Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 89-102).

As individuals and populations diverge ecologically, they become exposed to new parasites and pathogens with potentially harmful fitness consequences. Populations are therefore expected to evolve resistance, possibly at a cost of less resistance to parasites rarely encountered parasites. This trade-off in resistance should generate local adaptation to parasites in different habitats. In chapter one, I show how local adaptation can potentially evolve in response to variation in parasite exposure among eighteen ecologically variable populations of threespine stickleback (Gasterosteus aculeatus). Within populations infection appeared to reflect morphology/diet based exposure differences among individuals. Among populations, however, these patterns were absent or reversed, consistent with the evolution of local adaptation. In chapters two and three I set out to test whether variation major histocompatibility (MHC) genes can underly such local adaptation in stickleback. MHC genes are important components of vertebrate immunity; however, there is little direct empirical support for spatially divergent selection driving local adaptation on MHC loci in the wild. In chapter two I tested for the action of parasite mediated balancing and divergent selection on on MHC loci using naturally infected stickleback in three replicate lake-stream pairs. Despite consistent divergence in parasites and MHC alleles, lakes tended to show decreased parasite burdens with increased allelic richness (consistent with balancing selection), while streams showed some support for divergent selection between lake and stream types. In chapter three I use the same lake-stream pairs to investigate how divergent selection could instead be reflected in variation in the effects of individual MHC alleles among populations. When comparing parapatric populations experiencing gene flow, MHC alleles maintained at relatively high frequency in one population were more likely to be associated with reduced, rather than increased, parasite abundances in that population. Allopatric populations experiencing no gene flow showed no such general relationship between allele frequency and resistance. These results are only consistent with spatially divergent selection, and imply that gene flow and environmental heterogeneity can be important for maintaining MHC diversity. / text

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (Ph.D. in Immunology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 133-156). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

La SpA est un rhumatisme inflammatoire chronique fréquent, dont la prévalence est de 0,3% en France. Les mécanismes pathologiques qui en sont à l’origine demeurent largement incertains. Néanmoins, l’héritabilité de la maladie est élevée, impliquant de multiples facteurs génétiques, dont la région du complexe majeur d’histocompatibilité (CMH) et plus particulièrement l’allèle HLA-B27 qui y exerce un rôle prédominant. L’objectif de ce travail était d’identifier de nouvelles cibles moléculaires, en vue d’améliorer la compréhension de la physiopathologie de la SpA, par des approches génétiques et de génomiques fonctionnelles.La première partie de mon travail a consisté en l’identification de polymorphismes du CMH associés à la SpA et distinct de HLA-B27. Les études d’association portant sur les données génétiques de 3 cohortes indépendantes nous ont permis d’identifié 5 variants associés à la SpA indépendamment du HLA-B27. Les deux polymorphismes situés à proximité des gènes MICA et MAPK14 semblent particulièrement intéressants pour leur implication potentielle dans la pathogénèse de la SpA. En marge de cette étude, nous avons entrepris de déterminer la prévalence du HLA-B27 dans une cohorte française représentative de la population générale, qui était de 6,9% chez les témoins et de 74,2% chez les sujets atteints de SpA.Les études fonctionnelles conduites sur des cellules dendritiques dérivées de monocytes (MD-DCs) ont permis d’identifier un défaut de réponse proliférative des LT CD4+ stimulés par les MD-DCs de patients atteints de SpA, ainsi qu’une signature transcriptomique de 81 gènes caractéristique des MD-DCs de ces patients. Parmi les gènes validés, la surexpression d’ADAMTS15, de F13A1 et de SELL pourrait jouer un rôle dans l’inflammation liée à la pathologie, alors que la sous-régulation de CITED2 paraitrait corrélée à une dérégulation de la voie Wnt. Enfin, nos investigations sur les MD-DCS nous ont amené à identifier une corrélation entre l’haplotype d’ERAP1 prédisposant à la SpA, et un niveau accru d’expression de ce gène ainsi que de la protéine ERAP1. / Spondyloarthritis (SpA) is a frequent chronic inflammatory rheumatic disorder, with a prevalence of 0.3% in France. Pathological mechanisms leading to SpA remain largely uncertain. Nevertheless, the heritability of this disorder is high, likely involving multiple genetic factors, among which the major histocompatibility complex (MHC) region and particularly the HLA-B27 allele which plays a prominent role. The objective of this work was to achieve a better understanding of SpA physiopathology via genetic and transcriptomic approaches. The first part of my work consisted in identification of MHC polymorphisms associated with SpA, distinct of HLA-B27. Association studies based on the genetic data of 3 independent cohorts have allowed to identify 5 SNPs associated to SpA, independently of HLA-B27. Two polymorphisms localized next to MICA and MAPK14 genes seem particularly interesting for their implication in SpA pathogenesis. In parallel of this study, we characterized HLA-B27 prevalence in a French cohort corresponding to 6.9% in healthy controls and 74.2% in SpA patients. Functional studies on monocyte-derived dendritic cells (MD-DCs) revealed altered capacity to stimulate allogeneic CD4+ T cell responses by MD-DCs from SpA patients and a transcriptomic signature of 81 genes differentially expressed in those cells, as compared to those from healthy controls. Among validated genes, ADAMTS15, F13A1 and SELL could play a role in SpA inflammation, whereas CITED2 seemed to be correlated to Wnt pathway. Finally, a strong correlation between ERAP1 SpA-susceptibility haplotype and an increased expression of this gene and the ERAP1 protein has been identified.

5 Abstract Products of major histocompatibility complex (MHC) plays key role in immune system of vertebrates. Prior studies on different vertebrate species show, that heterozygosity in MHC genes is linked to more efficient immune system and preferred in mate choice. Results of human studies are ambivalent, which can be due to the effect of some modulating factors like reproductive status. Therefore, our aim was to test heterozygosity related preferences in faces, odor and voice across menstrual cycle. Our sample consisted of 51 men and 52 women, from which 23 used hormonal contraception and 29 had natural cycle. They were genotyped in -A, -B and -DR alleles. All odor stimuli, face photos and voice records were rated on seven-point scale in both follicular and luteal phase. Repeated measures ANOVA was used for the analysis. Changes in ratings across the menstrual cycle and heterozygosity were most discernible on voice ratings. Voices of homozygous males were rated more attractive than voices of heterozygous males especially in follicular phase. Similar shift to higher ratings in follicular phase was manifested in ratings of homozygous male faces, but the difference between homozygous males and heterozygous males was not significant. Women with natural cycle also rated voices higher in their follicular phase...

Indiana University-Purdue University Indianapolis (IUPUI) / The function of major histocompatability complex (MHC) class II molecules is to present antigenic peptides to CD4+ T cells. Typically, MHC class II molecules present peptides derived from exogenous sources. Yet, certain endogenous antigens (Ags) have been found to be presented by class II molecules. Studies suggest that specific heat shock protein family members may play a role in Ag processing and subsequent class II presentation. The studies presented here using B lymphoblasts demonstrate the importance of HSP90α, HSP90β, and possibly HSP70 in selectively regulating MHC class II presentation. Inactivation of HSP90 function using pharmacological inhibitors inhibited class II presentation of exogenous and endogenous GAD, but did not perturb the presentation of several other intra- and extracellular Ags. Individual knockdown of HSP90 isoforms using isoform specific siRNA selectively inhibited GAD Ag presentation. These results demonstrate a requirement for HSP90α and HSP90β in regulating MHC class II presentation of select Ags. Studies to explore mechanistically the roles of HSP90α and HSP90β in regulating GAD Ag presentation were pursued. The pathways of exogenous and endogenous MHC class II presentation of GAD Ag are distinct yet converge with shared terminal processing of GAD within endosomal/lysosomal vesicles. The effect of HSP90 manipulation on various shared components of the MHC class II pathway was examined. The studies presented here suggest that HSP90α and HSP90β regulate MHC class II presentation of GAD Ag at discrete steps most likely involving HSP90 binding to GAD Ag rather than perturbing overall MHC class II function. vi Studying the role of HSP90 in MHC class II presentation in B cells revealed the potential requirement for HSP70 in the presentation of select Ags. The studies presented here demonstrate a possible role for HSP70 in the presentation of Ags such as SMA or Ig kappa by MHC class II molecules. Also included in this work is a study of a rare case of diabetes caused by type B insulin resistance due to development of insulin receptor autoantibodies during the treatment of hepatitis C with interferon alpha and ribavirin. Clinical and laboratory findings in the case are presented.

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