Gespeichert in:
| Beteilige Person: | |
|---|---|
| Format: | Hochschulschrift/Dissertation Buch |
| Sprache: | Englisch |
| Veröffentlicht: |
2008
|
| Schlagwörter: | |
| Links: | https://open.fau.de/handle/openfau/720 https://nbn-resolving.org/urn:nbn:de:bvb:29-opus-11132 http://d-nb.info/990710041/34 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016740122&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| Umfang: | 149 S. Ill., graph. Darst. |
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| 245 | 1 | 0 | |a Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis |c von Iryna Prots |
| 264 | 1 | |c 2008 | |
| 300 | |a 149 S. |b Ill., graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
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Datensatz im Suchindex
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|---|---|
| DE-BY-TUM_katkey | 1648259 |
| DE-BY-UBR_katkey | 4391304 |
| _version_ | 1835114664665546753 |
| adam_text | Table of contents 1
Table of contents
Table of contents 1
ABSTRACT 4
ZUSAMMENFASSUNG (German summary) 6
1 INTRODUCTION 9
1.1 CD4 T cells in the immune response 9
1.1.1 General properties of the immune response 9
1.1.2 CD4 T cell effectors 11
1.1.2.1 T helper I/T helper 2 effectors II
1.1.2.2 IL-17-producingT helper cells 13
1.1.3 Regulatory CD4 T cell subsets 14
1.2 IL-4 as a regulator of the immune response 15
1.3 IL-4 receptor biology 17
1.3.1 IL-4 receptor complexes 17
1.3.2 IL-4R protein structure 17
1.3.3 IL-4R signaling 18
1.3.4 Molecular aspects of IL-4-mcdiatcd regulation of effector
Tcell development 20
1.3.5 1L4R gene organization 21
1.3.5.1 SNPs in the IL4R gene 21
1.3.5.2 Importance of/L4R SNPs for IL-4 signaling 23
1.3.5.3 IL4R SNP association with immune pathology 25
1.4 Pathogenesis of RA 27
1.4.1 General characteristics of RA 27
1.4.2 Central role of CD4T cells in RA pathogenesis 28
1.4.3 Genetic contribution to RA pathology.... 30
1.4.3.1 RA susceptibility 30
1.4.3.2 RA severity 33
1.4.4 Link between IL-4 and RA pathology 34
AIMS OF THE THESIS J6
2 MATERIALS AND METHODS 37
2.1 Materials 37
2.1.1 Reagents, enzymes, cytokincs 37
2.1.2 Antibodies 38
2.1.3 SNP genotyping assays 40
2.1.4 TaqMan Gene Expression assays 40
2.1.5 Primers 41
2.1.6 Kits 41
2.2 Methods 43
2.2.1 Study population and clinical evaluation 43
2.2.2 DNA isolation and genotyping 44
2.2.2.1 GenomicDNA isolation 44
2.2.2.2 IL4R genotyping 44
Table of contents 2
2.2.2.3 HLA-DRBI genotyping 45
2.2.3 Cell purification 47
2.2.3.1 Isolation of human CD4T cells 47
2.2.3.2 MACS separation of CD25 positive and negative T cells 48
2.2.4 Cell culture 49
2.2.4.1 In vitro IL-4R expression assay 4
2.2.4.2 Analysis of STAT6 phosphorylation 49
2.2.4.3 Analysis ofIL-12Rp2 chain and GAT A3 expression 50
2.2.4.4 In vitro CD4 T cell differentiation 50
2.2.4.5 In vitro CD4+CD25+ Treg generation 51
2.2.4.6 Analysis of PMCH protein expression 52
2.2.4.7 Analysis of CEACAM1 expression 52
2.2.4.8 T cell proliferation assay 53
2.2.4.9 Suppression assay of T cell proliferation 53
2.2.5 Flow cytometry (FACS analysis) 53
2.2.5.1 Flow cytometry of surface molecules 53
2.2.5.2 Intracellular flow cytometry 54
2.2.6 SDS-PAGE and Western blotting 54
2.2.7 PMCHELISA 55
2.2.8 DNA gel electrophoresis 56
2.2.9 Total RNA isolation 56
2.2.10 cDNA synthesis and real-time PCR 57
2.2.11 Statistical analysis 57
2.2.12 DNA Microarrays 58
2.2.12.1 Control of total RNA quality 58
2.2.12.2 Two-step biotin-labelcd cRNA synthesis 59
2.2.12.3 Hybridization, washing, staining and scanning of the arrays 60
2.2.12.4 Data transformation and analysis 61
3 RESULTS 62
3.1 Association of IL4R SNPs with RA 62
3.1.1 Study cohorts 62
3.1.2 IL4R is not associated with RA susceptibility 62
3.1.3 The I50V 1L4R SNP is associated with early erosive RA 64
3.1.4 High predictive value of !he/iV^V50allele 66
3.2 Functional effects of the I50V and Q551R IL4R SNPs in T cells 68
3.2.1 V5O/V50 homozygosity is associated with decreased IL-4 regulation
ofCD4T cell differentiation 68
3.2.1.1 Diminished IL-4-mediated inhibition of Thl cell differentiation
in V50/V50, Q551/Q551 naive CD4 T cells 68
3.2.1.2 V5O/V5O, Q551/Q551 homozygous memory CD4 T cells show
reduced IL-4-mediated Thl inhibition 70
3.2.1.3 The Th2 promoting capacity of IL-4 is not 1L4R genotype
dependent under strong stimulation 71
3.2.1.4 The V50 allele is associated with less pronounced Th2 cell
differentiation 72
3.2.2 Proliferation of CD4 T cells is not influenced by IL-4, independent on
the IL4R genotype 73
3.2.3 V50 homozygous CD4 T cells are characterized by decreased IL-4
signaling 74
3.2.3.1 IL-4R expression is similarly induced in 150 and V50 IL4R
Table of contents 3
homozygous CD4 T cells 75
3.2.3.2 STAT6 phosphorylation is impaired in V50 homozygous
CD4T cells 76
3.2.3.3 IL-4-induced GATA3 activation and IL-12R02 inhibition are
impaired in V5O/V5O IL4R CD4 T cells 77
3.3 IL-4-induced gene expression profile in CD25+ Treg cell development 79
3.3.1 IL-4 induces development of CD25+ Trcg cells from human naive
CD4T cells 79
3.3.2 Gene expression profile of developing Treg cells in the presence of
IL-4 80
3.3.2.1 Genes upregulatcd in CD25+ over CD25- T cells in the presence
of IL-4 84
3.3.2.2 Genes downrcgulatcd in CD25+ versus CD25- T cells in the
presenceofIL-4 85
3.3.2.3 IL-4-spccific gene regulation during Trcg development 86
3.3.3 Validation of microarray data by real-time PCR analysis 92
3.3.3.1 Upregulatcd genes 92
3.3.3.2 Downrcgulatcd genes 94
3.3.4 Analysis of the candidate gene expression in freshly isolated
CD25+Trcg cells 95
3.3.5 Protein expression analysis of CEACAM 1 97
3.3.6 Preliminary analysis of PMCH expression in Trcg cells 99
4 DISCUSSION 100
4.1 Genetic contribution of IL4R to RA pathology 100
4.1.1 RA susceptibility 100
4.1.2 RA severity 105
4.2 The functional effects of IL4R SNPs in CD4 T cells 109
4.2.1 1L4R SNP effects in IL-4-regulatcd CD4 T cell differentiation 109
4.2.2 Influencing molecular events in CD4 T cells by the IL4R I50V
SNPalleles 112
4.2.3 Possible regulation of the immune response by the 1L4R SNP allclcs 115
4.3 DNA microarray analysis of IL-4 regulation of Treg development 117
4.3.1 Generation of Treg cells in vitro 118
4.3.2 Genes differently regulated in CD25+ T cells generated in
the presence of IL-4 119
4.3.2.1 Early upregulatcd genes in developing Treg cells 119
4.3.2.2 Constant and late upregulatcd genes in developing Trcg cells 121
4.3.2.3 Genes downregulatcd in Treg ceils 124
4.3.3 Analysis of CEACAM1 and PMCH in Treg cells 127
4.3.3.1 CEACAMI 127
4.3.3.2 PMCH 128
CONCLUDING REMARKS 130
Abbreviations 131
Bibliography 136
Acknowledgements 148
Curriculum vitae 150
|
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| dewey-sort | 3616.7 |
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| spellingShingle | Prots, Iryna 1976- Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis Interleukin 4 (DE-588)4212826-2 gnd Rheumatoide Arthritis (DE-588)4076708-5 gnd SNP (DE-588)4789542-1 gnd |
| subject_GND | (DE-588)4212826-2 (DE-588)4076708-5 (DE-588)4789542-1 (DE-588)4113937-9 |
| title | Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis |
| title_auth | Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis |
| title_exact_search | Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis |
| title_full | Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis von Iryna Prots |
| title_fullStr | Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis von Iryna Prots |
| title_full_unstemmed | Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis von Iryna Prots |
| title_short | Mechanisms of IL-4-mediated immune dysregulation in rheumatoid arthritis |
| title_sort | mechanisms of il 4 mediated immune dysregulation in rheumatoid arthritis |
| topic | Interleukin 4 (DE-588)4212826-2 gnd Rheumatoide Arthritis (DE-588)4076708-5 gnd SNP (DE-588)4789542-1 gnd |
| topic_facet | Interleukin 4 Rheumatoide Arthritis SNP Hochschulschrift |
| url | https://open.fau.de/handle/openfau/720 https://nbn-resolving.org/urn:nbn:de:bvb:29-opus-11132 http://d-nb.info/990710041/34 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016740122&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT protsiryna mechanismsofil4mediatedimmunedysregulationinrheumatoidarthritis |