Teses / dissertações: "Immunoglobulin A"

1

Das, Mrinmoy. "The regulatory effects of circulating normal immunoglobulins on autophagy and Th17 response". Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066153/document.

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Les immunoglobulines circulantes jouent un rôle critique dans l’homéostasie immune en modulant les fonctions des cellules du système immunitaire. Au cours de ma thèse, j’ai exploré les effets régulateurs des immunoglobulines G thérapeutiques (IVIG) et des immunoglobulines A monomériques circulantes (mIgA) sur l’autophagie et les réponses Th17 respectivement. Les IVIg sont une préparation thérapeutique d’IgG normales poolées. Elles ont utilisées comme agent anti-inflammatoire dans le traitement de maladies auto-immunes et inflammatoires variées. Cependant, les mécanismes ne sont pas complètement élucidés et plusieurs mécanismes mutuels et non exclusifs ont été proposés. L’autophagie est un important processus biologique impliquant la dégradation lysosomale des composants cellulaires endommagés et des protéines mal repliées. Il y a plusieurs preuves montrant l’implication de l’autophagie dans les maladies auto-immunes et auto-inflammatoires incluant la découverte de polymorphismes dans des gènes liés à l’autophagie. J’ai montré que l’induction de l’autophagie par les IVIG représente un nouveau mécanisme d’action permettant leur effet thérapeutique dans les maladies auto-immunes et inflammatoires. Les Th17 représentent une cible attractive pour traiter plusieurs maladies inflammatoires et auto-immunes. Malgré le fait qu’elles sont le deuxième anticorps le plus abondant dans la circulation, la function immunorégulatrice des IgA n’est relativement pas explorée. J’ai montré que les IgA monomériques (mIgA) inhibent la différentiation et l’amplification des cellules Th17 humaines et la production de leur cytokine effectrice IL-17A
Circulating immunoglobulins play a critical role in the immune homeostasis by modulating the functions of immune cells. In my thesis, I investigated the regulatory effects of therapeutic immunoglobulin G (IVIG) and circulating monomeric immunoglobulin A (mIgA) on autophagy and human Th17 response respectively. IVIG is a therapeutic preparation of pooled normal IgG. It is used as an anti-inflammatory agent in the treatment of a wide variety of autoimmune and inflammatory diseases. However, the mechanisms are not yet fully elucidated and several mutually non-exclusive mechanisms have been proposed. Autophagy is an important biological process involving lysosomal degradation of damaged cellular components and misfolded proteins. There are several evidences that support the involvement of autophagy in autoimmune and auto- inflammatory disorders including the discovery of polymorphisms in autophagy-related genes. I show that induction of autophagy by IVIG represents a novel mechanism of action in achieving therapeutic effect in autoimmune and inflammatory diseases. Th17 cells represent an attractive target to treat several inflammatory and autoimmune diseases. Despite being second most abundant antibody in the circulation, the immunoregulatory function of IgA is relatively unexplored. I have shown that monomeric IgA (mIgA) inhibits differentiation and amplification of human Th17 cells and the production of their effector cytokine IL-17A

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2

Carpenet, Guéry Hélène. "Radiomarquage au 99mTc des IgA et IgG : optimisation du marquage, étude in vitro, biodistribution chez l'animal sain et sur modèle tumoral". Thesis, Limoges, 2015. http://www.theses.fr/2015LIMO0074/document.

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Depuis leur découverte en 1975 par Köhler et Milstein, le monde des Ac monoclonaux a beaucoup évolué. Ils occupent actuellement une place prépondérante dans la prise en charge de nombreux cancers. De nos jours, les Ac monoclonaux, ayant une AMM ou en essai clinique, sont tous de classe IgG voire IgG1. Cette classe d’Ac a cependant montré des limites à son utilisation, et l’étude d’autres isotypes d’Ac, comme les IgA, pourrait être intéressante. Les IgA, isotype d’Ac particulier en raison notamment de leur hétérogénéité dans les formes moléculaires, demeurent peu étudiées à l’instar des IgG. Dans ce travail, nous proposons un radiomarquage des IgA monomériques, polymériques et sécrétoires, avec le 99mTc par une méthode indirecte impliquant le 2-iminothiolane et le cœur tricarbonyl. Par le biais de ce radiomarquage, la biodistribution des IgA monomériques et polymériques après administration i.v. a été évaluée chez l’animal sain et chez l’animal porteur de tumeur à localisation muqueuse. Ces études nous ont permis d’entrevoir le potentiel diagnostique des IgA, mais aussi leur intérêt en thérapie ciblée de tumeurs à localisation muqueuse. D’autre part, grâce à leur résistance enzymatique et au phénomène de retranscytose, une nouvelle voie d’administration des Ac monoclonaux pourrait être développée. Dans cette optique, des IgA sécrétoires ont été administrées par voie orale lors d’études préliminaires de biodistribution
Since their discovery in 1975, by Köhler and Milstein, monoclonal antibodies (mAbs) world has significantly evolved and they currently hold a prominent place in cancers care. Today, the mAbs, having a marketing authorization or in clinical trial, are all IgG class (IgG1). However, this Ab class showed limitations on its use, and the study of other isotypes, such as IgA, could be interesting. Unlike IgG, IgA, original isotype particularly because of their heterogeneity in molecular forms, remains understudied. In this work, we propose a radiolabeling of monomeric, polymeric and secretory IgA with 99mTc by an indirect method, involving 2-iminothiolane and tricarbonyl core. Biodistribution of radiolabeled monomeric and polymeric IgA was evaluated, after intravenous administration, in healthy animals and in mucosal tumor-bearing animals. These studies have allowed us to glimpse the IgA diagnostic potential, but also their interest in targeted therapy of tumors with mucosal localization. Moreover, thanks to their enzymatic strength and retranscytosis, a new administration route of mAbs could be developed. In this context, secretory IgA were administered orally in preliminary biodistribution studies

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3

Hirano, Ayumi. "T dependent B cell help in cattle : immunoregulatory function of interleukin-4 and CD40-CD40L interactions /". free to MU campus, to others for purchase, 1997. http://wwwlib.umi.com/cr/mo/fullcit?p9841150.

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4

Almroth, Gabriel. "Immunoglobulins, immunoglobulin subclass-distributions and serologic markers in some renal and systemic disorders /". Linköping : Univ, 2000. http://www.bibl.liu.se/liupubl/disp/disp2000/med646s.pdf.

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5

Rogers, Kenneth Alton. "Immunoglobulins and Immunoglobulin Fc Receptors in Nonhuman Primates Commonly Used in Biomedical Research". Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/biology_diss/6.

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Antibodies neutralize and eliminate pathogens, malignancies, and toxins by acting either alone or in association with Fc receptors which, once engaged, activate the elimination mechanisms of phagocytic cells. Based on structural differences, antibodies are divided into functionally distinct classes (IgM, IgD, IgG, IgE and IgA). Structure-function relationships within these classes are not well characterized. In addition, animal models for the assessment of potential therapeutic strategies for the modulation of the interaction between antibodies and Fc receptors are not established. Nonhuman primates are widely used to model human diseases and, represent excellent in vivo systems for this assessment. Therefore, we have studied nonhuman primate IgD as well as IgG and IgA specific Fc receptors in rhesus macaques, cynomolgus macaques, baboons and sooty mangabeys. IgD genes had not been identified in nonhuman primates nor the IgD receptors characterized in any species. We characterized IgD genes of the four monkey species, as well as chimpanzees and dogs. In contrast to other antibody classes, the IgD hinge regions are highly conserved between human and nonhuman primates, thus indicating a role in Fc receptor binding. In humans, Fc receptors CD16a (natural killer cells) and CD16b (neutrophils) bind IgG1 and IgG3, and CD89 (myeloid cells) binds IgA. To assess ligand binding and glycosylation properties of nonhuman primate CD16a, CD16b, and CD89, we sequenced, cloned, and generated recombinant molecules in a mammalian expression system. Our results verify the presence of CD16a, but not CD16b in nonhuman primates. CD16a is expressed on monocytes and a subpopulation of lymphocytes. In sooty mangabeys, CD16 is also expressed on neutrophils. Recombinant sooty mangabey/baboon CD16a binds to human IgG1 and IgG2, but not IgG3 and IgG4. Monkey CD89 has the same peripheral blood leukocyte expression profiles as humans, and binds human and recombinant macaque IgA. Blocking of N-glycans inhibited expression of CD89, but only marginally CD16a expression. Although extensive similarities of antibody/Fc receptor interactions exist between human and nonhuman primates, several differences must be considered when evaluating therapeutic strategies. However, these differences can be exploited to further characterize the structure-function relationships existing within antibody molecules and respective receptors.

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6

Ding, Cheng. "Siglec-G is a negative regulator of NF-[kappa]B activation and has pivotal roles in B-1 cell development and resistance to sepsis /". Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1226876722.

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7

Laurencikiene, Jurga. "Regulation of germline transcription in the immunoglobulin heavy chain locus /". Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-989-7/.

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8

Couston, Ruairidh Gair. "Characterising immunoglobulin-polysorbate interactions". Thesis, University of Strathclyde, 2013. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18963.

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Therapeutic proteins, such as immunoglobulins, are typically formulated with polysorbates as stabilisers. However, the nature of the immunoglobulin-polysorbate interaction, particularly at the solid-liquid interface, is poorly characterised. This thesis presents an investigation of immunoglobulin (mAb-1)-surfactant interaction in bulk solution with particular focus on the interaction at the solid-liquid interface. It was first established using isothermal titration calorimetry that no specific binding interaction between mAb-1 and surfactant in solution takes place. Furthermore, circular dichroism and differential scanning calorimetry showed surfactant inclusion had no effect on mAb-1 native structure or thermal stability. The adsorption/desorption of mAb-1 and the effect of polysorbate was quantified in real-time by total internal reflection fluorescence. MAb-1 desorption was dependent on polysorbate concentration, fatty acid tail group and point of injection relative to mAb-1. MAb-1 adsorption to a hydrophobic surface was significantly less than to a hydrophilic surface. Concomitant conformational changes to mAb-1 were not apparent upon adsorption to a hydrophilic surface but a varying degree of β-sheet loss was observed upon adsorption to hydrophobic surfaces. This was corroborated by neutron reflectivity (NR) data which modelled a bilayer for mAb-1 adsorbed to a hydrophilic surface and a monolayer for mAb-1 adsorbed to a hydrophobic surface. These NR data suggested a range of mAb-1 orientations were adopted. This combination of orthogonal surface analytical techniques can build up a detailed molecular-level image of the adsorbed protein layer enabling rapid characterisation of protein surface adsorption which will improve bioprocess design and formulation.

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9

Pouria, Shideh. "A study of immunoglobulin A biology in primary and hepatic immunoglobulin A nephropathy". Thesis, King's College London (University of London), 2005. https://kclpure.kcl.ac.uk/portal/en/theses/a-study-of-immunoglobulin-a-biology-in-primary-and-hepatic-immunoglobulin-a-nephropathy(e31804ca-526c-49d0-8767-9110d84f7a4b).html.

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10

Mason, J. O. "Regulation of immunoglobulin gene expression". Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384506.

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11

Hunt, James. "Structural studies of immunoglobulin E". Thesis, King's College London (University of London), 2004. https://kclpure.kcl.ac.uk/portal/en/theses/structural-studies-of-immunoglobulin-e(251aec27-5e3a-4ce5-9fbe-9493d158129d).html.

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12

Wang, Hui. "Immunoglobulin binding proteins in ticks". Thesis, University of Oxford, 1995. http://ora.ox.ac.uk/objects/uuid:7c09068b-82fb-4434-9e84-4663cbab7795.

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13

Sukumaran, Muralidharan. "Optical sensors for immunoglobulin G". Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620564.

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14

Doré, Katy Alison. "The evolution of immunoglobulin E". Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/the-evolution-of-immunoglobulin-e(4c611aa6-eed9-4abb-81f7-b9afe97e78bb).html.

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Allergic asthma is a type I hypersensitivity reaction, mediated by IgE. Severe asthma is inadequately treated with existing medicines. A greater understanding of IgE structure and function, and how it relates to its receptors,FcεRI and CD23, is required to improve therapeutic intervention. An evolutionary approach has been used to further this understanding, with the investigation of three proteins that are evolutionarily related to human IgE: platypus IgE, chicken IgY and human IgM. The sequences of these proteins were compared and constructs were designed that contained different fragments of the constant regions of these antibodies. A (His)6-tag was attached to the C-terminus of IgM-Fc, Fcμ3-4 (fragment containingonly CH3-4domains), IgY-Fc, and platypus IgE-Fc, and these were successfully purified using two different methods: one using affinity columns specific to the protein and the other method using a nickel NTA column and size exclusion chromatography. The proteins were then checked using SDS PAGE analysis and Mass Spectrometry. The proteins were successfully crystallized and significant steps taken to improve the diffraction quality of the crystals. A crystal structure of human Fcε3-4 was determined at the highest resolution seen to date and a more extensive carbohydrate structure was observed. A detailed analysis of the flexibility of the Cε3 was performed using B-factors and a new method for comparing the quaternary structure of IgE is proposed and comparison made with all previously determined free and receptor bound structures. The thermal stability of the antibody structures was measured using Differential Scanning Fluorimetry to identify different unfolding characteristics for the Cε2 and Cε3 domains. Substantial progress towards the structure determination of IgM-Fc, which crystallised as a hexamer, is reported.

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15

Habich, Hans. "Immunoglobulin therapy in ophthalmic diseases /". [S.l : s.n.], 1986. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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16

Koch, Urs Daniel. "Immunoglobulin therapy for herpes zoster /". [S.l.] : [s.n.], 1985. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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17

Searle, Stephen M. J. "Molecular modelling of immunoglobulin folds". Thesis, University of Bath, 1997. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246005.

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18

Didriksen, Nancy A. (Nancy Andrews). "Psychological Stress: Effect on Humoral Immune Functioning as Measured by Immunoglobulin Levels". Thesis, North Texas State University, 1986. https://digital.library.unt.edu/ark:/67531/metadc331278/.

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The purpose of the present study was to determine if psychological stress, defined as academic examination stress, would systematically produce changes in immune parameters (immunoglobulin concentration) and psychological functioning. It was hypothesized that as examination stress occurred there would be an effect on immunological function consistent with heightened psychological activity/stress. Subjects were 23 master's and doctoral students in psychology who volunteered for the research project. All subjects were administered a series of psychological tests to measure stress, personality factors, emotional states, and anxiety levels. All tests were administered and.blood samples drawn over a period of 15 months across two lowstress and two high-stress periods. Immunological tests included white blood cell (WBC) differential count and radial immunodiffusion (RID) for the determination of concentration of different immunoglobulin classes (IgA, IgG, IgM) in serum. Data were treated to a one-way analysis of variance (ANOVA) with repeated measures, t /test for correlated samples correlational matrix between variables across assessments and discriminant function analysis. Results showed (1) increased immunoglobulin levels during periods of stress; (2) immunoglobulin G most consistently related to stress and probably most indicative of the stressed condition and biological resistance to stress; (3) anxiety related to external events; (4) increase in anxiety under stress; and (5) anxiety inversely correlated with emotional stability and coping skills while positively related to tension, increased number of somatic complaints, and obsessive-compulsive trends. Firm support was provided for the hypothesis that as stress occurred, there would be consistent changes in immunological functioning associated with heightened psychological activity/stress. It was concluded that a response pattern to stress was adaptive along both psychological- and immunological dimensions and that the concept of bodymind interaction was the most realistic approach to understanding the total response patterns.

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19

Sellers, Lisa K. "Exercise-induced alterations in immunoglobulin (IgA, IgG, IgM) levels in cancer versus non-cancer patients". Muncie, Ind. : Ball State University, 2008. http://cardinalscholar.bsu.edu/384.

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20

Pratt, Stephanie Ann. "Immunoglobulin A1 protease of Streptococcus pneumoniae". Thesis, University of Leicester, 1988. http://hdl.handle.net/2381/35410.

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The aim of this project was to examine the Streptococcal IgA1 proteases, with particular interest on the Streptococcus pneumoniae enzyme. IgA1 protease of S. pneumoniae was identified and characterised. A non-reducing polyacrylamide gel system was employed to screen clinical isolates for IgA1 protease activity. Of 187 isolates tested 18% were found to be IgA1 protease negative, there was no correlation with the site of isolation of the organism and its ability to produce the enzyme. Attempts were made to clone the pneumococcal IgA1 protease gene using the cosmid pEMBLcos4, the plasmid vector pLG339 and the ? replacement vector ?EMB4. Libraries were screened for pneumolysin and IgA1 protease activity. Clones that expressed pneumolysin were identified by overlaying with sheep red blood cells. One haemolytic clone was not inhibited in the presence of cholesterol. Screening for IgA1 protease activity identified clones with IgA1 protease-ike activity but this activity was not stably expressed. Closer analysis of the libraries suggested that pneumococcal DNA was highly unstable when cloned into E. coil plasmid and cosmid vectors.

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21

Yip, Bon-ham. "Immunoglobulin gene translocations in gastric lymphoma". Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37345321.

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22

Corbett, S. J. "The human immunoglobulin diversity segment repertoire". Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597991.

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Combination recombination of Variable (V), Diversity (D) and Joining (J) immunoglobulin gene segments with imprecise loss and gain of nucleotides at segment joins creates a diverse primary antibody repertoire. In humans it has also been proposed that utilisation of DIR segments, multiple D segments and inverted D segments increases diversity further. However to date, incomplete knowledge of the germline D segment repertoire has made it difficult to dissect out the precise mechanisms involved. This thesis describes the complete nucleotide sequence of the functional human D segment locus on chromosome 14q32.3, identifying a germline repertoire of 27 D segments, including 13 novel sequences. Criteria which confidently assign somatically rearranged sequences to germline D segments have been established and show that the human antibody repertoire is only created by the recombination of 25 functional D segments with extensive junctional diversity according to the "12/23 rule". No convincing evidence for inverted D joins, double D joins or the use of DIR segments in human antibodies could be found. Furthermore, the D segment repertoire in expressed human antibodies has been found to be markedly biased, with over-representation of particular segments and reading frames. In contrast to mouse, chicken and rabbit whose D segments are restricted to expression in only one reading frame comprising mainly hydrophilic residues, a significant proportion of human antibodies express D segments in reading frames comprising predominantly hydrophobic residues. D segments thereby impart a range of sequence characteristics to the third hypervariable loop of the human heavy chain variable domain at the heart of the antigen binding site.

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23

Yip, Bon-ham, e 葉邦瀚. "Immunoglobulin gene translocations in gastric lymphoma". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37345321.

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24

Watson, Nigel. "Monoclonal antibodies to human immunoglobulin allotypes". Thesis, University of Strathclyde, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304897.

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25

Tomlinson, Ian Michael. "The human immunoglobulin Vâ†H repertoire". Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295301.

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26

Sale, Julian Edward. "Constitutive immunoglobulin gene hypermutation in vitro". Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624417.

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27

Carrera, J. P., Zulma M. Cucunuba, Karen Neira, Ben Lambert, Yaneth Pitti, Jesus Liscano, Jorge L. Garzon et al. "Endemic and epidemic human alphavirus infections in eastern Panama: An analysis of population-based cross-sectional surveys". American Society of Tropical Medicine and Hygiene, 2020. http://hdl.handle.net/10757/655503.

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Madariaga virus (MADV) has recently been associated with severe human disease in Panama, where the closely related Venezuelan equine encephalitis virus (VEEV) also circulates. In June 2017, a fatal MADV infection was confirmed in a community of Darien Province. We conducted a cross-sectional outbreak investigation with human and mosquito collections in July 2017, where sera were tested for alphavirus antibodies and viral RNA. In addition, by applying a catalytic, force-of-infection (FOI) statistical model to two serosurveys from Darien Province in 2012 and 2017, we investigated whether endemic or epidemic alphavirus transmission occurred historically. In 2017, MADV and VEEV IgM seroprevalences were 1.6% and 4.4%, respectively; IgG antibody prevalences were MADV: 13.2%, VEEV: 16.8%, Una virus (UNAV): 16.0%, and Mayaro virus: 1.1%. Active viral circulation was not detected. Evidence of MADV and UNAV infection was found near households, raising questions about its vectors and enzootic transmission cycles. Insomnia was associated withMADVand VEEV infections, depression symptoms were associated with MADV, and dizziness with VEEV and UNAV. Force-of-infection analyses suggest endemic alphavirus transmission historically, with recent increased human exposure to MADV and VEEV in Aruza and Mercadeo, respectively. The lack of additional neurological cases suggests that severe MADV and VEEV infections occur only rarely. Our results indicate that over the past five decades, alphavirus infections have occurred at low levels in eastern Panama, but that MADV and VEEV infections have recently increased-potentially during the past decade. Endemic infections and outbreaks of MADV and VEEV appear to differ spatially in some locations of eastern Panama.
National Institute for Health Research
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28

Roberts-Thomson, Peter John. "Low molecular weight IgM in health and disease /". Title page, index and abstract only, 1987. http://web4.library.adelaide.edu.au/theses/09MD/09mdr648.pdf.

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29

Lohman, Isabelle Carlotta 1948. "THE PRODUCTION AND PURIFICATION OF RABBIT SERUM IMMUNOGLOBULIN-E, AND THE ROLE OF IMMUNOGLOBULIN-E IN SYSTEMIC ANAPHYLAXIS". Thesis, The University of Arizona, 1987. http://hdl.handle.net/10150/291183.

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30

Schiavo, Ebe. "Molecular mechanisms controlling immunoglobulin class switch recombination". Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ084/document.

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Lors des réponses immunitaires, le répertoire des lymphocytes B est diversifié par l’hypermutation somatique (HMS) et la commutation isotypique (CI), dépendant d’«activation-induced cytidine deaminase» (AID), qui introduit des lésions dans les gènes Ig. Une déficience d’AID cause un défaut d’HMS et de CI; par contre, une délétion du domaine C-terminal d’AID cause un défaut spécifique de la CI, suggérant que ce domaine interagit avec des facteurs spécifiques de la CI. Pour identifier ces facteurs, nous avons étudié une immunodéficience présentant un défaut de la CI non lié à la carence d’AID ni à un défaut d’HMS. De plus, les cassures de l’ADN ne sont pas détectées au niveau des gènes Ig suggérant qu’AID n’est pas correctement ciblée dans ces loci. Nous avons identifié et analysé des candidats : Spt6, les cohésines et le complexe Smc5/6. Dans les cellules B activées, AID interagit avec Spt6, Spt5, l’ARN polymérase II et le complexe PAF. Par contre, les cohésines pourraient réguler la structure du locus IgH lors de la CI et la voie de réparation des cassures de l’ADN générées pendant la CI. Ces résultats contribuent à une meilleure compréhension des étapes de la CI
During immune responses, B cell repertoire is diversified through somatic hypermutation (SHM) and class switch recombination (CSR). SHM and CSR require activation-induced cytidine deaminase (AID), which induces DNA damage. While AID deficiency abrogates SHM and CSR, C-terminal truncations impair CSR without affecting SHM and it has been proposed that AID C-terminal domain associates with CSR-specific factor(s). In order to identify these factors, we studied a human CSR-specific immunodeficiency, characterized by normal SHM and AID expression. B cells from these patients do not display DSBs at switch (S) regions, suggesting that they might lack an AID-binding factor(s) required to target AID to S regions during CSR. Through a multi- approach strategy, we identified and analyzed candidate factors, including Spt6, the cohesin complex and the Smc5/6 complex. We show that, in B cells poised to undergo CSR, AID is in a complex with Spt6, Spt5, the RNA polymerase II and the PAF complex while cohesins might regulate the 3D structure of the IgH locus and the pathway of DSBs repair at the Ig S regions. Our work thus contributes to a better understanding of the CSR reaction

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31

Ordinario, Ellen. "Dynamics and mechanism of immunoglobulin gene diversification /". Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/9266.

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32

Field, Helen. "On production of recombinant immunoglobulin variable domains". Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.330288.

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33

de, Bono B. "Immunoglobulin superfamily proteins in human and mouse". Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598443.

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Automated gene-prediction procedures have a number of shortcomings, and a method has been developed to address some of these. My approach drew upon the ability of hidden Markov models to detect distantly-matching patterns of IgSF sequences at both transcript and genomic DNA level. Ensembl gene predictions were used to locate the majority of human and mouse genes, but my method also detected IgSF genes just out of reach of standard pairwise techniques, resulting in a significantly improved coverage of IgSF genome coding sites. The experimental characterisation of two novel non-classical MHC mouse genes was carried out by a collaborating group. In total, the IgSF numbers 893 genes in human and 758 genes in mouse. This description of the IgSF domain across two distinct species allows us to chart the conservation and diversification process that occurs in a functionally important superfamily. The human-mouse common ancestor possessed at least 315 IgSF genes and, subsequent to divergence, a further 43 genes in mouse and 61 genes in human have been created by duplication. Six antibody and six TCR segment libraries in human, mouse and rat, were also annotated. These provide a similar function in both organisms, and are located in a single, well-circumscribed region of the genome. Comparative structural analysis of the repertoire of functional segments of the human and mouse VH locus was also carried out. Although the mouse repertoire (92 functional VH segments) is twice the size of the human set, the main families/groups of V_H sequences and the canonical structure combinations are conserved. 70% of the human sequences and 97% of the mouse sequences therefore belong to an equivalent family/group and also have the same canonical structure combination. Phylogenetic analysis revealed that these sequences have arisen subsequent to the divergence of the mouse and human from their common ancestor.

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34

George, Laura. "Regulation of extrafollicular immunoglobulin class switch recombination". Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5109/.

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The humoral immune response is characterised by the production of antibody secreting B cells. Some of these cells have cycled through the germinal centre, diversifying and optimising their antigen receptors to produce affinity-matured, class switched antibody. As this is a relatively slow process, the first class switched antibody is produced by non-mutated B blasts that have differentiated independently of the germinal centre reaction outside B-cell follicles. Extrafollicular foci of plasmablasts provide the first line of defence within the adaptive antibody response. IRF4 has been shown to be essential for Ig class switching and plasma-cell differentiation. Two expression levels of IRF4 were reported, with intermediate levels proposed to regulate CSR in the GC, while high levels regulate plasma-cell differentiation. We have correlated the two phases of IRF4 induction with specific stages of B-cell differentiation. Following immunisation of quasi-monoclonal mice with NP-Ficoll, intermediate levels of IRF4 protein are expressed by all B blasts as they move to the outer T zone and before the formation of germinal centres or plasma cells. This is followed by expression of AID and CSR. In contrast, plasma-cell differentiation occurs with high level expression of IRF4, expression of Blimp1 and complete suppression of AID and CSR. The NFκB family signalling molecules C-REL and NFκB1 have been shown to be required for the induction of IRF4 protein in B cells following stimulation. We show that these signalling molecules are not necessary to induce the early rapid intermediate level expression of IRF4, and extrafollicular expression of AID and CSR occur normally when they are absent. IRF4-high expression and plasma-cell differentiation, however, are blocked in the absence of these molecules.

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35

Wright, Caroline Fiona. "Folding and aggregation of an immunoglobulin domain". Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616276.

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36

Fraser, Louise. "Immunoglobulin light chains in Systemic Lupus Erythematosus". Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/immunoglobulin-light-chains-in-systemic-lupus-erythematosus(759b46c1-24bc-427d-8b25-8987eec6f61f).html.

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Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease of elusive origin and characterised by polyclonal B cell hyperactivity and the production of pathogenic antibodies targeting self DNA and nucleoproteins. Clinical manifestations of SLE are highly heterogeneous and include multisystem inflammation of connective tissue and vasculitis of the central nervous system (CNS). SLE is known to have genetic associations, and is widely acknowledged to involve a profound breakdown in immune tolerance. The aim of this project was to identify whether defects in early B cell development that affect the expressed repertoire of immunoglobulin light chains could be observed and to ask whether receptor editing contributes to disease pathogenesis. Chapter 3 describes a high-throughput sequencing analysis of the human immunoglobulin kappa light chain gene repertoire in healthy and SLE mature naive peripheral B cells. We observed that involvement of gene segments as the repertoire develops is equivalent in health and SLE and that a previously described bias towards usage of the gene segment IGKV4-1 in SLE is only observed in the expressed repertoire analysed. Chapter 4 describes an inefficient function of the kappa deleting element (KDE) in SLE, which manifests as reduced frequency of KDE rearrangement status in populations of CD19+ B cells and a failure to inactivate alleles of IGK allowing them to accumulate somatic hypermutations within non-productive IGK rearrangements. Chapter 5 identifies a potential biological outcome of a failure to inactivate rearranged alleles of IGK in SLE; cell surface expression of both kappa and lambda light chains were observed by flow cytometry analyses. Efforts to disprove this were unsuccessful anddetection of both light chain transcripts was confirmed through single cell PCR amplification of cDNA. The data in this thesis suggest that the failure of the KDE to inactivate alleles of IGK efficiently in SLE permits the expression of IGK light chains that have been selected against resulting in allelic inclusion. This mechanism may account for the broader and less stringently regulated antigen-binding B cell repertoire associated with SLE.

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37

Farley, Carol J. "Stress, appraised control, and salivary immunoglobulin A". Thesis, Anglia Ruskin University, 2010. http://arro.anglia.ac.uk/188989/.

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Salivary IgA is the primary antibody of mucosal immunity. It has been suggested that chronic stress may lower levels of IgA and lead to an increased susceptibility to respiratory illness. It is also suggested that acute stress increases IgA during active coping (that involves mental effort or controllability, such as time-based mathematics or memory tests) and decreases it during passive coping tasks (with no mental effort required or uncontrollable, such as the passive viewing of disgust images). However, tasks often classed as stressors have produced consistent IgA effects in areas of passive coping and chronic stress. These inconsistencies might be a consequence of methodological issues, such as sampling procedures, or may reflect individual differences, for example how a task is appraised. This thesis examined appraisal effects with focus on control over a stressful event and a potential relationship with salivary IgA. Three different study designs were used to examine stress, appraised control and salivary IgA. To alter appraisal during passive coping, disgust images were presented as either real pictures or as fake effects from fictional films to change the participant's perception of control during the image presentations. The role of appraised control during a chronic stress situation was explored in caregivers, and finally, appraised control and subjective stress were investigated in relation to IgA daily for a week in undergraduates, alongside perceived stress and hassles from the prior month. Viewing disgusting images increased perceived stress, irrespective of whether the images were presented as real or fake. Crucially, control was lower and salivary IgA increased only in the group that were told the images were real. Appraised control over a chronic stressor of caregiving did not affect IgA, but neither did perceived stress. Finally, in undergraduates, stress measured at the same time as sampling showed a lower level of IgA on days rated the highest compared to lowest on stress, and appraised control had a negative correlation with IgA when averages were used over the week, but only in a sub-group of participants. Perceived stress or hassles from the prior month did not relate to IgA. The main conclusions are that a participant's appraisal of passive coping tasks can be altered and that this may lead to a change in their IgA response. The overall results challenge the view that IgA is a stress marker, as the only consistent effect of stress on IgA was its consistency. Yet inconsistent IgA responses are likely to be a recurring issue in research due to the sensitivity of IgA to a number of different methodological practices that may cause a direct effect, or may alter appraisals.

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38

Farley, Carol J. "Stress, appraised control, and salivary immunoglobulin A". Thesis, Anglia Ruskin University, 2010. https://arro.anglia.ac.uk/id/eprint/188989/1/Thesis_Farley_2010.pdf.

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Salivary IgA is the primary antibody of mucosal immunity. It has been suggested that chronic stress may lower levels of IgA and lead to an increased susceptibility to respiratory illness. It is also suggested that acute stress increases IgA during active coping (that involves mental effort or controllability, such as time-based mathematics or memory tests) and decreases it during passive coping tasks (with no mental effort required or uncontrollable, such as the passive viewing of disgust images). However, tasks often classed as stressors have produced consistent IgA effects in areas of passive coping and chronic stress. These inconsistencies might be a consequence of methodological issues, such as sampling procedures, or may reflect individual differences, for example how a task is appraised. This thesis examined appraisal effects with focus on control over a stressful event and a potential relationship with salivary IgA. Three different study designs were used to examine stress, appraised control and salivary IgA. To alter appraisal during passive coping, disgust images were presented as either real pictures or as fake effects from fictional films to change the participant's perception of control during the image presentations. The role of appraised control during a chronic stress situation was explored in caregivers, and finally, appraised control and subjective stress were investigated in relation to IgA daily for a week in undergraduates, alongside perceived stress and hassles from the prior month. Viewing disgusting images increased perceived stress, irrespective of whether the images were presented as real or fake. Crucially, control was lower and salivary IgA increased only in the group that were told the images were real. Appraised control over a chronic stressor of caregiving did not affect IgA, but neither did perceived stress. Finally, in undergraduates, stress measured at the same time as sampling showed a lower level of IgA on days rated the highest compared to lowest on stress, and appraised control had a negative correlation with IgA when averages were used over the week, but only in a sub-group of participants. Perceived stress or hassles from the prior month did not relate to IgA. The main conclusions are that a participant's appraisal of passive coping tasks can be altered and that this may lead to a change in their IgA response. The overall results challenge the view that IgA is a stress marker, as the only consistent effect of stress on IgA was its consistency. Yet inconsistent IgA responses are likely to be a recurring issue in research due to the sensitivity of IgA to a number of different methodological practices that may cause a direct effect, or may alter appraisals.

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39

Dixon, Emma Victoria. "Mechanisms of immunoglobulin deactivation by Streptococcus pyogenes". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:ec80e3f9-0c73-4d39-bc68-c39b927365d4.

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The bacteria Streptococcus pyogenes produces a multitude of proteins which interact with and alter the functions of the host immune system. Two such proteins, Endoglycosidase S (EndoS) and Immunoglobulin G-degrading enzyme from S. pyogenes (IdeS) are able to specifically alter the effector functions of immunoglobulin G (IgG). EndoS is a glycoside hydrolase which removes the conserved N-linked glycan from IgG Fc whereas IdeS is a cysteine protease that cleaves the exible protein hinge of IgG. The activity of both proteins results in the reduced ability of IgG to elicit immune responses through Fc receptor binding and complement activation. Amongst other applications, both EndoS and IdeS are actively being explored as new therapeutics for IgG-mediated autoimmune diseases. Given the therapeutic potential of EndoS and IdeS, experiments were designed to investigate the structural and functional characteristics of these enzymes in an effort to understand their specficity for and activity against IgG. Here, bioinformatic and biophysical characterisation of EndoS identified subdomains outside of the catalytic domain which contribute to glycoside hydrolase activity. The substrate specificity of EndoS was also explored and showed that EndoS hydrolyses a broad range of glycans from the IgG scaffold. EndoS was also shown to have activity against alternative glycoprotein substrates, however, this non-specific activity was negligible in the context of whole serum. The effect of EndoS-mediated deglycosylation on the structure of the IgG Fc domain was explored using both X-ray crystallography and small-angle X-ray scattering. Small angle X-ray scattering was also used to characterise both EndoS and IdeS in complex with IgG Fc. Solution-state models of each complex were produced providing preliminary data towards how these enzymes interact with IgG. Overall, the results presented here contribute to our understanding of these enzymes which is of importance as they go forward into clinical applications.

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40

Chintalacharuvu, Koteswara Rao. "Disulfide bond formation between dimeric immunoglobulin A and the polymeric immunoglobulin receptor in cultured epithelial cells and rat liver". Case Western Reserve University School of Graduate Studies / OhioLINK, 1991. http://rave.ohiolink.edu/etdc/view?acc_num=case1055268413.

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41

Borthakur, Susmita. "Structural flexibility and immunoglobulin constant domains : role of the intrinsic flexibility of the C&3 domain of immunoglobulin E". Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531955.

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42

Bartholomeuz, Risien Chiron Andrew. "Polymeric IgA antibody in humans after vaccination and in disease /". Title page, contents and abstract only, 1989. http://web4.library.adelaide.edu.au/theses/09MD/09mdb287.pdf.

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43

Johansson, Karin. "Analysis of immunoglobulin gene expression focus on Oct2 /". Lund : Dept. of Cell and Molecular Biology, Lund University, 1995. http://catalog.hathitrust.org/api/volumes/oclc/39776663.html.

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44

Heidari, Ramesh. "Immunoglobulin VH gen analys in human B-cell". Thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7392.

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Malt lymphoma is a malignant disease that can arise in a variety of extra nodal sites. Previous studies indicate that tumour arise from more mature B-cells.

Our purpose was to examine the presence of clonality and somatic hypermutation of immunoglobulin (IgVн) of MALT lymphomas.

Paraffin-embedded tumour samples from13 MALT lymphoma were subjected to rearrangement analysis, by using PCR, heteroduplex gels and sequence analysis.

Successful amplification was seen in 10/13 cases and sequences of IgVн genes were obtained in 6/13, all of them were mutated. The percentage of mutation compared to germline sequences was 1,1% to 8,6% monoclonal rearrangemang. It was demonstrated that 5 of 7 clones were derived from the Vн3 family, 2 from Vн1 and 1 from the Vн 4 family.

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45

Oancea, Adriana Ecaterina. "Immunoglobulin heavy chain gene expression in hybridoma cells". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0010/NQ28030.pdf.

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46

Andersson, Tove. "Transcription factors regulating the immunoglobulin heavy chain locus /". Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3559-9/.

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47

Betz, Alexander Guido. "Somatic hypermutation of immunoglobulin #KAPPA# light chain genes". Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319561.

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48

Duncan, Alexander Robert. "The location of effector sites in immunoglobulin IgG". Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238535.

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49

Preston, Alexandra McEwan. "Interactions of immunoglobulin superfamily leukocyte cell surface molecules". Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318630.

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50

Hamill, S. J. "Folding and evolution of the immunoglobulin-like superfold". Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603613.

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In this study, the structure, folding and stability of a number of proteins with the Ig-like fold are compared. This 'fold approach' is a new direction in the experimental study of the folding proteins with similar 3D structures but no sequence homology. Two evolutionary distinct superfamilies with the Greek key immunoglobulin-like (Ig-like) fold are considered: the immunoglobulins (Igs) and fibronectin type IIIs (fnIIIs). Part I focuses on the third fnIII domain of human tenascin, TNfm3. This module is 90 amino acids in length, has no disulphides, bound ions, cofactors, or cis prolines. Part II focuses on comparative studies of two other Ig-like proteins, rat CD2 domain 1 (CD2d1) and Ig18' of C. elegans twitchin (TWIg18'). Comparison of the folding of these proteins and several others, shows a distinct correlation between stability and folding rate. This trend is unique amongst protein families characterised to date, and implies that the stability of regions of conserved structure drives the folding reaction. Structural alignment reveals that the strongest bioinformatic signal, in terms of residue identity, is the tyrosine coroner motif that is found at the same position in each protein and is found ubiquitously and exclusively in Greek key proteins. Comparative protein engineering shows that the tyrosine corner is not a kinetic signal, but one for the structural stability, perhaps reflecting an evolutionary 'cul-de-sac'. Results from parts I and II are then drawn together to produce a model for the folding of Ig-like proteins. The common core of Ig-like domains consists of strands B, C, E and F, which form a double 'β-zipper' by the intercalculation of strands B-C and E-F. The stability of BCEF drives the folding of Ig-like proteins. Regions that also fold early may do so due to topological restriction. The BCEF unit is efficiently packed and the stability conferred from this is probably central to the evolutionary favourability of Greek key proteins.

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