on the murine immune system : especially induction of systemic autoimmunity." Doctoral thesis, Linköping : Univ, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-6315.
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22
Haynes, Eric E. "Identifying Common Genes from Rheumatoid Arthritis, Systemic Lupus, Multiple Sclerosis and Sjogrens Syndrome by Pooling Existing Microarray Data." University of Toledo Health Science Campus / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1374011043.
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23
Fan, Run. "The potential role of VH replacement in editing and generating autoreactive antibodies." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2010r/fan.pdf.
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24
Lintner, Katherine E. "The Roles of Complement C4A and C4B Genetic Diversity and HLA DRB1 Variants on Disease Associations with Juvenile Dermatomyositis and Systemic Lupus Erythematosus." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460986052.
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25
Kenyon, Karla. "The physiological and pathological regulation of apoptotic cell clearance /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
Знайти повний текст джерелаАнотація:
Thesis (Ph.D. in Immunology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 177-196). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
26
Wall, Gerard. "A study of anti-DNA autoantibodies in systemic lupus erythematosus." Thesis, University of Aberdeen, 1993. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU549890.
Повний текст джерелаАнотація:
Two anti-DNA autoantibody-secreting hybridomas, derived from murine models of the disease systemic lupus erythematosus (SLE), were provided. MAb-32, an IgG1, kappa, bound both single- (ss) and double-stranded (ds) DNA while mAb F-423, an IgG3, kappa, bound only ssDNA. F-423 also reacted with RNA and poly (dA) and its binding to ssDNA was found to be greatly amplified by histones. The VH genes of both antibodies and the VK gene of mAb F-423 were isolated by PCR, cloned, and sequenced. The two VH genes were also cloned into the pSW1.Fab expression vector and bacterial clones which showed DNA-binding were isolated. Continued induction of these clones led to the loss of their DNA-binding activity, due to a recombination event within the expression vector leading to the loss of its heavy chain-encoding genes. This event, seen only in anti-DNA clones, was proposed to be due to toxicity of the anti-DNA Fab fragments, leading to selection of recombinant bacteria. A number of experiments were carried out to improve the stability of the anti-DNA vector in E.coli. E.coli XL1-Blue was found to be preferable to E.coli TG1 as host strain both in terms of its lower frequency of recombination and tighter control of expression, while maximal production of Fab fragments was shown to be achieved after only 1-3 hours of induction. Furthermore, antigen binding of antibody fragments produced at 25[Special character omitted]C was found to be considerably higher than that of fragments produced at 37[Special character omitted]C. Mixing of CDRs from the two anti-DNA autoantibodies was carried out by CDR grafting.
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Dawson, Luke Jonathan. "Salivary gland hypofunction and Sjögren's syndrome". Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250430.
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Sköldberg, Filip. "Studies of Autoantibodies in Systemic and Organ-Specific Autoimmune Disease." Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3421.
Повний текст джерелаАнотація:
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease, whereas autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal disorder characterized by combinations of organ-specific autoimmune manifestations including hypoparathyroidism and intestinal dysfunction, and may serve as a model for organ-specific autoimmunity. Autoantibodies directed against proteins expressed in the affected tissues are found in both diseases. From a chondrocyte cDNA expression library, we identified the protein AHNAK as an autoantigen in SLE. Anti-AHNAK antibodies were found in 29.5% (18/61) of patients with SLE, 4.6% (5/109) of patients with rheumatoid arthritis, and 1.2% (2/172) of blood donors. Using a candidate approach, we analyzed the prevalence in APS1 and other organ-specific autoimmune diseases, of autoantibodies against the pyridoxal phosphate-dependent enzymes histidine decarboxylase (HDC) and cysteine sulfinic acid decarboxylase (CSAD), which are structurally closely related to known autoantigens. Anti-HDC and anti-CSAD reactivity was detected exclusively in APS1 patient sera. Anti-HDC antibodies were detected in 37.1% (36/97) of the APS1 sera, did not cross-react with aromatic L-amino acid decarboxylase, and were associated with intestinal dysfunction and loss of histamine-producing gastric enterochromaffin-like cells. In contrast, anti-CSAD reactivity was detected in 3.6% (3/83) of APS1 sera and cross-reacted with recombinant glutamic acid decarboxylase. From a parathyroid cDNA expression library, novel spliced transcripts of the CLLD4 gene on human chromosome 13q14, encoding 26 and 31 kDa isoforms recognized by autoantibodies in 3.4% (3/87) of APS1 patients, were identified and found to be preferentially expressed in lung and ovary. Both isoforms contain an N-terminal BTB/POZ domain, similarly to the TNF-alpha-regulated protein B12, localize both to the cytoplasm and nucleus in transfected COS cells, and form oligomers in vitro. The CLLD4 gene is located in a region frequently deleted in several forms of cancer, including lung and ovarian tumors. In conclusion, we have identified and partially characterized AHNAK and HDC as two common targets of autoantibodies in SLE and APS1, respectively. We have also identified CSAD and CLLD4 as two minor autoantigens in APS1, one of which is a novel protein with unknown function.
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Sköldberg, Filip. "Studies of autoantibodies in systemic and organ-specific autoimmune disease /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3421.
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Amel, Kashipaz Mohammad Rasoul. "Investigations of cytokine production by lymphocytes and autologous mixed lymphocyte reaction in relation to systemic lupus erythematosus." Thesis, Nottingham Trent University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272764.
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Sahlqvist, Anna-Stina. "Genetic Characterization of Chicken Models for Autoimmune Disease." Doctoral thesis, Uppsala universitet, Autoimmunitet, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-182843.
Повний текст джерелаАнотація:
Autoimmune diseases are endemic, but the disease mechanisms are poorly understood. A way to better understand these are to find disease-regulating genes. However, this is difficult as the diseases are complex, with several genes as well as environmental factors influencing the development of disease. A way to facilitate the search for genes responsible for the diseases is to use comparative genomic studies. Animal models are relatively easy to analyze since control of environment and breeding are obtained. The University of California at Davies – line 200 (UCD-200) chickens have a hereditary disease that is similar to systemic sclerosis. Using a backcross between UCD-200 chickens and red junglefowl (RJF) chickens we identified three loci linked to the disease. The loci contained immune-regulatory genes suggested to be involved in systemic sclerosis in humans, as well as a previously unidentified linkage between systemic sclerosis in UCD-200 chickens and IGFBP3. The Dark brown (Db) gene enhances red pheomelanin and restricts expression of eumelanin in chickens. The Db phenotype is regulated by an 8 kb deletion upstream of SOX10. Pigmentation studies are potentially useful when trying to identify pathogenic mechanisms and candidate genes in vitiligo The Obese strain (OS) of chickens spontaneously develops an autoimmune thyroiditis which closely resembles human Hashimoto’s thyroiditis. By using an intercross between OS chickens and RJF chickens, we found several disease phenotypes that can be used in an ongoing linkage analysis with the goal to find candidate genes for autoimmune disease. An important phenotype to record and add to the linkage analysis is autoantibodies against thyroid peroxidase, since this phenotype is a key feature in Hashimoto’s thyroiditis. Previous attempts to measure these titres in OS chickens have failed, hence an assay was developed for this purpose.
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Slingsby, Jason Hardwick. "The genetic basis of SLE in the BXSB mouse strain." Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300455.
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Peixoto, Tatiana Vasconcelos. "Aumento de células T CD4+CD69+ e redução de células T reguladoras CD4+CD25+FoxP3+ em camundongos com Lúpus Eritematoso Sistêmico (LES) induzido por pristane." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5165/tde-14122015-152214/.
Повний текст джерелаАнотація:
Introdução: O Lúpus Eritematoso Sistêmico (LES) é uma doença autoimune multissistêmica de etiologia complexa que envolve fatores ambientais, genéticos e hormonais. É caracterizada pela produção de autoanticorpos e mediadores inflamatórios, ativação e proliferação de células T autorreativas e perda da autotolerância imunológica. Em pacientes com LES, a expressão do receptor primário de ativação CD69 é aumentada e a de células T supressoras/reguladoras (Treg) CD4+CD25+FoxP3+ é reduzida. O CD69 é essencial para ativação de células T CD4 autorreativas enquanto que as células Treg são importantes na manutenção da autotolerância. Desta forma, células T tem um papel central na patogênese do LES, mas os mecanismos implicados na falência da autotolerância ainda não são elucidados, destacando a importância de estudos em modelos experimentais da doença, como o de LES-induzido por pristane. Objetivo: Quantificar células T CD4+CD69+ ativadas e Treg CD4+CD25+FoxP3+ no sangue, baço e LP de camundongos Balb/c LESinduzido por pristane no sentido de avaliar a falência de autotolerância neste modelo. Métodos: Analisamos 84 camundongos Balb/c fêmeas: 52 receberam por via intraperitoneal uma dose única de 0,5 ml de pristane e 32 a mesma dose de salina. Amostras de sangue, baço e LP dos camundongos eutanasiados foram coletadas 90, 120, 180 e 300 (T90, T120, T180 e T300) dias após a inoculação de pristane ou salina. Células mononucleares do sangue periférico (CMSP), do LP (CMLP) e esplenócitos foram obtidos por lise das hemácias seguida de lavagens com RPMI medium 1640 e centrifugação, e posteriormente criopreservadas até a avaliação por citometria de fluxo usando o aparelho Guava EasyCyteTM HT (Millipore). Para esta etapa, as células foram descongeladas, lavadas com RPMI medium 1640 e incubadas com anticorpos monoclonais dirigidos contra CD3, CD4, CD25, CD28, CD69, CTLA-4, FoxP3, CD14 e Ly6C (BD PharmingenTM). Os resultados foram expressos como média ± DP e teste de Mann-Whitney foi utilizado para análises estatísticas, sendo p<0,05 considerado significante. Resultados: Comparados aos animais controles, animais com LES-induzido por pristane apresentaram aumento de células T CD4+CD69+ no sangue nos T90, T120 e T180 (p < 0,022, p=0,008 e p=0,010, respectivamente) e no baço no T120 (p=0,049), enquanto que, no LP, houve redução destas células nos T120, T180 e T300 (p=0,001, p=0,001 e p < 0,001, respectivamente). A porcentagem de células Treg CD4+CD25+FoxP3+ foi menor no sangue nos T90, T120 e T180 (p=0,018, p=0,012, p < 0,046, respectivamente), no baço, nos T120 e T180 (p=0,018 e p=0,013), e no LP nos T90 e T300 (p=0,008 e p=0,005). Conclusão: Aumento da expressão de células T CD4+CD69+ e redução da expressão de Treg CD4+CD25+FoxP3+ sugerem células T CD4 ativadas e perda da autotolerância periférica em camundongos com LES-induzido por pristane. Estas alterações são semelhantes às observadas no lúpus humano, de modo que demonstramos que este modelo também pode ser útil na avaliação de mecanismos de ativação celular, tolerância periférica desequilíbrio imune homeostático envolvidos no LESIntroduction: Systemic Lupus Erythematosus (SLE) is multisystemic autoimmune disease with complex etiology that involves environmental, genetic and hormonal factors. Is characterized by auto-antibodies and inflammatory mediators production, autoreactive T cells activation and proliferation and loss of immunogenic autotolerance. In patients with SLE, expression of CD69 activation primary receptor is increased and the CD4+CD25+FoxP3+ suppressor/regulatory T cell (Treg) is reduced. CD69 is essential for activation of autoreactive CD4 T cells while Treg cells are important in autotolerance maintenance. In this way, T cells have a central role in the pathogenesis of SLE however, the mechanisms implied in the autotolerance failure are still not elucidated, highlighting the importance of studies in this disease\'s experimental models, such as pristane-induced SLE. Objective: Quantify activated CD4+CD69+ T cells and CD4+CD25+FoxP3+ Treg in blood, spleen and peritoneal lavage (PL) of Balb/c mice with pristane-induced SLE in order to evaluate autotolerance failure in this model. Methods: 84 female Balb/c mice were analyzed: 52 received a single intraperitoneal 0,5 ml dose of pristane and 32 the same dose of saline. Euthanized mice samples of blood, spleen and peritoneal lavage were collected 90, 120, 180 and 300 (T90, T120, T180 and T300) days after inoculation of pristane or saline. Mononuclear cells from peripheral blood (PBMC), PL (PLMC) and splenocytes were obtained by lysis of erythrocytes followed by washings with RPMI medium 1640 and centrifugation, subsequently criopreserved until evaluation by flow cytometry using the appliance GuavaEasyCyteTM HT (Millipore). For this step, cells were unfrozen, washed with RPMI medium 1640 and incubated with monoclonal antibodies against CD3, CD4, CD25, CD28, CD69, CTLA-4, FoxP3, CD14 and Ly6C (BD PharmingenTM). The results were expressed as mean ± SD and Mann-Whitney 11 test was used for statistical analysis, being considered significant p < 0,05. Results: Compared to control animals, SLE pristane-induced animals presented increase of CD4+CD69+ T cells in blood on T90, T120 and T180 (p=0.022, p=0.008 and p=0.010, respectively) and in spleen on T120 (p=0.049), while, in PL, there was reduction of these cells on T120, T180 and T300 (p=0.001, p=0.001 and p < 0.001, respectively). The porcentage of Treg CD4+CD25+FoxP3+ was smaller in blood on T90, T120 and T180 (p=0.018, p=0.012 and p < 0.046, respectively), in spleen on T120 and T180 (p=0.018 and p=0.013), and in PL on T90 and T300 (p=0.008 and p=0.005). Conclusion: Increase of CD4+CD69+ T cell and reduction of CD4+CD25+FoxP3+ Treg expression suggests activated T CD4 cells and loss of peripheral autotolerance in pristane-induced SLE mice. These alterations are similar to observed in human lupus, in order we showed that this model can also be useful in evaluating the mechanisms of cellular activation, peripheral tolerance and homeostatic immune imbalance involved in the LES
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Zhu, Jing. "The modulation of autoimmune disease progression in mouse models." Diss., Virginia Tech, 2020. http://hdl.handle.net/10919/100945.
Повний текст джерелаАнотація:
B cells play crucial roles in the development of the two human autoimmune diseases, type 1 diabetes (T1D) and systemic lupus erythematosus (SLE). In the past decade, numerous studies showed positive responses of B cell depletion therapies in these two diseases. However, the beneficial effects are temporary and accompanied with adverse events. In this dissertation, we aimed to identify novel targets for a better modulation of disease development using mouse models. These diseases have circulating autoantibodies that are mostly mutated with an IgG isotype, indicating B cells that are producing them have been through the process of affinity maturation. Activation-induced cytidine deaminase (AID) is a core enzyme that regulates somatic hypermutation (SHM) and class switch recombination (CSR), the two key mechanisms in affinity maturation. We showed that genetic ablation of AID significantly inhibited the development of TID in NOD mice. Homologous recombination (HR) pathway is important for the repair of AID-induced DNA double strand breaks during CSR. 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid, also known as DIDS, is a small molecule that inhibits HR pathway and subsequently leads to apoptosis of class switching cells. DIDS treatment remarkably retarded the progression of TID, even when started at a relatively late stage, indicating the potential of this treatment for disease reversal. In both approaches, we observed a notable expansion of CD73+ B cells, which exerted an immunosuppressive role and could be responsible for T1D resistance. Next we examined the effect of targeting affinity maturation through these two approaches in lupus-prone mice. The genetic abrogation of AID in BXSB mice significantly ameliorated lupus nephritis and prolonged their lifespan. AID-deficient mice also exhibited improvement on disease hallmarks with increased marginal zone B cells and more normal splenic architecture. DIDS treatment notably reduced class switching when B cells were stimulated in vitro. However, the administration of DIDS did not strikingly alter the course of SLE in either BXSB mice or MRL/lpr mice. These findings demonstrated that affinity maturation could be a potential target for T1D and SLE, while further explorations into targeting other components in the repair pathway are warranted for SLE. Lastly, we assessed the effect of maternal AID modulation on the SLE development in the offspring using BXSB mouse model. Interestingly, the absence of maternal AID resulted in offspring that developed significantly more severe lupus nephritis compared to control. The offspring born to AID-deficient dams also exhibited elevated levels of pathogenic autoantibodies and exacerbated disease features. Therefore, the modulation of maternal AID could influence the SLE development in the offspring, and future investigations are needed to determine the underlying mechanisms responsible for the disease acceleration.Doctor of Philosophy
The failure of the immune system to differentiate self from non-self leads to the development of autoimmune diseases. Type 1 diabetes (T1D) and systemic lupus erythematosus (SLE) are complex autoimmune diseases affecting millions of people in the world. Despite intensive research regarding these two diseases, no known cure is available indicating an imperative need for the development of novel therapies. With the importance of B cells in the pathogenesis of these two diseases, intensive research focused on whole B cell depletion therapies. However, these therapies exhibited high risks of infections as a result of depleting all the B cells. In this dissertation, we sought to selectively target specific B lymphocyte subsets that are crucial contributing factors in the development of T1D and SLE. While the effect of therapeutic treatment varied among different mouse models, the genetic manipulation of specific B cells successfully retarded the progression of both T1D and SLE and extended the lifespan of the mice. Further studies shed light on the possible mechanisms that are responsible for the disease inhibition. These data proved that targeting specific B cell compartment could be a potential disease management in T1D and SLE patients. In addition, using the established mouse model, we demonstrated the modulation of maternal factors significantly impact the SLE development in the offspring. Future experiments to identify the underlying mechanisms could provide more targets for the therapeutic development.
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Fitch, Megan. "The Effects of Air Pollution on the Intestinal Microbiota: A Novel Approach to Assess How Gut Microbe Interactions with the Environment Affect Human Health." Thesis, University of North Texas, 2017. https://digital.library.unt.edu/ark:/67531/metadc984173/.
Повний текст джерелаАнотація:
This thesis investigates how air pollution, both natural and anthropogenic, affects changes in the proximal small intestine and ileum microbiota profile, as well as intestinal barrier integrity, histological changes, and inflammation. APO-E KO mice on a high fat diet were randomly selected to be exposed by whole body inhalation to either wood smoke (WS) or mixed vehicular exhaust (MVE), with filtered air (FA) acting as the control. Intestinal integrity and histology were assessed by observing expression of well- known structural components tight junction proteins (TJPs), matrix metallopeptidase-9 (MMP-9), and gel-forming mucin (MUC2), as well known inflammatory related factors: TNF-α, IL-1β, and toll-like receptor (TLR)-4. Bacterial profiling was done using DNA analysis of microbiota within the ileum, utilizing 16S metagenomics sequencing (Illumina miSeq) technique. Overall results of this experiment suggest that air pollution, both anthropogenic and natural, cause a breach in the intestinal barrier with an increase in inflammatory factors and a decrease in beneficial bacteria. This evidence suggests the possibility of air pollution being a potential causative agent of intestinal disease as well as a possible contributing mechanism for induction of systemic inflammation.
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Liu, Ke (Coco). "X Chromosome Gene Dosage in Autoimmune Disease Susceptibility and B Cell Development." University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1470753675.
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Melki, Isabelle. "Clinical and molecular characterisation of type I interferonopathies." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB122/document.
Повний текст джерелаАнотація:
Les interférons de type I (IFN I) sont des cytokines antivirales aux propriétés puissantes. L’induction, la transmission et la résolution de la réponse immunitaire engendrée par les IFN I est minutieusement régulée. Le concept d’interféronopathie de type I, récemment individualisé par notre équipe, repose sur l’hypothèse que certaines pathologies seraient secondaires au déséquilibre de ces voies de signalisation complexes et à la sécrétion excessive et inappropriée d’IFN I. L’inhibition de celle-ci par des thérapeutiques ciblées permettrait de valider cette hypothèse, si les symptômes allégués s’amélioraient, voire disparaissaient. Ce travail de thèse s’est initialement concentré sur la caractérisation clinique et biologique des interféronopathies monogéniques et polygéniques, et secondairement sur l’identification moléculaire de nouvelles mutations du gène TMEM173 à l’origine de l’interféronopathie liée à STING, également appelée SAVI (STING associated vasculopathy with onset in infancy), syndrome auto-inflammatoire associant une atteinte sévère cutanée et pulmonaire. De nouvelles techniques ont permis la sélection de patients présentant une augmentation de l’IFN I en comparaison à des contrôles sains : la signature IFN I, qPCR de 6 gènes stimulés par l’IFN (IFN stimulated genes – ISGs) et le dosage d’IFN alpha sérique ou plasmatique par méthode du SIMOA (single molecule array) permettant la détection de molécules d’IFN de l’ordre du femtogramme (10-18g). Ces méthodes nous ont ainsi permis d’élargir le spectre clinique phénotypique des interféronopathies de type I, initialement considéré comme essentiellement neurologique. Les patients atteints du syndrome d’Aicardi-Goutières, première interféronopathie monogénique décrite, présentaient les signes suivants : dystonie, spasticité, décalage des acquisitions, calcifications intra-cérébrales et anomalies de la substance blanche. Cependant, l’utilisation systématique de nos méthodes de criblage associée à l’avènement des technologies de séquençage à haut débit (next generation sequencing – NGS) a permis de révéler un phénotype plus large, caractéristique des interféronopathies de type I : sur le plan cutané (engelures, vascularite nécrosante des extrémités, sclérodermie), pulmonaire (pneumopathie interstitielle isolée ou non), musculo-squelettique (arthralgies, arthrites, arthropathie de Jaccoud, myalgies et myosites), ophtalmologique (glaucome), néphrologique (néphropathies lupiques), gastro-entérologique (maladies inflammatoires chroniques intestinales précoces), associées à de l’auto-immunité ou un déficit immunitaire inconstants. Notre méthode de sélection nous a notamment permis d’identifier des patients présentant de manière variable des signes cardinaux de SAVI et une de trois nouvelles mutations activatrices dans une région spécifique du gène TMEM173 (codant pour STING). Ces mutations circonscrivent une région de la protéine à ce jour encore jamais impliquée dans le contrôle de la voie de l’IFN I. STING est une protéine du réticulum endoplasmique qui agit comme adaptateur cytosolique de senseurs intracellulaires d’ADN viral dans une voie de signalisation de l’IFN I. STING active TBK1 (TANK-binding kinase) et permet la transcription des IFN I par la phosphorylation d’IRF3. La Janus Kinase 1 (JAK1) et la tyrosine kinase 2 (TYK2) sont activées suite à la stimulation des récepteurs de l’IFN I et phosphorylent les facteurs de transcription STAT1 et STAT2, conduisant à l’expression de nombreux ISGs. Les analyses génétiques, de conformation tridimensionnelle, sur un modèle cellulaire in vitro (HEK293T) et ex vivo sur cellules mononuclées périphériques des patients nous ont ainsi permis de mettre en évidence pour ces mutations un caractère constitutionnellement activé, indépendant de la liaison au ligand cGAMP, mais transmettant ce signal à travers la voie d’aval par TBK1. (...)Type I interferons (IFN I) are antiviral cytokines with potent properties. Hence, the induction, transmission and resolution of the immune response generated by IFN I is tightly regulated. The concept of the type I interferonopathies, recently formulated by our team, rests on the assumption that some diseases arise from a disturbance of this complex signalling pathway, leading to excessive and inappropriate IFN I secretion. On this basis, targeted therapeutics should improve or cure features of such type I interferonopathies, thereby providing a validation of the underlying hypothesis. This PhD project initially focused on the clinical and biological characterisation of monogenic and polygenic interferonopathies, and secondarily on the molecular identification of novel mutations in the gene TMEM173 causing the interferonopathy called STING associated vasculopathy with onset in infancy (SAVI), an auto-inflammatory syndrome with severe cutaneous and pulmonary features. Our selection of patients in comparison to healthy controls was made possible through the use of novel screening tools: IFN signature (qPCR of 6 IFN stimulated genes – ISGs), and measurement of IFN alpha protein levels in serum or plasma (SIMOA-single molecule array - enabling the detection of molecules of IFN in the femtogram [10-18g]) range. In this way, we have been able to expand the phenotypic spectrum of the interferonopathies, which was initially considered as primarily neurological. Patients with Aicardi-Goutières syndrome (AGS), the first described of the monogenic interferonopathies, exhibit dystonia, spasticity, developmental delay, intra-cranial calcifications and white matter abnormalities. However, the systematic use of our interferon screening assays, plus the advent of next-generation sequencing technology, has revealed a much broader set of features relevant to this novel disease grouping – involving the skin (chilblains, necrotising vasculitis, scleroderma), lungs (isolated lung interstitial disease or associated with other signs), musculoskeletal system (joint pain, arthritis, Jaccoud’s arthropathy, muscle pain and myositis), eyes (glaucoma), kidneys (lupus nephritis) and gastro-intestinal tract (early inflammatory bowel disease), as well features of autoimmunity and immunodeficiency. Using our screening assays enabled us to identify three patients variably exhibiting the core features of SAVI, all of whom were found to harbour distinct novel activating mutations in STING. These mutations highlight a protein domain not previously implicated in the control of IFN I signalling. STING is an endoplasmic reticulum protein, acting as a cytosolic adaptor of intracellular sensors of viral DNA in the type I IFN signalling pathway. STING activates TANK-binding kinase (TBK1), allowing transcription of IFN I through phosphorylation of IRF3. Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) are activated following stimulation of the IFN I receptor, leading to phosphorylation of the transcription factors STAT1 and STAT2 and the subsequent induction of a large number of ISGs. Genetic analysis, conformational studies, an in vitro cellular model (HEK293T) and ex vivo experimental data (using patient peripheral blood mononuclear cells - PBMCs) enabled us to confirm the constitutive activating nature of these variants, and show that this activation did not require binding with cGAMP, but was dependent on signalling through TBK1. Ruxolitinib, a JAK1/2 inhibitor, could antagonise this constitutive activation ex vivo. These results indicate a promising therapeutic approach in such patients, and more widely in the monogenic, and perhaps even, polygenic, interferonopathy context
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Reighard, Seth D. "A natural killer cell-centric approach toward new therapeutics for autoimmune disease." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563273969849993.
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Prado, Danilo Marcelo Leite do. "Efeito de um programa de treinamento físico aeróbio supervisionado em crianças com lúpus eritematoso sistêmico juvenil." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5164/tde-12022014-143034/.
Повний текст джерелаАнотація:
INTRODUÇÃO: O treinamento físico é considerado como um importante recurso terapêutico no que concerne a melhora da disfunção física observada em adultos com lúpus eritematoso sistêmico. Entretanto, até o momento não há estudos longitudinais que avaliaram os possíveis efeitos terapêuticos de um programa de treinamento físico em crianças e adolescentes com lúpus eritematoso sistêmico juvenil (LES-J). OBJETIVO avaliar a segurança e a eficácia de um de um programa de treinamento físico aeróbio supervisionado de 12 semanas no aumento da capacidade cardiorrespiratória em pacientes com LES-J. MÉTODOS: Dezenove crianças e adolescentes com LES-J foram aleatoriamente randomizadas em dois grupos: treinamento físico aeróbio (LESJ TF, n=10; 12,9 + 2,3 anos) e grupo controle (LES-J C, n=9; 13,0 + 1,8 anos). Dez crianças saudáveis (CS) pareadas por idade e peso corporal foram recrutadas como controle. As crianças foram submetidas a um teste de esforço cardiorrespiratório máximo em esteira ergométrica antes e após 12 semanas de intervenção para determinação do consumo de oxigênio de pico (VO2pico), reserva cronotrópica (RC) e a frequência cardíaca de recuperação no primeiro (deltaFCR1) e segundo minuto (deltaFCR2) após exercício. RESULTADOS: Os pacientes com LES-J que não realizaram treinamento físico aeróbio não apresentaram alteração em qualquer dos parâmetros cardiorrespiratórios analisados (p > 0,05). Por outro lado, os pacientes com LES-J que foram submetidos ao programa de treinamento físico aeróbio demonstraram um aumento significativo no tempo de exercício (p = 0,01; TE = 1,07), na velocidade de pico (p = 0,01; TE = 1,08), no VO2 pico (p = 0,04; TE = 0,86), na RC (p = 0,06; TE = 0,83), e na deltaFCR1 e deltaFCR2 (p = 0,003; TE = 1,29 e p = 0,0008; TE = 1,36, respectivamente). Além disso, os parâmetros cardiorrespiratórios foram comparáveis após o período de intervenção entre os pacientes com LES-J submetidos ao treinamento físico aeróbio e os CS, tal como evidenciado pela análise ANOVA (p > 0,05, LES-J TF vs CS). O índice de atividade da doença SLEDAI-2K manteve-se estável ao longo do estudo. CONCLUSÃO: Este estudo demonstrou pela primeira vez que um programa de treinamento físico aeróbio de intensidade moderada sob supervisão pode ser seguro e eficaz no aumento da capacidade cardiorrespiratória e do controle autonômico cardíaco em pacientes com LES-JINTRODUCTION: Exercise training has emerged as a promising therapeutic strategy to counteract physical dysfunction in adult systemic lupus erythematosus. However, no longitudinal studies have evaluated the effects of an exercise training program in childhood-onset systemic lupus erythematosus (C-SLE) patients. PURPOSE: To evaluate the safety and the efficacy of a supervised aerobic training program in improving the cardiorespiratory capacity in childhood-onset systemic lupus erythematosus (C-SLE) patients. METHODS: Nineteen physically inactive C-SLE patients were randomly assigned into two groups: trained (TR, n=10, supervised moderate-intensity aerobic exercise program) and non-trained (NT, n=9). Gender-, BMI- and age-matched healthy children were recruited as controls (C, n=10) for baseline (PRE) measurements only. C-SLE patients were assessed at PRE and after 12 weeks of training (POST). Main measurements included exercise tolerance and cardiorespiratory measurements in response to a maximal exercise (i.e.: peak VO2, chronotropic reserve [CR], and the heart rate recovery [deltaHRR] (i.e. the difference between HR at peak exercise and at both the first [deltaHRR1] and second [deltaHRR2] minutes of recovery after exercise). RESULTS: The C-SLE NT patients did not present changes in any of the cardiorespiratory parameters at POST (p > 0.05). In contrast, the exercise training program was effective in promoting significant increases in time-to-exhaustion (p=0.01; ES=1.07), peak speed (p=0.01; ES=1.08), peak VO2 (p=0.04; ES=0.86), CR (p=0.06; ES=0.83), and in deltaHRR1 and delta HRR2 (p=0.003; ES=1.29 and p=0.0008; ES=1.36, respectively) in the CSLE TR when compared with the NT group. Moreover, cardiorespiratory parameters were comparable between C-SLE TR patients and C subjects after the exercise training intervention, as evidenced by the ANOVA analysis (p > 0.05, TR vs. C). SLEDAI-2K scores remained stable throughout the study. CONCLUSION: A 3-month aerobic exercise training was safe and capable of ameliorating the cardiorespiratory capacity and the autonomic function in C-SLE patients
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Rossi, Giulio Antonino. "FOXP3, ICOS and ICOSL polymorphisms in an Italian population affected by systemic sclerosis." Doctoral thesis, Università di Catania, 2017. http://hdl.handle.net/10761/4031.
Повний текст джерелаАнотація:
Associated with substantial morbidity and mortality rates, systemic sclerosis (SSc) is an autoimmune disorder characterized by vasculopathy, inflammation, progressive perivascular and interstitial fibrosis. SSc pathogenesis is largely unknown, however strong evidences suggest that genetic predisposition may contribute to SSc development.
Dysregulation of co-stimulatory and/or co-inhibitory signals, including ICOS signalling, can cause a breakdown of self-tolerance, thus leading to autoimmunity. Furthermore, ICOS has been linked to the function of Tregs.
The aim of the present study was to investigate the association between the FOXP3 rs2294020, ICOS rs6726035 and ICOSL rs378299 SNPs and the susceptibility to SSc or to progression from preclinical SSc to definite SSc in a North Italian Caucasian population. Furthermore, we have extended our association analysis of the FOXP3 rs2294020 SNP also in 14 GWAS datasets in order to reveal association between this SNP and susceptibility to other autoimmune diseases in individuals of European ancestry. Autoimmune diseases studied included psoriasis, celiac disease, Crohn s disease, ulcerative colitis, multiple sclerosis, vitiligo, type-1 diabetes, rheumatoid arthritis, and ankylosing spondylitis.
Although analysis tests did not show any significant associations between the SNPs under study and SSc, the occurrence of FOXP3 rs2294020 in female patients was associated with an increased risk of progression from early to definite SSc, both in the allelic (HR = 1.43; CI = 1.03-1.99; p=0.03) and in dominant (HR = 1.54; CI = 1.04-2.28; p=0.03) models. The inclusion of presence of ACA, SCL70, and ANA autoantibodies in the model did not significantly change the estimates. Furthermore, the present study shows that rs2204020 may be associated with the susceptibility to autoimmune diseases involving the skin , such as vitiligo and psoriasis (p=0.01 and P=0.038, respectively).
In conclusion, this study provides evidence that rs2294020SNP may have a role in SSc evolution, modulating the time of progression from the diagnosis of early SSc to the diagnosis of definite SSc. Moreover, the results of the present study would suggest a potential involvevement of the rs294020 also in other skin-related autoimmune diseases, including vitiligo and psoriasis.
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Hayashi, Ana Paula Tanaka. "Eficácia e segurança da suplementação de creatina em pacientes com lúpus erimatoso sistêmico de início juvenil." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5164/tde-07022014-144017/.
Повний текст джерелаАнотація:
Introdução: A suplementação de creatina tem surgido na literatura como uma potencial estratégia terapêutica não farmacológica em diversas condições caracterizadas por disfunções musculares e baixa massa muscular, incluindo as doenças reumatológicas pediátricas. O objetivo deste estudo foi avaliar a eficácia e a segurança da suplementação de creatina em pacientes com lúpus eritematoso sistêmico de início juvenil (LESJ). Métodos: Trata-se de um estudo duplo-cego, crossover, balanceado e controlado por placebo. Os voluntários (n = 15) foram randomizados em duas condições que receberam creatina ou dextrose por 12 semanas, interpassadas por um período de washout de 8 semanas. A função muscular foi avaliada por testes de uma repetição máxima (1 RM), Timed-Up-And-Go, Timed-Stands e de preensão manual. Ainda, foram avaliados a composição corporal, os marcadores bioquímicos do remodelamento ósseo, a aptidão aeróbia, os parâmetros de qualidade de vida e a capacidade funcional dos voluntários. As possíveis alterações no consumo alimentar foram avaliadas por três recordatórios alimentares de 24h, enquanto o conteúdo de fosforilcreatina muscular foi avaliado por meio de espectroscopia de fósforo por ressonância magnética (31P-ERM). A segurança da intervenção foi avaliada por parâmetros laboratoriais e por clearance de 51Cr-EDTA e, por fim, os eventos adversos foram registrados durante todo o estudo. Resultados: Não houve diferença significativa no conteúdo intramuscular de fosforilcreatina entre as condições, antes e após as intervenções (creatina - Pré: 20,5 ± 2,6/ Pós: 20,4 ± 4,1; placebo - Pré: 19,8 ± 2,0/ Pós: 20,2 ± 3,2 mmol/kg peso úmido; p = 0,70 para interação entre condições). Ainda, provavelmente, como consequência do conteúdo intramuscular ter se mantido inalterado, não houve diferença significativa entre as condições para todos os parâmetros analisados (p > 0,05). Além do clearance de 51Cr-EDTA não ter sido alterado com a suplementação de creatina, nenhum efeito adverso foi observado. Conclusão: O protocolo de suplementação de creatina (0,1 g/kg/d) por 12 semanas foi bem tolerado e livre de efeitos adversos. Entretanto, a suplementação de creatina não foi eficaz no aumento do conteúdo intramuscular de fosforilcreatina, na melhora da função muscular, aptidão aeróbia, composição corporal e parâmetros de qualidade de vida em pacientes com LESJIntroduction: Creatine supplementation has emerged as a promising non-pharmacological therapeutic strategy to counteract muscle dysfunction and low lean mass in a variety of conditions, including in pediatric and rheumatic diseases. The objective of this study was to examine the efficacy and safety of creatine supplementation in childhood systemic lupus erythematosus (C-SLE). Methods: C-SLE patients with mild disease activity (n=15) received placebo or creatine supplementation in a randomized fashion using a crossover, double-blind, repeated-measures design. The subjects were assessed at baseline and after 12 weeks in each arm, interspersed by a 8-week washout period. The primary outcomes was muscle function, as assessed by a battery of tests including one-maximum repetition (1-RM) tests, the Timed-Up-And-Go test, the Timed-Stands test, and the handgrip test. Secondary outcomes included body composition, biochemical markers of bone remodeling, aerobic conditioning, quality of life, and physical capacity. Possible differences in dietary intake were assessed by three 24-h dietary recalls. Muscle phosphorylcreatine content was measured through phosphorus magnetic resonance spectroscopy (31P-MRS). The safety of the intervention was assessed by laboratory parameters and kidney function was measured by the 51Cr-EDTA clearance. Additionally, self-reported adverse events were recorded throughout the trial. Results: Intramuscular phosphorylcreatine content was not significantly different between creatine and placebo before or after the intervention (creatine - Pre: 20.5 ± 2.6, Post: 20.4 ± 4.1, placebo - Pre: 19.8 ± 2.0; Post: 20.2 ± 3.2 mmol/kg wet muscle; p = 0.70 for interaction between conditions). In addition, probably as a consequence of the lack of change in intramuscular phosphorylcreatine content, there were no significant changes between placebo and creatine for any muscle function and aerobic conditioning parameters, lean mass, fat mass, bone mass, and quality of life scores (p > 0.05). The 51Cr-EDTA clearance was not altered by creatine supplementation and no side effects were noticed. Conclusion: a 12-week creatine supplementation protocol at 0.1 g/kg/d is well tolerable and free of adverse effects but did not affect intramuscular phosphorylcreatine, muscle function, free-fat mass or quality of life in C-SLE patients with mild disease activity
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Nwaneshiudu, Adaobi I. "The Role of Gamma-Delta TCR+ T-cells in the Pathogenesis of Systemic Sclerosis." Diss., Temple University Libraries, 2008. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/11843.
Повний текст джерелаАнотація:
Microbiology and ImmunologyPh.D.
The human gamma-delta (gd) TCR+ T-cell subset may undergo specific antigen-driven activation and clonal expansion, in the context of systemic sclerosis (SSc) pathogenesis. The purpose of this study was; 1) To determine whether gd TCR+ T-cells are clonally expanded in skin biopsies and peripheral blood from patients with SSc; and 2) To develop approaches for identification of the antigens recognized by these clonally-expanded gd TCR+ T-cells. Total RNA was isolated from the skin biopsies and peripheral blood of patients with SSc (n=8). After cDNA synthesis, the g- and d-chain TCR transcripts were amplified by PCR, cloned and sequenced for analysis. Full length copies of the TCR transcripts were constructed, expressed in a TCR-negative Jurkat T-cell line using retroviral gene transduction, and verified by RT-PCR and flow cytometry for gd TCR expression. Putative antigen recognition, by the transduced gd TCR+ Jurkat T-cell lines, was assessed via; 1) Measuring intracellular calcium flux in the transduced cells after stimulation with putative SSc antigens, including DNA topoisomerase I, centromere proteins A and B, hsp 27, hsp 90 and the viral lysate of human cytomegalovirus; and 2) Cytotoxicity against human endothelial cell lines (HUVEC and HLMVEC) via measurement of lactate dehydrogenase release from the targets. We report the presence of substantial, statistically-significant, proportions of identical g- and d-chain transcripts in skin biopsies and PBMC of patients with SSc, demonstrating the presence of antigen-driven clonal expansions. Jurkat T-cells, transduced with the clonally-expanded gd TCR transcripts from a patient, showed no evidence of cytotoxicity against the human endothelial cell lines, or calcium flux in response to stimulation with the putative SSc antigens assessed. In conclusion, extensive clonal expansions of g- and d-chain TCR transcripts were identified in skin biopsies and peripheral blood of patients with SSc, demonstrating the presence of oligoclonal populations of gd TCR+ T-cells in these patients. These gd TCR+ T-cells have undergone proliferation and clonal expansion in vivo in response to as yet unidentified antigens. Furthermore, an approach has been developed for the identification of the antigens recognized by the clonally-expanded gd TCR transcripts, which can be expanded to additional patients with SSc.
Temple University--Theses
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Mesa, Annia. "Auto-antigenic Properties of the Spliceosome as a Molecular Tool for Diagnosing Systemic Lupus Erythematosus and Mixed Connective Tissue Disease Patients." FIU Digital Commons, 2014. http://digitalcommons.fiu.edu/etd/1126.
Повний текст джерелаАнотація:
Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD) are chronic, autoimmune disorders that target overlapping autoantigens and exhibit similar clinical manifestations. Despite 40 years of research, a reliable biomarker capable of diagnosing these syndromes has yet to be identified. Previous studies have confirmed that components of the U1 small nuclear ribonucleoprotein complex (U1 snRNP) such as U1A are 1000 fold more autoantigenic than any other nuclear component in SLE patients. Based on these findings, I hypothesize that models derived from the U1 snRNP autoantigenic properties could distinguish SLE from MCTD patients. To test this hypothesis, 30 peptides corresponding to protein regions of the U1 snRNP were tested in triplicates by indirect ELISA in sera from SLE or MCTD subjects. In addition laboratory tests and clinical manifestations data from these patients were included and analyzed in this investigation. Statistical classification methods as well as bioinformatics pattern recognition strategy were employed to determine which combination, if any, of all the variables included in this study provide the best segregation power for SLE and MCTD. The results confirmed that the IgM reactivity for U1 snRNP and U1A have the power to significantly distinguish SLE from MTCD patients as well as identify kidney and lung malfunctions for these subjects (p ≤ 0.05). Furthermore, the data analysis revealed eight novel classification rules for the segregation of SLE and MCTD which are a better classification tool than any of the currently available methods (p ≤ 0.05). Consequently, the results derived from this study support that SLE and MCTD are indeed separate disorders and pioneer the description of eight novel classification criteria capable of significantly discerning between SLE and MCTD patients (p ≤ 0.05).
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Singthongthat, Wanwisa. "Analysis and validation of Interferon Regulatory Factor 5 (IRF5) on circulating microparticles in patients with SLE." Thesis, Uppsala universitet, Institutionen för kvinnors och barns hälsa, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-415148.
Повний текст джерелаАнотація:
Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease that cause various inflammatory conditions in the body. The pathogenesis of this disease is yet unknown, and the diversity within the patients bring on major obstacle to clinical research for specific diagnostic markers. As a biomarker of SLE, both Interferon Regulatory Factor-5 (IRF5) and Microparticles (MP) have been suggested. Recently a study demonstrated higher concentration of IRF5+ MP in a small number of SLE patients compared to controls. Aim: The purpose of this study was to validate and analyze IRF5+ MPs in a larger number of SLE patients and compare the results to known SLE subgroup based on IRF5 concentration. Materials and methods: Totally 50 plasma samples from a larger cohort of SLE-patients (n=35) was analyzed together with population-based controls(n=15). Three different antibodies (in-house and commercial) were used for detection of IRF5+ MP with flow cytometry. Students t-test was used to investigate significant differences between SLE subgroup, controls and compared to the previous values. Results and Conclusion: The concentration of IRF5+ MP in SLE subgroup was significantly higher compared to controls (p<0,05). However, there were no correlations between our results and the values from the previous study, suggesting that both methods measure various forms of IRF5. These results imply that IRF5+ MP could be a possible biomarker for pathogenesis in SLE, but further studies are needed for a better understanding of IRF5, as well as of MP.
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Schubert, David. "Arthritisinduktion durch Immunität gegen ein systemisch exprimiertes Autoantigen." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2005. http://dx.doi.org/10.18452/15271.
Повний текст джерелаАнотація:
Ungefähr 1% der Bevölkerung der westlichen Welt leidet an rheumatoider Arthritis (RA). In einem T-Zellrezeptor transgenen Mausmodell, dem K/BxN Modell, wird die ubiquitär exprimierte Glukose-6-phosphat Isomerase (G6PI) von autoreaktiven T- und B-Zellen erkannt. Diese Mäuse entwickeln spontan eine antikörpervermittelte Arthritis, die viele Gemeinsamkeiten mit der humanen RA aufweist. In dieser Arbeit wurde untersucht, ob die Immunisierung mit G6PI eine Arthritis auch in nicht-transgenen Mäuse induzieren kann. Die Immunisierung mit heterologer humaner G6PI führte zur Entwicklung einer peripheren symmetrischen Polyarthritis in über 95% der DBA/1 Mäuse. Damit konnte zum ersten Mal gezeigt werden, dass eine Immunreaktion gegen ein systemisches exprimiertes Antigen zur einer organspezifischen Erkrankung in normalen nicht-transgenen Mäusen führt. Die Tiere entwickeln nach 9 Tagen eine Arthritis, die bis Tag 15 ihr Maximum erreicht hat und dann langsam abnimmt. Histologisch ist die Arthritis durch eine frühe Synovitis charakterisiert, gefolgt von massiven Erosionen des Knorpel und Knochens und anschließenden Reparaturprozessen, inklusive Fibrose. Obwohl die Tiere hohe Antikörpertiter entwickeln, kann die Arthritis nicht durch aufgereinigte Antikörper kranker Mäuse transferiert werden. Trotzdem spielen Antikörper eine große Rolle, da FcR-gamma-Kette defiziente Mäuse eine Arthritis mit geringer Inzidenz und mildem Verlauf entwickeln. Die Depletion der CD4 positiven Zellen verhindert die Entwicklung der Arthritis völlig, und eine Depletion während der Erkrankung führt zur schnellen Heilung. Daneben ist für die Entwicklung der Arthritis auch das Komplementsystem und TNF-alpha entscheidend, was durch Depletion von C5 bzw. durch Blockade von TNF-alpha gezeigt wurde. Zusätzlich wurde die Rolle der G6PI bei der Pathogenese der RA im Menschen untersucht. RA-Patienten zeigten keine erhöhte Frequenz von CD4 positiven T-Zellen, die nach Restimulation mit G6PI TNF-alpha oder IFN-gamma produzierten. Außerdem konnten keine erhöhten anti-G6PI Titer in Patienten mit RA oder anderen rheumatischen Erkrankungen detektiert werden.About 1% of the of the population of the western world suffers from rheumatoid arthritis (RA). In a T-cell receptor transgenic mouse model, the K/BxN model, the ubiquitously expressed glucose-6-phosphate isomerase (G6PI) is recognized by autoreactive T- and B-cells. These mice do develop an antibody dependent arthritis which show a lot of features of human RA. In this study it was examined whether arthritis could be induced in normal non-transgenic mice by immunization with G6PI. Immunization with heterologous human G6PI induces a symmetric polyarthritis in over 95% of DBA/1 mice. Therewith showing for the first time that an immune reaction against an systemic expressed antigen will lead to the development of an organ specific disease in normal non-transgenic mice. The mice develop arthritis 9d after immunization, reach their maximum at d15 and then arthritis slowly resolve. Histologically, the disease is characterized by early synovitis followed by massive cartilage destruction and erosions of the bones and later repair processes including fibrosis. Although antibody titers in the mice are high, transfer of purified anti-G6PI antibodies of sick mice alone do not transfer disease. Anyway, antibodies seem to play a major role since FcR-gamma-chain deficient mice develop disease with a much lower frequency and reduced severity. Depletion of CD4 positive T cells completely prevents disease and depletion during disease leads to an rapid resolution of arthritis. Aside this, complement and TNF-alpha is critical for the development of arthritis, which could shown by depletion of C5 and blockade of TNF-alpha. In addition, the role of G6PI in the pathogenesis of RA in humans was examined. RA patients do not show a higher frequency of CD4 positive T-cells which produce TNF-alpha and IFN-gamma after restimulation with G6PI. Furthermore, no elevated anti-G6PI titers could be detected in RA patients and in patients with other rheumatic diseases.
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Abbud, Filho Mario. "Microquimerismo fetal em pacientes com lupus eritematoso sistêmico: uma contribuição para o estudo da fisiopatologia das doenças auto-imunes." Faculdade de Medicina de São José do Rio Preto, 2006. http://bdtd.famerp.br/handle/tede/237.
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Previous issue date: 2006-12-01Systemic lupus erythematosus (LES) is a serious systemic autoimmune disease of which the pathogenesis remains elusive. Bi-directional cell traffic during pregnancy gives rise to fetal microchimerism (FMC). There is accumulating evidence suggesting that FMC can cause or exacerbate autoimmunity. Objetive. To determine the incidence of FMC in LES patients (pts) and to assess the effect of pregnancy and some epidemiological characteristics of LES on the FMC. Patientes and Methods. Real time polymerase chain reaction for specific Y chromosome sequences was used to detect fetal male cells (IPF) in the peripheral blood of 46 women selected according to this criteria: 1- pregnancy of at least one male offspring; 2- absence of history of previous transfusions, miscarriages or transplants. Information was obtained on the age of the mother at first male birth, number of male offspring, time since birth of the first son (time of microchimerism), time since disease diagnosis and renal involvement of LES.Results.Twenty eight pts and 18 healthy women were included in the study. The number of fmc/ml of maternal blood was higher among LES pts than in control group (252 ± 654 vs 2,13 ± 3,7 fmc/ml; p= 0,029). Multiple linear regression did show a strong positive correlation between the number of fmc/ml and the length of the disease (p= 0,027). The number of male cells also increase with duration of microchimerism in LES pts ( 15y = 140 ± 382; >15y = 395 ± 860 fmc/ml; p= 0,003) while slightly decreasing among healthy women during the same time periods (2,55 ± 4,34; 2,66 ± 3,79; 1,64 ± 3,81fmc/ml; p= NS). FMC was not associated with this number of male births and was also not associated with the mother s age at the birth of the first son. Higher numbers of fmc/ml were detected among pts without nephropathy when compared to those of pts with lupus nephritis (388 ± 827 YV 95,5 ± 338 fmc/ml; xiii p=0,019). This same observation was made in pts 18 years old at first male birth 9=(355 ± 623 YV 0,23 ± 0,22 fmc/ml respectively; p= 0,028). Conclusions. Our data demonstrates that the number of fmc/ml is higher in LES pts than in healthy women and it does increase with length of disease and duration of microchimerism. These results strongly suggest that in LES pts fetal microchimeric cells do proliferate with time but decrease or tend to disappear in healthy women. It is possible that FMC may not be totally detrimental to the host because it may provide some benefits in lupus nephritis cases.
Lupus eritematoso sistêmico (LES) é uma doença auto-imune grave com fisiopatologia ainda desconhecida. Na gestação o trânsito bidirecional que ocorre entre as células da mãe e feto causa o aparecimento do microquimerismo fetal (MCF). Existem evidências que a persistência do MCF poderia causar ou exacerbar doença auto-imune. Objetivo: Determinar a freqüência de ocorrência de MCF em pacientes (pts) acometidas pelo LES e avaliar o efeito da gestação e de características epidemiológicas do LES sobre o MCF. Pacientes e Métodos. Reação em cadeia da polimerase em tempo real para seqüências de DNA específicas do cromossomo Y foi a técnica usada para detectar células fetais masculinas (IPF) no sangue de 46 mulheres selecionadas conforme os critérios: 1- história com presença de pelo menos uma gravidez do sexo masculino; 2- ausência de abortos, transfusão sanguínea ou transplantes prévios. Foram ainda obtidas informações sobre tempo decorrido desde o nascimento do primeiro filho (tempo de microquimerismo), número de gestações do sexo masculino, idade ao nascimento do primeiro filho, tempo de diagnóstico de LES e evidências de nefrite lúpica. Resultados. Vinte oito pts e 18 mulheres saudáveis foram incluídas no estudo. O número de fmc/ml de sangue materno foi maior nas pts com LES do que no grupo controle (252 654) YV (2,13 3,7) fmc/ml; (p=0,029). Regressão linear múltipla mostrou significante correlação positiva entre o número de fmc/ml e o tempo de doença lúpica (p=0,027). Enquanto nas pts com LES a quantidade de fmc/ml aumentou progressivamente com o tempo de microquimerismo (. DQRV . fmc/ml; 11 - 15a = 140 382; >15a = 395 860 mfc/ml; p=0,003) nas mulheres saudáveis ocorreu uma leve redução nos mesmos intervalos de tempo (respectivamente 2,55 4,34; 2,66 3,79; 1,64 3,81 fmc/ml; p= NS). MCF não foi associado com o número de gestações do sexo masculino nem com a idade ao nascimento do primeiro filho. Nota de Resumo número de gestações do sexo masculino nem com a idade ao nascimento do primeiro filho. Maior número de fmc/ml foi detectado nas pacientes sem nefrite lúpica quando comparado com as pts com doença renal (388 827 YV 95,5 338 fmc/ml; p=0,019). Essa observação também foi notada entre pts sem nefrite que pariram o primeiro filho até 18 anos de idade (355 623 YV 0,23 0,22 fmc/ml respectivamente; p=0,028). Conclusões.A quantidade de células fetais microquiméricas é maior entre as pts com LES e o número dessas células aumenta com decorrer do tempo de doença e do tempo de microquimerismo. Essas observações sugerem que as células fetais masculinas podem proliferar, aumentando nas pts com LES e diminuindo ou mesmo desaparecendo nas mulheres saudáveis. Ainda é possível que o FMC não tenha apenas um papel deletério no LES podendo produzir benefícios nos casos de nefrite lúpica.
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Bobé, Pierre. "La gestation : un modele d'etude de la regulation de la reponse immunitaire." Paris 7, 1987. http://www.theses.fr/1987PA077192.
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Chausse, Anne-Marie. "Approche moleculaire de l'association entre le complexe majeur d'histocompatibilite et les maladies dans deux especes differentes." Paris 7, 1988. http://www.theses.fr/1988PA077033.
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Ribeiro, Francisco de Sousa Sebastião Alexandre. "Anti-Ro/SSA and the development of hematological malignancy in systemic autoimmune diseases." Master's thesis, 2021. http://hdl.handle.net/10451/52026.
Повний текст джерелаАнотація:
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2021Os auto-anticorpos estão associados a um número considerável doenças autoimunes. O anticorpo anti-Ro/SSA faz parte deste grupo vasto de anticorpos, podendo encontrar-se em doentes com Síndrome de Sjögren (SS) e Lupus Eritematoso Sistémico (LES), entre outros. O anticorpo anti-Ro tem como alvo o antigénio Ro que se compõe de duas proteínas diferentes, Ro60 e Ro52. Tem sido amplamente reconhecido na literatura que doentes com patologia autoimune como LES e SS têm um risco acrescido de desenvolver doenças hemato-oncológicas. Coincidentemente, tem sido descrita uma elevada incidência de anticorpos anti-Ro em doentes com patologia do foro hemato-oncológico, com diagnóstico autoimune prévio ou sem doença autoimune conhecida. Os potenciais mecanismos interligando a actividade dos anticorpos anti-Ro, o antigénio Ro e o desenvolvimento de doença hemato-oncológica permanecem ainda sob esclarecimento. O autor apresenta uma pequena série de doentes com patologia autoimune, positividade para anticorpos anti-Ro e desenvolvimento de doença hemato-oncológica, revendo a literatura mais recente e enfatizando o potencial papel da ativação da via de sinalização NF-kB como elo fisiopatológico entre doença autoimune, anti-Ro e malignidade hematológica.
Autoantibodies are associated with a considerable number of autoimmune diseases. Anti-Ro/SSA antibody is one of this vast group of antibodies and can be found in patients with Sjögren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE), among other pathologies. The antibody anti-Ro targets the Ro antigen, composed of two different proteins, Ro52 and Ro60. It has been widely recognized in the literature that patients with autoimmune pathology such as SLE and SS have an increased risk of developing hemato-oncological diseases. Coincidentally, a high incidence of anti-Ro antibodies has been described in patients with hemato-oncological pathology, with a previous autoimmune diagnosis or without known autoimmune disease. The potential mechanisms linking the activity of anti-Ro antibodies, the Ro antigen and the development of hemato-oncological disease remain under elucidation. The author presents a small series of patients with autoimmune pathology, positivity for anti-Ro antibodies and development of hemato-oncological disease, reviewing the most recent literature and emphasizing the potential role of activation of the NF-kB signaling pathway as a pathophysiological link between disease autoimmune, anti-Ro and hematologic malignancy.
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AMADOR, CAROLINA. ""Fetal programming" e patologie reumatiche autoimmuni: il caso della sclerosi sistemica." Doctoral thesis, 2015. http://hdl.handle.net/2158/999007.
Повний текст джерелаАнотація:
Lo studio si inserisce nel panorama dell’‘early life programming’ di fronte alle evidenze che anche il sistema immune presenta grande plasticità durante lo sviluppo per cui è possibile che già in utero subisca una programmazione di molte sue funzioni.
Il peso alla nascita, la condizione di restrizione fetale ( IUGR) e la condizione di piccolo per l’età gestazionale (SGA) sono stati presi in considerazione in diversi studi come prototipi di un ambiente fetale avverso per cercare di individuare una possibile correlazione tra queste condizioni e lo sviluppo di malattie legate al sistema immune.