Tesi: "Autoimmunity"

1

Cucurella, Paula. "Autoimmunity in Antipoetry". Thesis, State University of New York at Buffalo, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10639684.

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Antipoetry, a form of poetry developed by the Chilean poet Nicanor Parra, instances a privileged example of a self-regulatory trait of the poetic genre which responds to poetry’s need to destroy itself in order to renew itself. This need reveals a structural mechanism or a logic of autoimmunity, which informs the possibility of language and, moreover, of all living beings.

Antipoetry’s departure from the Nerudean poetic tradition justifies the use of a colloquial language that also preserves and continues Neruda’s interest in opening a space for the “popular” in poetry. Against Neruda, Antipoetry also consciously repels romantic and heroic aesthetic principles and ideas.

Parra’s aesthetic principles, however, do not result solely from avoidance. Parra is a realist poet heavily influenced by physics. His poetry needs to mirror reality. The principles of relativity and indetermination play major roles in his poetic experimentations, and will come to the aid of Antipoetry’s need to create in times of censorship. Parra’s experiments with language are in large measure interpretations of the laws of physics. In this regard, his scientific realism is related to Gertrude Stein’s work. The poetry and poetics of the latter provides a touchstone and a constant reference in Autoimmunity in Antipoetry.

Like all artistic expressions during the Chilean military dictatorship of Augusto Pinochet, Antipoetry was forced to negotiate what could be said with what the poet wanted to say. The necessary negotiation that Parra’s poetry needed to undergo gave rise to many experiments with language, including systematic ambiguity, contestation of the authority of the author, and of his own authorial control over his poetry. The use of masks, the multiplication of referents, and the systematic use of contradiction name some of Antipoetry’s tools for obstructing the univocal determination of meaning.

Antipoetry’s systematic explorations toward the creation of a poetry that attempts to fight all forms of dogmatism nevertheless reaches a limit in its figuration of gender. Antipoetry’s gender politics makes concessions to a type of gender dogmatism (sexism and homophobia) that contradicts the antipoetic program and reveals an inherent fear of gender contamination that jeopardizes Antipoetry’s most fortunate aspects.

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2

Grant, Michael David. "Alloimmunity, autoimmunity, and AIDS". Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/27465.

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The sensitivity of the human immune system to the retrovirus HIV is difficult to explain on the basis of viral cytopathicity. AIDS develops often long after initial HIV infection in spite of a vigorous and sustained immune response against the virus which effectively contains viral replication. Although more virulent strains of HIV can be isolated from immunodeficient persons, there is no evidence that these strains predominate in vivo or that a large increase in production of infectious virus accompanies progression to disease. There is as yet no satisfactory mechanism to explain the immunosuppression, T4 cell depletion, autoimmunity, and immunodeficiency associated with HIV infection. An hypothesis that AIDS results from immune responses to HIV gp120 and to allogeneic cells stems from recent developments in the symmetrical network theory. It is proposed that T-cell selection processes produce a T-cell idiotypic network "centrepole," which bears an internal image of self MHC class II within T-cell receptors. This network centrepole interacts with the anti-class II helper cell repertoire to stabilize both its own expression and expression of the helper T-cell repertoire. The idiotypes involved in this mutual stabilization are related to certain idiotypes present on allogeneic lymphocytes and to the envelope glycoprotein of HIV gp120. Through its relationship to CD4 protein, and hence class II MHC, HTV gp120 is thought to mimic the T-cell network centrepole. Anti-host class II receptors on allogeneic lymphocytes induce antibodies which also mimic the proposed centrepole. The immune response to gp120 is directed against the centrepole and against the antibodies (anti-anti-class II) induced by the receptors of allogeneic lymphocytes. The hypothesis evaluated in this thesis project is that the immune responses described above synergize in an attack on both the centrepole and the helper cell repertoire, resulting in aberrant immune regulation, autoimmunity, and eventually, AIDS. Sera from persons with AIDS or at risk of AIDS were examined for antibodies implicated in the above scheme. Anti-anti-CD4/anti-gp120 antibodies (putative anti-centrepole) were found in only a small minority of subjects and did not correlate with disease, while anti-anti-class II antibodies were almost never detected. Anti-MHC class I antibodies, reflecting alloimmunity, were associated with HIV infection and to some extent with disease progression. Autoantibodies against denatured collagen, reflecting autoimmunity, were found in almost all AIDS patients. The prevalence of these autoantibodies increases in HIV infection and with disease expression. Antibodies against denatured collagen show an interesting distribution which suggests they are related to the idiotypic determinants involved in the pathogenesis of AIDS and other similar immune disorders. The specificity of these antibodies suggests they arise through immunoregulatory defects induced through idiotypic network interactions.
Science, Faculty of
Microbiology and Immunology, Department of
Graduate

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3

Ye, Ping. "Autoimmunity in chronic periodontitis". Thesis, The University of Sydney, 2003. http://hdl.handle.net/2123/4256.

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Profound perturbation of epithelial structure is a characteristic feature of the immunopatholoical response to bacterial antigens considered to be central in the pathogenesis of the destructive lesion of periodontitis. The pathological basis for the disturbance of epithelial structure is not understood. It was demonstrated that the structural integrity and functional differentiation of the lining epithelium is compromised in relation to inflammatory changes associated with destructive periodontitis. In the pathological lining epithelium of the periodontal pocket there was a marked reduction of epithelial cadherin important in intercellular adhesion, of involucrin, a marker of terminal differentiation, and of the gap junction connexions that form intercellular communication channels. These changes were associated with alterations of filamentous actin expression, collectively indicating profound perturbation of epithelial structure. The data reported support the concept that the ability of the pathological lining epithelium to function as an effective barrier against the ingress of microbial products into the tissues is severely compromised (Ye et al., 2000). In addition, a recent study (Ye et al., 2003) by Western analysis of serum IgG from all 22 patients with chronic periodontitis tested indicated recognition of multiple epithelial components in individual patterns. In contrast, subjects with a healthy periodontium displayed only trace recognition of epithelial antigens. Levels of epithelial-reactive antibodies were significantly correlated with attachment loss as an indication of disease activity. To investigate a possible relationship between the bacterial flora adjacent to the diseased sites and the presence of epithelial-reactive antibodies, subgingival plague samples were taken from deep periodontal pockets and cultured anaerobically. Gram positive bacteria containing antigens potentially cross-reactive with epithelial cells were reproducibly isolated by probing membrane colony lifts with affinity-isolated (epitheial-specific) antibodies. The bacteria were identified as streptococci (S. mitis, S. constellatus and two S. intermedius strains) and Actinomyces (A. georgiae, and A. sp. oral clone) by 16S rDNA sequence homology. Recognition by affinity-isolated antibodies of antigens from the captured organisms was confirmed by Western analysis. Conversely, absorption of affinity-isolated antibodies with bacterial species specifically reduced subsequent recognition of epithelial antigens. To identify the auto-antigens, a human keratinocyte cDNA expression library in Lambda phage was probed using a pooled sera. Groups of responders were detected for CD24 (a recently described adhesion molecule also known as P-selectin ligand), antioxidant protein 2 (a newly recognised member of the thiol-dependment anti-oxidant proteins), lavtate dehydrogenase A, the transcription factor NFAT5, and for three genes encoding novel proteins. Six identified bacteria, especially S intermedius were demonstrated to absorb antibodies reaching with identified auto-antigens in patterns varying between individuals. This evidence indicated that during the course of periodontits, subjects develop increased levels of antibodies to common oral bacteria amongst which are included tissue cross-reactive antigens. Periodontitis could therefore present a risk for the subsequent initiation or exacerbation of a broad spectrum of disease processes including autoimmune, inflammatory, proliferative and degenerative disorders.

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4

Ye, Ping. "Autoimmunity in chronic periodontitis". University of Sydney, 2003. http://hdl.handle.net/2123/4256.

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Abstract (sommario):

Doctor of Philosophy
Profound perturbation of epithelial structure is a characteristic feature of the immunopatholoical response to bacterial antigens considered to be central in the pathogenesis of the destructive lesion of periodontitis. The pathological basis for the disturbance of epithelial structure is not understood. It was demonstrated that the structural integrity and functional differentiation of the lining epithelium is compromised in relation to inflammatory changes associated with destructive periodontitis. In the pathological lining epithelium of the periodontal pocket there was a marked reduction of epithelial cadherin important in intercellular adhesion, of involucrin, a marker of terminal differentiation, and of the gap junction connexions that form intercellular communication channels. These changes were associated with alterations of filamentous actin expression, collectively indicating profound perturbation of epithelial structure. The data reported support the concept that the ability of the pathological lining epithelium to function as an effective barrier against the ingress of microbial products into the tissues is severely compromised (Ye et al., 2000). In addition, a recent study (Ye et al., 2003) by Western analysis of serum IgG from all 22 patients with chronic periodontitis tested indicated recognition of multiple epithelial components in individual patterns. In contrast, subjects with a healthy periodontium displayed only trace recognition of epithelial antigens. Levels of epithelial-reactive antibodies were significantly correlated with attachment loss as an indication of disease activity. To investigate a possible relationship between the bacterial flora adjacent to the diseased sites and the presence of epithelial-reactive antibodies, subgingival plague samples were taken from deep periodontal pockets and cultured anaerobically. Gram positive bacteria containing antigens potentially cross-reactive with epithelial cells were reproducibly isolated by probing membrane colony lifts with affinity-isolated (epitheial-specific) antibodies. The bacteria were identified as streptococci (S. mitis, S. constellatus and two S. intermedius strains) and Actinomyces (A. georgiae, and A. sp. oral clone) by 16S rDNA sequence homology. Recognition by affinity-isolated antibodies of antigens from the captured organisms was confirmed by Western analysis. Conversely, absorption of affinity-isolated antibodies with bacterial species specifically reduced subsequent recognition of epithelial antigens. To identify the auto-antigens, a human keratinocyte cDNA expression library in Lambda phage was probed using a pooled sera. Groups of responders were detected for CD24 (a recently described adhesion molecule also known as P-selectin ligand), antioxidant protein 2 (a newly recognised member of the thiol-dependment anti-oxidant proteins), lavtate dehydrogenase A, the transcription factor NFAT5, and for three genes encoding novel proteins. Six identified bacteria, especially S intermedius were demonstrated to absorb antibodies reaching with identified auto-antigens in patterns varying between individuals. This evidence indicated that during the course of periodontits, subjects develop increased levels of antibodies to common oral bacteria amongst which are included tissue cross-reactive antigens. Periodontitis could therefore present a risk for the subsequent initiation or exacerbation of a broad spectrum of disease processes including autoimmune, inflammatory, proliferative and degenerative disorders.

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5

Ye, Ping. "Autoimmunity In Chronic Periodontitis". Thesis, The University of Sydney, 2003. http://hdl.handle.net/2123/4872.

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6

Crisi, Giovanna M. "Autoimmunity and effect of ageing". [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 1999. http://arno.unimaas.nl/show.cgi?fid=8571.

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7

Wodzig, Karel Willem Henricus. "Cyclosporine A-induced experimental autoimmunity". Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1993. http://arno.unimaas.nl/show.cgi?fid=9486.

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8

Johnstone, Thomas W. "Neutrophil serine proteinases and autoimmunity". Thesis, Queen's University Belfast, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241372.

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9

Bari, Abu-saleh Mahfuzul. "Autoimmunity in canine joint disease". Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257145.

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10

D'Cruz, David Pascal. "Autoimmunity, endothelium and vascular disease". Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298705.

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11

Young, Joyce L. "The control of erythrocyte autoimmunity". Thesis, University of Bristol, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292470.

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12

Palacios, Cuervo Fernando, Rivera Andrea Calderón, Reyes Fátima Espinal e Aybar Carlos Canelo. "Autoimmunity in dengue: Literature review". Elsevier B.V, 2015. http://hdl.handle.net/10757/595420.

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13

Palacios, Cuervo Fernando, Rivera Andrea Calderón, Reyes Fátima Espinal e Aybar Carlos Canelo. "Autoimmunity in dengue: Literature review". Elsevier B.V, 2016. http://hdl.handle.net/10757/609496.

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14

Selli, Mehmet Emrah. "Autoimmunity in obesity and myocarditis". Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.702465.

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Autoimmunity is responsible for a wide spectrum of degenerative diseases, including metabolic disorders such as type I diabetes. If the triggering antigen or antigens can be identified, immune tolerization with peptides may be an effective therapy. Mitochondrial heat shock protein 60 (HSP60) has been implicated as an autoantigen in several diseases. Furthermore, ectopic HSP60 over expression was recently linked to human obesity and could therefore act as an autoantigen causing obesity-related metabolic dysfuntion. Using high fat fed C57BL6 mice as a' model, we observed increased circulating HSP60 levels and both T cell and B cell (antibody) responses against HSP60. Hence, HSP60 does indeed appear to be one of the mystery autoantigens triggering the early T and B cell responses during obesity. Furthermore, using previously-defined, immunodominant murine HSP60 peptide combinations in a dose escalation protocol we attempted peptide therapy. Peptide therapy did not significantly reduce T or B cell responses to HSP60 but nevertheless significantly improved glucose tolerance and circulating LDLlVLDL. HSP60 peptide therapy could therefore be helpful in reversing the metabolic consequences of obesity. Myocarditis is defined as damage to heart muscle coupled with an inflammatory infiltrate and left ventricular dysfunction. Clinically, the acute phase is usually caused by viral cardiac damage but it can progress to chronic myocarditis when autoimmunity develops. Exposure of intracellular cardiac proteins, especially cardiac a-myosin, has been implicated. Autoimmunity to a-myosin may arise because it is not expressed in the thymus and therefore tolerance does not develop. We developed a humanised HLA-DR4 transgenic mouse model of a-myosin induced autoimmune myocarditis. Moreover, we were able to downregulate autoimmune responses against a-myosin, reduce inflammatory cell infiltration and improve left ventricular cardiac function using tolerogenic peptide combinations determined from epitope prediction studies. In summary, our findings provide proof of principle for peptide therapy to treat obesity-associated metabolic complications and autoimmune myocarditis.

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15

Hansson, Monika. "Mercury-induced autoimmunity : Genetics and immunoregulation". Doctoral thesis, Stockholm University, Wenner-Gren Institute for Experimental Biology, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-47.

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The existence of immune self-tolerance allows the immune system to mount responses against infectious agents, but not against self-molecular constitutes. Although self-tolerance is a robust phenomenon, in some individuals as well as in experimental models, the self-tolerance breaks down and as a result, a self-destructive autoimmune disease emerges. The underlying mechanisms for the development of autoimmune diseases are not known, but genetic, environmental and immunological factors are suggested to be involved. In this thesis, we used murine mercury-induced autoimmunity to test this suggestion.

In susceptible mice mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of IgG1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. In contrast, in resistant DBA/2 (H-2^d) mice, none of these characteristics develop after exposure to mercury. By crossing and backcrossing mercury-resistant DBA/2 mice to mercury susceptible strains, we found that the resistance was inherited as a dominant trait in F1 hybrids and that one gene or a cluster of genes located in the H-2 loci determined the resistance to ANolA production, whereas resistance to the other characteristics was found to be controlled by two or three non-H-2 genes.

We further put forward the “cryptic peptide hypothesis” to investigate whether mercury and another xenobiotic metal use similar pathway(s) to induce the H-2 linked production of ANolA. We found that while mercury stimulated ANolA synthesis in all H-2 susceptible (H-2^s, H-2^q and H-2^f) mouse strains, silver induced only ANolA responses in H-2^s and H-2^q mice, but not in H-2^fmice. Further studies showed that the resistance to silver-induced ANolA production in H-2^fmice was inherited as a dominant trait.

We next tested the proposition that mercury induces more adverse immunological effects in mouse strains, which are genetically prone to develop autoimmune diseases, using tight-skin 1 mice, an animal model for human Scleroderma. It was found that in this strain, mercury induced a strong immune activation with autoimmune characteristics, but did not accelerate the development of dermal fibrosis, a characteristic in Tsk/1 mice.

Finally we addressed the Th1/Th2 cross-regulation paradigm by examining if a Th1-type of response could interact with a Th2-type of response if simultaneous induced in susceptible mice. Our findings demonstrated that mercury-induced autoimmunity (Th2-type) and collagen-induced arthritis (CIA) (Th1-type) can interact in a synergistic, antagonistic or additive fashion, depending on at which stage of CIA mercury is administered.

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16

Kozhakhmetova, Aizhan. "Multiple autoimmunity in type 1 diabetes". Thesis, University of Bristol, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.715747.

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17

McKall-Faienza, Kim J. "The role of TNFRp55 in autoimmunity". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq28774.pdf.

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18

Astern, Joshua Michael Falk Ronald J. Preston Gloria A. "Myeloperoxidase in vascular disease and autoimmunity". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1209.

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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Mar. 26, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pathology and Laboratory Medicine." Discipline: Pathology and Laboratory Medicine; Department/School: Medicine.

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19

Buckley, Camilla. "Autoimmunity in thymoma-associated Myasthenia gravis". Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394014.

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20

Lewis, Graham Matthew. "The genetic basis of systemic autoimmunity". Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424728.

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21

Walker, Jennifer Anne. "CD22, autoimmunity and the B cell". Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612192.

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22

Thompson, Clare. "The role of iodine in autoimmunity". Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615656.

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23

Dalin, Frida. "Model diseases for studies of autoimmunity". Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-265276.

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The events triggering autoimmune diseases are to large extent unknown and model diseases are an important tool in studies aiming to elucidate molecular mechanisms in autoimmunity. Autoimmune Addison’s disease (AAD) is a rare disease characterized by autoimmune destruction of adrenal glands and most patients with AAD have autoantibodies against the enzyme 21‑hydroxylase in the adrenal cortex. The autoimmune destruction in AAD is however suspected to be initiated by T cells. One of the most important investigations in this thesis was to characterize the T cell response in AAD. It could be concluded the T cells in AAD patients respond to three immunodominant epitopes on the 21-hydroxylase. In addition, this thesis aims to gain updated data on comorbidities, replacement therapy, autoantibody profiles, and metabolic factors in AAD. A cohort of 660 AAD patients was studied and it was found that AAD patients are prone to develop other autoimmune conditions. AAD is one of three main disease components Autoimmune Polyendocrine Syndrome type 1 (APS-1), a rare disorder caused by mutations in the AutoImmune REgulator gene (AIRE) that can be potentially fatal without timely diagnosis. Screening for autoantibodies against interferon-ω, interferon-α4, and interleukin-22 revealed four new APS-1 patients among the AAD cohort, confirmed by the presence of disease causing mutations in the AIRE gene. Cancer Associated Retinopathy (CAR) is a paraneoplastic phenomenon arising as a consequence to an autoimmune response triggered by a malignant neoplasm present in the body. This disease is devastating and it is valuable to identify new biomarkers associated with CAR, not least from a tumor diagnostic perspective. In this thesis, a patient with osteosarcoma and CAR was studied and by screening of a proteom array, and the novel CAR autoantigen Aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) was identified. In conclusion, this thesis covers studies on T cell and B cell responses in AAD. Moreover, it includes an update on clinical and immunological characterisation of AAD patients. Finally, a novel autoantigen in CAR was identified and proposed as a diagnostic marker for the paraneoplastic syndrome.

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24

Hornsby, E. "Development of IL-17A-associated autoimmunity". Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/20224/.

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Autoimmunity results from a breakdown in tolerance to self-antigens. Interleukin-17A (IL-17A) is a cytokine that has been implicated in the development of certain autoimmune disorders, notably multiple sclerosis and its mouse model experimental autoimmune encephalomyelitis (EAE). In order to further understand mechanisms that lead to the development of autoimmunity, the objectives of this study were to investigate the sequence of immunological events that lead to the development of an autoimmune response and to generate and characterise a reporter mouse for IL-17A. EAE is a well-established model of an autoimmune response directed against selfantigens in the central nervous system and mimics many aspects of the human disease multiple sclerosis. EAE is a CD4 T cell-mediated disease, in that these cells can be used to transfer disease to naïve recipient mice. Following EAE induction, IL-17A-expressing cells were increased in frequency within the CD4 and γδ T cell populations in the draining lymph nodes, with a simultaneous increase in the number of these cell populations in the blood. Disease development was associated with the appearance of IL-17A and IFN-γ-expressing CD4 T cells, as well as IL-17Aexpressing γδ T cells in the spinal cord. EAE induction requires the systemic administration of pertussis toxin for disease development. It was found that pertussis toxin enhanced antigen-specific IL-17A and IFN-γ production in the periphery. An IL-17A reporter mouse was generated in which activation of the IL-17A promoter is reported by expression of Enhanced Yellow Fluorescence Protein (EYFP). In order to generate the mouse, a strain was first generated in which Cre recombinase expression is driven by the IL-17A promoter. This mouse was then crossed with a ROSA-26_EYFP strain in which expression of EYFP in the ubiquitously expressed ROSA-26 locus is usually inhibited by the presence of a LoxP-flanked-transcriptional stop sequence. Expression of Cre recombinase would remove the transcriptional stop sequence, leading to irreversible expression of EYFP in all cells that had activated IL-17A and their progeny. The results from this study suggest that pertussis toxin can amplify antigen-specific cytokine responses in EAE, an effect which could be attributed to enhancing disease pathogenesis. The IL-17A reporter mouse will be an invaluable tool to investigate the generation, lifespan and function of IL-17A-expressing cells in the development of immune responses.

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25

Prahalad, Sampath. "Juvenile Rheumatoid Arthritis and Familial Autoimmunity". University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin991251421.

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26

Gerhardt, Teresa [Verfasser], Andreas [Akademischer Betreuer] Zirlik e Marco [Akademischer Betreuer] Idzko. "Loss of protective autoimmunity in atherosclerosis". Freiburg : Universität, 2021. http://d-nb.info/1238016073/34.

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27

Jha, Vibha. "Cellular regulation of mercury-induced autoimmunity". Diss., Temple University Libraries, 2009. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/60597.

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Microbiology and Immunology
Ph.D.
Etiological agents causing autoimmune diseases largely remain unknown. However, several lines of evidence suggest that environmental factors such as heavy metals (arsenic, lead and mercury) play a crucial role in the development of autoimmune disorders. In our model of mercury-induced autoimmunity, administration of subtoxic doses of HgCl2 to genetically susceptible strains of mice result in an autoimmune disease characterized by the production of highly specific anti-nucleolar autoantibodies, hypergammaglobulinemia and nephritis. However, mice can be tolerized to the disease by a single low dose administration of HgCl2 (tolerogenic dose). Previous studies from our lab had demonstrated that CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) control the induction and maintenance of tolerance to mercury. We investigated the therapeutic role of Tregs in our model by utilizing agents that are known to stimulate in vivo expansion of Tregs. We studied two such agents, CD3-specific non-Fc receptor-binding [(Fab’)2 fragment] monoclonal antibody (Anti-CD3) and immune complexes containing recombinant IL-2 and anti-IL-2 monoclonal antibody (IC). In our model, treatment of mice with Anti-CD3 had no effect on Treg population. Administration of Anti-CD3 with the tolerogenic dose prevented induction of tolerance and failed to improve the maintenance period of tolerance. Anti-CD3 in presence of mercury activated the immune-system causing splenomegaly and expansion of B cell population. Overall, in contrast to its protective role in other experimental autoimmune disease models, Anti-CD3 exacerbated mercury-induced autoimmune syndrome. Treatment of mice with IC resulted in selective expansion of Tregs with a modest decrease in IgE levels and autoantibody production. Administration of IC with the tolerogenic dose led to a reduction in autoantibody response, thus IC was able to extend the maintenance period of tolerance to mercury. Lymphocyte Activation Gene-3 (LAG-3) is an inhibitory molecule that maintains lymphocyte homeostatic balance by controlling effector T cell expansion and contributing to the suppressive functions of Tregs. Thus, with the goal to understand the impact of homeostatic balance on Hg-induced autoimmunity, we investigated the role of LAG-3 in our model. Administration of an anti-LAG-3 monoclonal antibody broke tolerance to Hg resulting in autoantibody production and an increase in levels of serum IgE. Additionally, LAG-3-deficient B6.SJL mice exhibited an increased susceptibility to mercury-induced autoimmunity whereas, wild type controls suffered only from a mild disease. Moreover, adoptive transfer of wild-type CD4+ T cells protected LAG-3-deficient mice from mercury-induced autoimmunity. Therefore, we conclude that LAG-3 exerts an important regulatory effect on autoimmunity elicited by a common environmental pollutant.
Temple University--Theses

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28

Villard, Marine. "Rôle de la profération induite par la lymphopénie dans la rupture de la tolérance périphérique des lymphocytes T CD8+". Thesis, Montpellier 2, 2013. http://www.theses.fr/2013MON20172/document.

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La tolérance des lymphocytes TCD8+ est essentielle pour empêcher l'apparition d'auto-immunité mais représente un obstacle pour le développement de réponses cytotoxiques contre les tumeurs. La lymphodéplétion est utilisée comme adjuvant pour l'immunothérapie par transfert adoptif de cellules T cytotoxiques car elle améliore leur efficacité en favorisant la rupture de la tolérance périphérique. En condition lymphopénique aiguë, les lymphocytes T naïfs prolifèrent en absence apparente de stimulation antigénique et vont acquérir un phénotype et une fonctionnalité semblable aux cellules mémoires (LIP pour Lymphopenia Induced Proliferation). Les cellules mémoires ayant un seuil d'activation inférieur cellules naïves, il a été proposé que la différentiation des cellules TCD8+ potentiellement autoréactives en cellules de type mémoire dans des conditions lymphopéniques pouvait conduire à la rupture de la tolérance. Pendant ma thèse, j'ai étudié si la LIP est nécessaire pour la rupture de la tolérance croisée des cellules TCD8+ chez des souris transgéniques irradiées exprimant un antigène modèle dans les cellules β du pancréas. De manière surprenante, nous avons constaté que le blocage de la LIP ne permet pas d'inhiber l'apparition d'auto-réactivité : les lymphocytes TCD8+ qui ne transitent pas par un stade de différenciation de type mémoire parviennent à se différencier en cellules effectrices suite à la présentation croisée de l'antigène et à migrer vers le pancréas. Néanmoins, la LIP est requise pour induire de l'auto-réactivité lorsque la fréquence de lymphocytes T CD8+ est faible ; non pas à cause du déséquilibre de la population de cellules T régulatrices, mais dû à une nette augmentation du nombre de cellules TCD8+ autoréactives. Ainsi, bien que la LIP améliore les réponses auto- réactives des cellules TCD8+, la différentiation en cellules de type mémoire n'est pas indispensable pour la rupture de la tolérance croisée en condition lymphopénique induite par irradiation
The immune system has evolved multiple mechanisms of peripheral tolerance to control CD8+ T cell responses and to prevent autoimmunity. However, they also represent a barrier for the development of cytotoxic responses against tumors. Lymphodepleting protocols are currently used as adjuvants for adoptive cytotoxic T cell immunotherapy because they enhance their potency. These protocols are thought to promote the breakdown of peripheral CD8+ T cell tolerance. Under acute lymphopenic conditions, naive T cells proliferate, in the apparent absence of antigenic stimulation at least in part due to a greater availability of the cytokine IL-7. Proliferating CD8+ T cells acquire a phenotype and functionality that is similar to memory cells and are termed memory-like cells. Since memory cells have a lower activation threshold than naïve cells, it has been proposed that differentiation of potentially autoreactive CD8+ T cells into memory-like cells under lymphopenic conditions could drive the breakdown of peripheral tolerance. Here we studied whether lymphopenia induced proliferation and differentiation are required for the breakdown of CD8+ T cell cross-tolerance in irradiated transgenic mice expressing a model antigen in the beta cells of the pancreas. Surprisingly, we found that blocking lymphopenia-induced proliferation and differentiation into memory-like cells did not prevent self-reactivity. CD8+ T cells that did not differentiate into memory-like cells still became effectors upon antigen cross-presentation and migrated to the site of antigen expression. Nonetheless, LIP did enhance CD8+ T cell mediated self-reactivity at low T cell frequencies. This effect could not be explained by a Treg imbalance but by a net increase in autoreactive CD8+ T cell numbers. Thus, although LIP enhances CD8+ T cell anti-self responses, differentiation into memory-like cells is not essential for the breakdown of cross-tolerance under the lymphopenic conditions provided by irradiation

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Beijleveld, Leonardus Johannes Josephus. "Thymus dependent autoimmunity thymic selection versus peripheral tolerance in the model of experimental Cyclosporin-A induced autoimmunity /". [Maastricht : Maastricht : Rijksuniversiteit Limburg] ; University Library, Maastricht University [Host], 1996. http://arno.unimaas.nl/show.cgi?fid=6692.

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30

Rodríguez, Fernández Silvia. "Phosphatidylserine-rich liposomes to tackle autoimmunity. En route to translationality". Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667944.

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Abstract (sommario):

Les malalties autoimmunitàries estan causades per defectes en la tolerància immunològica, i afecten a gairebé un 10% de la població. Darrerament, diverses intervencions mèdiques han convertit aquestes malalties en cròniques, però el seu diagnòstic encara comporta morbiditat i mortalitat elevades. Així, un repte biomèdic urgent és el desenvolupament de teràpies que puguin restablir selectivament la tolerància, aturin l’atac autoimmunitari i permetin la regeneració del teixit danyat. En condicions fisiològiques, la fagocitosi de cèl·lules apoptòtiques per part de fagòcits com les cèl·lules dendrítiques (CDs) —procés que rep el nom d’eferocitosi— els indueix propietats tolerogèniques i l’habilitat de restaurar la tolerància. Una demostració d’això és que una immunoteràpia cel·lular consistent en CDs tolerogèniques (CDtols) degut a l’eferocitosi de cèl·lules β apoptòtiques va aturar l’atac autoimmunitari contra les cèl·lules β en un model experimental de diabetis tipus 1 (DT1). Donades les dificultats en obtenir i estandarditzar cèl·lules β apoptòtiques autòlogues humanes per la seva implementació clínica, es va dissenyar una nanoteràpia basada en liposomes que simulen cèl·lules apoptòtiques. Les principals característiques d’aquestes vesícules sintètiques són: elevat percentatge de fosfatidilserina (FS) —fosfolípid característic de la membrana de les cèl·lules apoptòtiques—, diàmetre major de 500 nm, càrrega negativa i eficient encapsulació de pèptids d’insulina. Aquesta estratègia és tant efectiva en generar CDtols i aturar l’autoimmunitat contra les cèl·lules β com la immunoteràpia basada en cèl·lules apoptòtiques. La hipòtesi d’aquest treball és que els FS-liposomes poden restablir la tolerància en diverses malalties autoimmunitàries antigen-específiques mitjançant la generació de CDtols i l’expansió de limfòcits T reguladors, i que tenen el potencial translacional per abordar patologies autoimmunitàries humanes. L’objectiu principal d’aquest estudi ha estat caracteritzar globalment el potencial tolerogènic dels FS-liposomes. Amb aquesta finalitat, diferents pèptids autoantigènics rellevants en malalties autoimmunitàries s’han encapsulat en FS-liposomes de manera eficient i sense dificultats en mantenir el diàmetre i la càrrega, demostrant la versatilitat de l’estratègia a diferents patologies autoimmunitàries. En el model experimental de DT1, l’administració de FS-liposomes ha expandit clons de cèl·lules T CD4+ reguladores i T CD8+ que contribueixen a l’efecte tolerogènic de la teràpia a llarg termini. En el mateix model, s’ha demostrat la biocompatibilitat i seguretat del producte final donada la seva òptima tolerabilitat. D’altra banda, els FS-liposomes s’han adaptat al model d’esclerosi múltiple experimental simplement reemplaçant el pèptid encapsulat. En aquest model, els FS-liposomes han induït CDtols i han reduït la incidència i severitat de la malaltia correlacionant amb un increment en la freqüència de cèl·lules T reguladores, fet que valida el potencial dels FS-liposomes a constituir una plataforma per a la recuperació de tolerància en diferents malalties autoimmunitàries. Finalment, i de cara a una futura implementació clínica, s’han determinat els efectes de la teràpia en CDs humanes obtingudes de pacients amb DT1. En CDs de pacients adults, els FS-liposomes han estat fagocitats eficientment per les CDs amb una ràpida cinètica dependent de la FS, i això ha causat l’adquisició d’un transcriptoma, fenotip i funcionalitat tolerogènics similars als observats en els models experimentals. En CDs de pacients pediàtrics, però, les CDs han presentat defectes en la seva capacitat fagocítica correlacionant amb el temps de progressió de la malaltia; tanmateix, el seu fenotip i expressió de gens immunoreguladors després de la fagocitosi dels FS-liposomes són indicatius d’una habilitat tolerogènica òptima. En conclusió, la immunoteràpia liposomal descrita, que es basa en l’eferocitosi com a mecanisme inductor de tolerància, assoleix el mimetisme apoptòtic de manera simple, segura i eficient. A més, els liposomes ofereixen avantatges quant a producció i estandardització. Per tant, els FS-liposomes tenen potencial translacional i constitueixen una estratègia prometedora per recuperar la tolerància immunològica en malalties autoimmunitàries antigen-específiques.
Autoimmune diseases are caused by defective immunological tolerance, and reportedly affect up to 10% of the global population. In the last years, current medical interventions have transformed these disorders into chronic and manageable, but they still entail high rates of morbidity and mortality. Hence, there is an urgent need to develop therapies capable of restoring the breach of tolerance selectively, which halt the autoimmune aggression and allow the regeneration of the targeted tissue. In physiological conditions, the phagocytosis of apoptotic cells performed by phagocytes such as dendritic cells (DCs) —a process termed efferocytosis— prompts the acquisition of tolerogenic features and the ability to restore tolerance. Indeed, a cell immunotherapy consisting of DCs rendered tolerogenic (tolDCs) by apoptotic β-cell efferocytosis arrested the autoimmune attack against β-cells in an experimental model of type 1 diabetes (T1D). However, in light of the hurdles in obtaining and standardising human autologous apoptotic β-cells for its implementation in the clinics, a nanotherapeutic strategy based on liposomes mimicking apoptotic cells was designed. The fundamental characteristics of these synthetic vesicles are: a high percentage of phosphatidylserine (PS) —phospholipid unique to the apoptotic cell membrane—, diameter superior to 500 nm, negative charge and efficient encapsulation of insulin peptides. Importantly, this strategy was equally effective in inducing tolDCs and blunting β-cell autoimmunity as the immunotherapy based on apoptotic cells. The hypothesis of this work is that autoantigen-loaded PS-liposomes can re-establish tolerance in several antigen-specific autoimmune diseases through the induction of tolDCs and the expansion of regulatory T lymphocytes, and that they have translational potential to tackle human autoimmune disorders. The main aim of the present work has been to characterise the tolerogenic potential of PS-liposomes globally. To this end, different autoantigenic peptides relevant in autoimmune diseases have been efficiently encapsulated into PS-liposomes, without difficulties in preserving their appropriate diameter and charge, thus demonstrating the versatility of the therapy to different autoimmune pathologies. In the experimental model of T1D, the administration of PS-liposomes causes the expansion of clonal CD4+ regulatory T cells and CD8+ T cells, which contribute to the long-term re-establishment of tolerance. Moreover, in the same model, the biocompatibility and safety of the final product have been confirmed given its optimal tolerability. Furthermore, PS-liposomes have been adapted to the experimental multiple sclerosis model by merely replacing the encapsulated autoantigen. In this model, PS-liposomes elicit the generation of tolDCs and decrease the incidence and severity of the disease correlating with an increase in the frequency of regulatory T cells, a fact that validates the potential of PS-liposomes to serve as a platform for tolerance re-establishment in different autoimmune diseases. Finally, considering its future clinical implementation, the effect of the PS-liposomes therapy has been determined in human DCs obtained from patients with T1D. In DCs from adult patients, PS-liposomes are efficiently phagocyted by DCs with rapid kinetics dependent on the presence of PS, and this induces a tolerogenic transcriptome, phenotype and functionality that are similar to those observed in experimental models. However, DCs from paediatric patients display defects in their phagocytic capacity correlating with the time of disease progression, albeit their phenotype and immunoregulatory gene expression after PS-liposomes phagocytosis point to an optimal tolerogenic ability. In conclusion, the liposomal immunotherapy herein described, which is based on efferocytosis as a powerful tolerance-inducing mechanism, achieves apoptotic mimicry in a simple, safe and efficient manner. Additionally, liposomes offer advantages in terms of production and standardisation. Therefore, PS-liposomes possess translational potential and constitute an encouraging strategy to restore immunological tolerance in antigen-specific autoimmune diseases.

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Isaksson, Magnus. "Initiation of Autoimmunity in Experimental Autoimmune Encephalomyelitis". Doctoral thesis, Uppsala universitet, Molekylär medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-173427.

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The events that trigger an autoimmune disease remain largely unknown. To study these events animal models are necessary because symptoms of autoimmune diseases are preceded by a long asymptomatic period in humans. Experimental autoimmune encephalomyelitis (EAE) is the best characterized model for cell mediated autoimmunity and an animal model for the human disease multiple sclerosis. EAE is induced in rodents by immunization with myelin antigens (Ags) together with adjuvants. After immunization, T cells are primed in the periphery by Ag presenting cells and subsequently invade the central nervous system where they mediate parenchymal inflammation, resulting in demyelination and clinical symptoms of an ascending paralysis. It is now generally recognised that the main cell type mediating EAE is the T helper type 17 (Th17) cell. Tolerance to EAE can be attained by DNA vaccination, but how the immune response against the myelin Ags is abrogated after DNA vaccination is not known. By employing short interfering RNA technology, induction of the innate immune signalling molecule interferon (IFN) -β was found to be necessary for the protective effect of DNA vaccination in EAE. In addition, DNA vaccination inhibited subsequent autoimmune Th17 cell responses. The Toll-like receptors (TLRs) of the innate immune system have evolved to recognise conserved molecular structures on microbes and signalling through them almost exclusively converge on the molecule MyD88. Signalling via MyD88 was found to be required for induction of EAE since mice deficient in this molecule did not develop disease. Upstream signalling via TLR4 and TLR9 had tolerogenic properties. In studies of Ag presentation in EAE, two major subtypes of dendritic cells (DCs) were examined. Plasmacytoid DCs were found to have a promoting role in the induction of EAE, partly via type 1 IFNs. Myeloid DCs had a redundant role in the induction phase of EAE, neither disease severity nor encephalitogenic Th17 responses were affected by their absence during priming. These studies further demonstrate that the cells and molecules of the innate immune system exhibit a crucial role in controlling the adaptive immune system which mediates tissue damage in autoimmune diseases.

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De, Smet Joseph Marc Dominique. "Observations in clinical and experimental ocular autoimmunity". [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/83518.

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Proefschrift Universiteit van Amsterdam.
Omslagtitel: Observations on clinical and experimental ocular autoimmunity. - Auteursnaam op omslag: Marc D. de Smet. Met lit. opg. - Met samenvatting in het Nederlands.

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Pratigya, Gautam. "Deciphering the link between PTPN22 and autoimmunity". Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/54471/.

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Recent genetic studies have linked a C to T single nucleotide polymorphism (SNP) in the protein tyrosine phosphatase (PTP) non-receptor type 22 (PTPN22) to several autoimmune diseases (ADs). This changes amino acid at position 620 from an Arginine (R) to a Tryptophan (W) in the protein, Lyp. Lyp is thought to be a negatively regulator of TCR signalling by dephosphorylating Src family kinases Lck and Fyn, and Zap70. However, the cellular and molecular mechanisms of predisposition to ADs by the R620W polymorphism are not yet understood. Several studies have reported the R620W polymorphism as a “gain of function” change resulting in an increase in the PTP activity of Lyp. It has been further hypothesised that the W620 isoform suppresses TCR signalling more potently than the R620 isoform, resulting in the survival of auto-reactive cells that would normally be deleted by negative selection in the thymus. Alternatively, the impact of Lyp W620 on TCR signalling may have an effect on the development and functioning of T regulatory cells. To investigate the effect of the R620W polymorphism in T cells, lentivirus plasmids expressing the R and W isoforms of Lyp were generated and used to introduce the Lyp and wLyp isoforms in leukaemic T cells thereby generating H9 and E6.1 cell lines over- R W expressing the Lyp and Lyp isoforms. Investigation of activation marker expression and cytokine production by these T cell lines post activation showed no differences in CD69 activation marker expression between the RLyp and wLyp expressing T cells or between the R/wLyp expressing and control cells (not expressing exogenous Lyp). However, there was a trend towards a reduction in IL-2 production observed by R/WLyp expressing H9 T cells compared to control cells. In addition, a significant reduction in IL-10 production by R/wLyp expressing H9 T cells compared to control cells was observed. This effect of Lyp on IL-10 production suggests a potential mechanism by which wLyp, if indeed a more active PTP, may predispose to ADs.

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Pritchard, Nicholas Russell. "Regulation of inhibitory receptor expression and autoimmunity". Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619621.

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Badami, Ester. "Mechanisms of activation and regulation in autoimmunity". Thesis, University of Southampton, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443060.

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Hendler, Assi. "The link between autoimmunity and periodontal disease". Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/3344.

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The primary etiologic factor of periodontitis is bacterial plaque biofilm. Nevertheless, the factors that determine the progression of periodontitis are complex and poorly understood. Hence, the potential involvement of autoimmunity in the pathogenesis of periodontitis has been considered intermittently for years. The basic hypothesis for this PhD was that autoimmunity to native and/or posttranslationally modified periodontal extracellular matrix proteins is involved in the progression of periodontitis. Objectives The main objective of the study was to extend the understanding of periodontal disease pathogenesis beyond the common bacterial etiology and to address the hypothesis that periodontal disease is an auto-immune disease. This research will try to identify the exact neoepitope. Specific aims (i). To investigate the involvement of autoimmune reactivity towards native collagen type I (CI) and collagen type III (CIII), as well as CI and CIII posttranslationally modified by reactive oxygen specious (ROS) known to present in the inflamed tissue, ROS-CI and ROS-CIII, respectively. (ii). Develop human antibody fragment(s) specific to CI, ROS-CI, CIII and ROSCIII for diagnostic application. Methods Modification of CI or CIII was confirmed by SGS-PAGE, Capillary Electrophoresis and 3D-fluorescence. The presence of autoantibodies to ROS-CI and ROS-CIII in sera and saliva were then studied by ELISA and Western blotting using sera and saliva from individuals with Aggressive Periodontitis (AgP), Chronic Periodontitis (CP) and Gingivitis (G). Antibodies specific to ROS-CI and ROS-CIII were developed using phage display semi-synthetic human single chain fragment variable (scFv) libraries. Results Autoantibodies to native CI, native CIII, ROS-CI and ROS-CIII were observed exclusively in patients with AgP. Human antibody fragments specific to native and ROS-CI were developed and evaluated. Conclusions A. Autoimmune reactions to native and post-translationally modified self antigens may play a role specifically in the pathogenesis of AgP. B. Anti-ROS scFv specific to ROS-CI and ROS-CIII may have diagnostic future applications.

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Kiely, Patrick David Wolfenden. "Cellular mechanisms in mercuric chloride-induced autoimmunity". Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627575.

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Coutinho, Maria Ester Freitas Barbosa Pereira. "Central nervous system autoimmunity in neuropsychiatric disorders". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:389fb830-4b4e-4201-9965-19acb2c63ff3.

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The recent history of autoimmune neurology is marked by the discovery of many central nervous system (CNS) antibody-mediated diseases. These disorders are caused by antibodies that target important proteins expressed in the neuronal surface, which are believed to be directly pathogenic. These antibodies are immunoglobulin G (IgG) isotype and, as such, have the potential to cross the placenta during gestation. Foetal exposure to CNS-targeting antibodies could alter developing neuronal circuits, leading to disease. However, the consequences of exposure to these antibodies during neurodevelopment has hardly been considered. To study the relationship between maternal antibodies towards neuronal surface proteins and neurodevelopmental disorders in the foetus a dual approach was undertaken. First, pregnancy serum samples from mothers of children later diagnosed with a neurodevelopmental disorder and from mothers of children with typical development were screened for the presence of neuronal surface antibodies. Next, the effects of pathogenic neuronal surface antibodies in the offspring were assessed in a maternal-to-foetal transfer mouse model. Antibodies to neuronal surface proteins in the gestational serum, particularly CASPR2 antibodies, were found to associate with an increased risk of mental retardation and disorders of psychological development in the progeny. The animal model showed that mice exposed in utero to CASPR2 antibodies have long term behavioural sequelae and histological findings suggestive of abnormalities in brain development. These findings support a model in which maternal antibodies towards foetal neuronal proteins cause long-term behavioural deficits and permanent abnormalities at the cellular and synaptic level in a subset of children with neurodevelopmental disorders.

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Connor, Ruth Redlich. "Autoimmunity to cardiac muscle in myasthenia gravis /". The Ohio State University, 1988. http://rave.ohiolink.edu/etdc/view?acc_num=osu148759165817591.

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Huizinga, Hendrika Geertruida. "Autoimmunity to neuronal antignes in multiple sclerosis". [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/13809.

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Weiss, Julia Miriam. "Characterization of thymic hyperplasia associated with autoimmune Myasthenia Gravis : role of the chemokines CXCL12 and CXCL13". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA114831/document.

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La myasthénie (Myasthenia Gravis) est une maladie neuromusculaire impliquant des auto-anticorps dirigés majoritairement contre le récepteur à l’acétylcholine (RACh) et entrainant une fatigabilité musculaire. Ces auto-anticorps pathogènes sont produits principalement par le thymus qui présente une hyperplasie caractérisée par le développement de centres germinatifs ectopiques. De récentes études ont démontré la surexpression de chimiokines dans le thymus des patients et la présence anormale de vaisseaux sanguins de type HEV (cellules endothéliales à paroi haute). L’objectif de ma thèse a été de mieux comprendre les mécanismes physio-pathologiques conduisant à l’hyperplasie thymique en étudiant le rôle des chimiokines dans la myasthénie.Nous avons tout d’abord démontré que le nombre de HEV thymiques est proportionnel au degré d’hyperplasie suggérant leur implication directe dans le recrutement des cellules périphériques. En analysant les chimiokines exprimées sur ces HEV, nous observons l’expression sélective de SDF-1/CXCL12. En parallèle, la présence de lymphocytes B, de cellules dendritiques myéloïdes ou plasmacytoïdes et de monocytes/macrophages exprimant le récepteur au SDF-1, CXCR4, a été observée au niveau des HEV. En périphérie, nous montrons une diminution de l’expression de CXCR4 ainsi que du nombre de mDC et de monocytes dans le sang des patients suggérant le recrutement de ces cellules dans le thymus.Le thymus des patients myasthéniques est aussi caractérisé par une surexpression de la chimiokine CXCL13 par les cellules épithéliales thymiques. Pour mieux comprendre les mécanismes conduisant à l’hyperplasie thymique, nous avons développé un modèle de souris transgéniques avec surexpression thymique de CXCL13. Dans le thymus de ces souris, nous observons une surexpression de CXCL13 et une augmentation de nombre de lymphocytes B, notamment pour les souris jeunes. Nous étudions maintenant si l’immunisation de ces souris avec du RACh purifié induit une myasthénie expérimentale associée à une hyperplasie thymique ; un nouveau modèle animal de la maladie qui se rapprocherait mieux de la pathologie humaine.Dans la myasthénie, le thymus est aussi caractérisé par une signature inflammatoire, avec notamment une surexpression d’interféron de type I (IFN-I). Nous démontrons que le Poly(I:C), une molécule mimant les effets des ARN double-brin, induit spécifiquement la surexpression du RACh-α par les cellules épithéliales thymiques humaines via la libération d’IFN-I. L’IFN-I entraine aussi la surexpression des chimiokines CXCL13 et CCL21 comme dans le thymus des patients myasthéniques. Chez des souris C57Bl6, mais pas chez des souris KO pour le récepteur à l’IFN-I, des injections de Poly(I:C) entrainent des modifications thymiques avec une surexpression spécifique de RACh-α, d’IFN-I et de chimiokines. En périphérie, ces injections entrainent l’apparition dans le sérum d’anticorps contre le RACh-α spécifiques de la myasthénie.L’ensemble de ces résultats suggère que dans le thymus des patients myasthéniques, le développement anormal de HEV exprimant du SDF-1 et la surexpression de CXCL13 joueraient un rôle central dans le recrutement de cellules périphériques. Ces cellules, une fois dans l’environnement inflammatoire caractéristique du thymus myasthénique, pourraient alors développer une réaction auto-immune contre le RACh. De nouvelles molécules thérapeutiques contrôlant l’expression de ces chimiokines ou l’angiogenèse pourraient diminuer le développement de l’hyperplasie thymique et éviteraient la thymectomie ou l’utilisation des glucocorticoïdes par les patients atteints de myasthénie
Autoimmune myasthenia gravis (MG) is a muscular disease mediated by autoantibodies, mainly directed against the acetylcholine receptor (AChR). The pathogenic antibodies are especially produced in the thymus, which is often characterized by a hyperplasia with germinal centers. Recent studies demonstrated the overexpression of chemokines and the abnormal development of high endothelial venules (HEV) in the MG thymus. The aim of my thesis was to better understand the mechanisms that lead to thymic hyperplasia in MG by analyzing the role of chemokines in peripheral cell recruitment. We demonstrated that the number of HEVs correlated with the degree of hyperplasia suggesting a direct link between HEVs and peripheral cell recruitment. To define its mechanism of action, we examined which chemokines were expressed on thymic HEVs. We uniquely detected SDF-1 and observed that B cells, myeloid dendritic cells (mDCs), plasmacytoid DCs and monocytes/macrophages that expressed the SDF-1 receptor CXCR4 localized inside and around thymic HEV. In parallel we observed a decreased CXCR4 expression and a decreased number of mDCs and also monocytes in the periphery suggesting their recruitment to the MG thymus. As the MG thymus was recently characterized by the overexpression of CXCL13 in thymic epithelial cells (TECs), we investigated its contribution to thymic hyperplasia. We therefore generated a transgenic mouse model overexpressing in medullary TECs CXCL13 under the control of keratin 5. We demonstrated that transgenic K5-CXCL13 mice specifically overexpressed CXCL13 in the thymus, while no other tested chemokines were upregulated. Preliminary results showed that elevated levels of CXCL13 resulted in an increased number of B cells in the thymus of transgenic mice, which localized preferentially in loose aggregates in medullary areas. We are presently investigating if immunization with purified AChR induces experimental MG with thymic hyperplasia in these mice. Myasthenic mice with a hyperplastic thymus could present a new animal model for MG with a phenotype that is closer to the human disease than the current MG model. As the hyperplastic MG thymus displays the hallmarks of a viral signature, we investigated the effect of pathogen-associated molecules on thymic changes associated with MG. We demonstrated that dsRNA signaling induced by Poly(I:C) specifically triggers the overexpression of α-AChR in human TECs through the release of IFN-I. We also observed that IFN-I was able to upregulate CXCL13 and CCL21, similarly to what is observed in the MG thymus. In addition, Poly(I:C) injections in wildtype mice, but not in IFN-I receptor KO mice, specifically increase thymic expression of α-AChR and, in parallel, CXCL13 and CCL21 expression. In periphery, Poly(I:C) even induced an anti-AChR autoimmune response characterized by a significant production of serum anti-AChR antibodies and a specific proliferation of B cells. Overall the results obtained in the course of my PhD showed that the abnormal development of SDF-1-expressing HEVs and the CXCL13 overexpression play a central role in the recruitment of peripheral cells to the MG thymus. Once these cells have arrived in the inflammatory environment, which is characteristic for MG, they could develop an autoimmune reaction against AChR. New therapeutic molecules that control chemokine expression and angiogenic processes could diminish the development of thymic hyperplasia and avoid thymectomy or the use of corticoids

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Wallström, Erik. "Genetic regulation of, and autoimmunity in, myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis and multiple sclerosis /". Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4067-3/.

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Lundberg, Cecilia. "Autoimmune and innate inflammation in the nervous system : neurotrophin production and impact on neuronal survival /". Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4421-0/.

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44

Miyelani, Maringa Ignecious. "Implementation of an Aseptic Service for Radiolabelling of Autologous Blood Cells at the Department of Nuclear Medicine, Dr George Mukhari Hospital". Thesis, University of Limpopo (Medunsa Campus), 2013. http://hdl.handle.net/10386/1075.

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Thesis (MSc(Med)(Pharmacy))-- University of Limpopo, 2013.
Introduction: The Department of Nuclear Medicine at Dr George Mukhari Hospital (DGMH) received a biological safety cabinet (Laminar airflow hood - LAF) as a donation from the International Atomic Energy Agency (IAEA) in 2007, for the specific purpose of preparing radiolabelled blood cells. The laminar airflow hood was installed but has never been commissioned for use. Radiolabelled white blood cells are used in a range of Nuclear Medicine applications related to infection and pyrexia of unknown origin. Correct handling of the blood is essential for both patient and operator safety. A laminar airflow procedure is required for the radiolabelling of autologous blood. Therefore, there was a need to further investigate the guidelines for radiolabelling autologous blood cells with a view to commissioning the LAF and implementing a service for radiolabelling of autologous blood elements. Objectives: 1. Identify the equipment 2. Identify and development of the SOPs 3. Implement aseptic services to radiolabelling blood cells. Method: The study was conducted at the Department of Nuclear Medicine, Dr George Mukhari Hospital. The design of the study was prospective, descriptive and interventional. Data were collected through independent (objective) observation, questionnaires (subjective). In order to involve staff in the implementation of aseptic services in the respective department a focus group discussion (FGD) followed. The International Atomic Energy Agency (IAEA); Operational Guidance on Hospital Radiopharmacy and United Kingdom Radiopharmacy Group (UKRG) Guidelines were consulted to identify equipment and operational standards required. Permission to conduct the study was obtained from the Head of Department of Nuclear Medicine and Chief Executive Officer (CEO) of the Hospital. The proposal was approved by the Medunsa Campus Research and Ethics Committee (MCREC). xii Results: Premises: The room in which the LAF is situated is not in use as a clean room; hence few of the IAEA infrastructure and LAF requirements were met. Only, three aspects (18.75%) were compliant (type of LAF, lighting and dedicated equipment availability) and thirteen (81.25%) were not. For the hot lab only two (16.67%) of the fourteen items regarding structure and facilities were compliant, twelve (83.33%) were not (e.g. access, layout, cleanliness levels). The short term plan devised is to partition the area in which LAF is currently situated into a clean room and change room, seal the ceiling and windows, paint and ensure that walls, floors and surfaces are smooth and impervious in both the clean room and hot lab. The cost of alterations is (+/-) R50 000. The long term plan is to obtain funds (approximately R960 000) for the full development of the aseptic suite which will comply with local and international standards for radiolabelling of autologous blood cells recommended by ISORBE. Environment and Personnel: None of the four survey items on environment was compliant for the clean room (e.g. air not filtered, no temperature or humidity monitoring or control). Only in the hot lab was the temperature monitored. The LAF/clean room is not currently in use. In the hot lab, gowns and overshoes are not available. The plan is to have thermometers installed in both the clean room and hot lab and have log books for recording temperature. Microbial Contamination: In the Department, monitoring of microbial contamination is not performed. The IAEA recommends that surfaces, environment and equipment should be monitored for microbial contamination in an area where sterile products are handled. Staff Training & Improvement of Aseptic Services: Two staff had been trained in aseptic admixing. All eight respondents agreed that training on aseptic handling of radiopharmaceuticals is necessary. Hygiene and SOPs: Six respondents rated hygiene as satisfactory and two as not satisfactory. Despite these views, all felt that hygiene should be improved in the hot lab and that standard operating procedures (SOPs) should be developed. A group xiii was set up to develop SOPs. Four SOPs were developed - cleaning the clean room and LAF, hand washing, gowning/degowning and leukocyte radiolabelling. Radiolabelling of Autologous Blood Cells: Doctors in the Department want this service to help with the diagnosis of pyrexia of unknown origin (PUO) and infections. Therefore, they were supportive to the researcher in the project set-up the processes and facilities for radiolabelling cells. The short term plan is to train staff in radiolabelling of autologous blood cells. The long term plan is to have the facility to set-up correctly to facilitate service provision and research. Equipment: Staff mentioned that a centrifuge dedicated to the radiolabelling of blood cells should be obtained to ensure that all the procedures for labelling blood cells are followed. The short term plan is to commission the LAF (Cost: approximately R15 000 including VAT) and obtain a cooled centrifuge with sealable buckets (Cost: approximately R40 000 including VAT) for the purpose of commencing with the radiolabelling of blood cells service in the Department. Finance: Staff indicated that some of the problems in the department can be solved if they can obtain funding for infrastructure development. The short term plan is to have the budget for the upgrade of the facility included in the Departmental budget. And the long term plan is to obtain funds from the Gauteng Government for the full development of the facility Conclusion: Required standards and guidelines for radiolabelling of autologous blood cells in a radiopharmacy unit have been identified. Therefore, the upgrading process of the facility should commence and SOPs developed should be implemented. Recommendations: Necessary structural changes on the facility should be made to meet the local and international standards for radiolabelling blood products. Therefore, funds should be obtained for upgrading the facility and obtain the necessary minimum equipment for radiolabelling of autologous blood cells. It is recommended that a post for a radiopharmacist be created to increase capacity and help improve standards with regards to pharmaceutical services in the Department.

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45

Liu, George Yen-Hsi. "Tolerance induction in an experimental model of autoimmunity". Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387599.

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46

Bradley, Una Marie. "Insulin resistance : the effect of diet and autoimmunity". Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534638.

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47

Clatworthy, M. R. "The role of FcγRIIb in infection and autoimmunity". Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597749.

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A number of deletions have been identified within regulatory regions of the FcγRIIb gene in autoimmune-prone inbred mouse strains, such as NZB and NOD, which are associated with reduced expression of the receptor on macrophages and B cells. The FcγRIIb gene was sequenced in a number of inbred and wild mouse strains. Surprisingly, the autoimmune-prone FcγRIIb_low haplotype predominated in wild mice, suggesting that deficiency of FcγRIIb in the immune response to two important pathogens, Streptococcus pneumoniae and malaria. In pneumococcal infection, unimmunized FcγRIIb-deficient mice show increased bacterial phagocytosis and survival. Similarly, these mice have lower levels of parasitaemia following Plasmodium chabaudi chabaudi infection. In contrast, immunized FcγRIIb-deficient mice challenged with large inocula of Streptococcus pneumoniae showed reduced survival, correlating with increased TNFα production. Therefore FcγRIIb controls the balance between efficient pathogen clearance and the cytokine-mediated consequences of sepsis. This supports the hypothesis that the FcγRIIb_low haplotype predominates in wild mice because it confers increased resistance to important pathogens. Thus, autoimmunity may be an unfortunate evolutionary consequence of selecting an immune system that can better deal with infection. A polymorphism of human FcγRIIb has recently been described wit a single amino acid substitution (from isoleucine to threonine) at position 232 within its transmembrane domain (FcγRIIbT₂₃₂). In several racial groups, the frequency of homozygosity for this polymorphism (T/T) is doubled in SLE patients compared to healthy controls suggesting possible dysfunction of FcγRIIbT₂₃₂. I investigated the functional consequences of this amino acid substitution. The amino acid substitution appeared to prevent the inhibitory receptor from partitioning into sphingolipid rafts.

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Pereira, Leila Maria Moreira. "Hepatotropic viruses and autoimmunity in schistosomiasis in Brazil". Thesis, Open University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357964.

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49

Gramaglia, Irene. "MHC mimicry with autoantigens : possible role in autoimmunity". Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244691.

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50

Niederer, Heather Ann. "The role of FcγRIIIB in autoimmunity and infection". Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611793.

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Tesi sul tema "Autoimmunity"

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