Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A:
Gespeichert in:
| 1. Verfasser: | |
|---|---|
| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
2008
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| Schlagworte: | |
| Online-Zugang: | Volltext https://nbn-resolving.org/urn:nbn:de:bvb:29-opus-9846 http://d-nb.info/989638332/34 Inhaltsverzeichnis |
| Beschreibung: | XII, 134 S. Ill., graph. Darst. |
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| 245 | 1 | 0 | |a Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A |c von Christiane Mühle |
| 264 | 1 | |c 2008 | |
| 300 | |a XII, 134 S. |b Ill., graph. Darst. | ||
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Datensatz im Suchindex
| _version_ | 1804137757810884608 |
|---|---|
| adam_text | Table of contents
Abstract - iv
Zusammenfassung vi
Abbreviations xi
1. Introduction 1
1.1 Blood coagulation 1
1.2 Bleeding disorders - hemophilia A 4
1.3 Genomic organization of FS and molecular basis of hemophilia A 6
1.4 Structure and interaction sites of the coagulation factor VHI 9
1.5 FVIII-inhibitory antibodies in hemophiliacs 13
1.6 Objectives and experimental strategy 17
2. Results 19
2.1 Mutation mechanisms in patients with hemophilia A 19
2.1.1 Elucidation of a complex rearrangement with deletion, insertion and
inversion events in F8 19
2.1.1.1 Analysis ofF ?cDNA revealing absence of expression 19
2.1.1.2 Gross localization of deletion breakpoints 20
2.1.1.3 Identification of an additional insertion 21
2.1.1.4 Determination of a breakpoint within the int22hl region 25
2.1.1.5 Cytogenetic analysis suggesting gross chromosomal integrity 27
2.1.1.6 Identification of a concomitant inf.22fc-related inversion 29
2.1.1.7 Determination of the paternal origin of the defective X chromosome 31
2.1.2 Slipped strand mispairing leading to large deletions in F8 and concomitant
deletions/insertions 34
2.1.3 Previously undetected large deletions in F8 combined with recurrent int22h-
related inversions 36
2.1.4 Evaluation of the effect of substitution mutations insilico 38
2.1.5 Overview of analyzed mutations and mechanisms 43
2.2 Characterization of FVm antibody epitopes in hemophilia A patients 44
2.2.1 Characterization of patients material 44
2.2.2 Determination of the antigenicity profile of FVIII domains 45
2.2.2.1 Production of recombinant FVIII fragments 45
2.2.2.2 Immunoprecipitation of labeled FVIII domains with patients antibodies 46
2.2.3 Epitope mapping by phage display technology 50
2.2.3.1 Phage display strategy 50
2.2.3.2 Establishment and optimization of the phage display method 52
2.2.3.3 Isolation of FVIII-specific antibodies from plasma of hemophiliacs 53
2.2.3.4 Selection of phage-displayed peptides binding to patients FVHI-specific
antibodies 54
viii
2.2.3.5 Identification of overlapping peptide sequences for different patients
samples 57
2.2.4 Localization of putative epitopes in a three-dimensional FVIII model 58
2.2.5 Functional tests for putative epitopes 60
2.2.5.1 Synthetic peptides displacing patient s antibodies from FVIII in
competitive ELISA 60
2.2.5.2 Synthetic peptides partially neutralizing FVIII-inhibitory antibodies in
Bethesda Assay 61
2.2.6 Summary of antigenic domains and identified epitopes 63
3. Discussion 64
3.1 Heterogeneity of large deletion mutations in F8: combination with insertions
and inversions 64
3.2 New inversion polymorphism underlying the recurrent m/22A-related
inversion 67
3.3 New mechanism of a pathogenic X-chromosomal rearrangement 70
3.4 Influence of genetic and exogenous factors on the immune response of
hemophiliacs to FVIII 72
3.5 Broad spectrum of FVIII domain antigenicity and diverse role of specific
identified epitopes 75
3.6 Evaluation of methods for the identification of epitopes 81
3.7 Novel therapeutic including epitope-based approaches to FVIII inactivating
antibodies in hemophilia 83
3.8 Conclusion and Outlook 89
4. Materials and Methods 90
4.1 General materials 90
4.2 Biological samples 90
4.3 Equipment 90
4.4 Databases and Programs 91
4.5 General procedures 91
4.5.1 Agarose gel electrophoresis 91
4.5.2 Transformation of bacteria 91
4.5.3 Isolation and purification of bacterial plasmid DNA 92
4.5.4 Cloning of PCR products 93
4.5.5 Sequencing 93
4.5.6 SDS-PAGE 93
4.5.7 Western blot 94
4.6 Mutation analysis 94
4.6.1 Isolation of total RNA and genomic DNA from blood 94
4.6.2 RNA analysis 95
4.6.2.1 cDNA synthesis 95
4.6.2.2 RT-PCR 96
4.6.3 DNA analysis: standard methods 96
4.6.3.1 Southern blot, CSGE and DHPLC 96
ix
4.6.3.2 PCR amplification of exons in the F8 gene 97
4.6.4 DNA-analysis: methods for inversion/deletion/insertion mutations 97
4.6.4.1 PCR for gross localization of the deletion in the gene F8 97
4.6.4.2 PCR amplification to determine the extent of the MPPl insertion 98
4.6.4.3 Long range PCR across the deletion and inside int22hl 98
4.6.4.4 Quantitative real-time PCR 99
4.6.4.5 Analysis of sequence variations in the intron 22 homology regions 100
4.6.4.6 Long-range PCR for detection of m^2A-related inversions 101
4.6.5 DNA-analysis: identification of unknown flanking sequences 101
4.6.5.1 Whole genome amplification with phi29 DNA polymerase 101
4.6.5.2 Inverse PCR 101
4.6.5.3 Primer walking with the Seegene-Kit 102
4.6.5.4 TAIL-PCR 103
4.6.5.5 Unpredictably primed PCR 104
4.6.6 DNA-analysis: polymorphic markers 104
4.6.7 Cytogenetic methods 105
4.7 Production of recombinant FVIII fragments 105
4.7.1 Vector construction 105
4.7.2 Cell culture 106
4.7.3 Generation of stable cell lines producing recombinant proteins 106
4.7.4 Production and purification of His-tagged FVIII domains 106
4.8 Processing and analysis of plasma samples 107
4.8.1 Bethesda Assay 107
4.8.2 Radio-immunoprecipitation 107
4.8.3 Antibody purification 108
4.8.4 ELISA for total and FVIII-specific immunoglobulins 109
4.9 Phage Display Methods 109
4.9.1 Selection of random peptides displayed by phage 109
4.9.2 Phage titering Ill
4.9.3 Amplification and purification of phage Ill
4.9.4 Plaque amplification and rapid purification of sequencing templates 11
4.9.5 Evaluation of sequences Ill
4.9.6 Phage binding assays 112
4.9.7 Competitive ELISA with peptides 112
5. References 113
Appendix m 127
Additional tables 127
List of figures ]29
Acknowledgments 130
Curriculum vitae j31
List of publications 132
x
|
| adam_txt |
Table of contents
Abstract - iv
Zusammenfassung vi
Abbreviations xi
1. Introduction 1
1.1 Blood coagulation 1
1.2 Bleeding disorders - hemophilia A 4
1.3 Genomic organization of FS and molecular basis of hemophilia A 6
1.4 Structure and interaction sites of the coagulation factor VHI 9
1.5 FVIII-inhibitory antibodies in hemophiliacs 13
1.6 Objectives and experimental strategy 17
2. Results 19
2.1 Mutation mechanisms in patients with hemophilia A 19
2.1.1 Elucidation of a complex rearrangement with deletion, insertion and
inversion events in F8 19
2.1.1.1 Analysis ofF ?cDNA revealing absence of expression 19
2.1.1.2 Gross localization of deletion breakpoints 20
2.1.1.3 Identification of an additional insertion 21
2.1.1.4 Determination of a breakpoint within the int22hl region 25
2.1.1.5 Cytogenetic analysis suggesting gross chromosomal integrity 27
2.1.1.6 Identification of a concomitant inf.22fc-related inversion 29
2.1.1.7 Determination of the paternal origin of the defective X chromosome 31
2.1.2 Slipped strand mispairing leading to large deletions in F8 and concomitant
deletions/insertions 34
2.1.3 Previously undetected large deletions in F8 combined with recurrent int22h-
related inversions 36
2.1.4 Evaluation of the effect of substitution mutations insilico 38
2.1.5 Overview of analyzed mutations and mechanisms 43
2.2 Characterization of FVm antibody epitopes in hemophilia A patients 44
2.2.1 Characterization of patients' material 44
2.2.2 Determination of the antigenicity profile of FVIII domains 45
2.2.2.1 Production of recombinant FVIII fragments 45
2.2.2.2 Immunoprecipitation of labeled FVIII domains with patients' antibodies 46
2.2.3 Epitope mapping by phage display technology 50
2.2.3.1 Phage display strategy 50
2.2.3.2 Establishment and optimization of the phage display method 52
2.2.3.3 Isolation of FVIII-specific antibodies from plasma of hemophiliacs 53
2.2.3.4 Selection of phage-displayed peptides binding to patients' FVHI-specific
antibodies 54
viii
2.2.3.5 Identification of overlapping peptide sequences for different patients'
samples 57
2.2.4 Localization of putative epitopes in a three-dimensional FVIII model 58
2.2.5 Functional tests for putative epitopes 60
2.2.5.1 Synthetic peptides displacing patient's antibodies from FVIII in
competitive ELISA 60
2.2.5.2 Synthetic peptides partially neutralizing FVIII-inhibitory antibodies in
Bethesda Assay 61
2.2.6 Summary of antigenic domains and identified epitopes 63
3. Discussion 64
3.1 Heterogeneity of large deletion mutations in F8: combination with insertions
and inversions 64
3.2 New inversion polymorphism underlying the recurrent m/22A-related
inversion 67
3.3 New mechanism of a pathogenic X-chromosomal rearrangement 70
3.4 Influence of genetic and exogenous factors on the immune response of
hemophiliacs to FVIII 72
3.5 Broad spectrum of FVIII domain antigenicity and diverse role of specific
identified epitopes 75
3.6 Evaluation of methods for the identification of epitopes 81
3.7 Novel therapeutic including epitope-based approaches to FVIII inactivating
antibodies in hemophilia 83
3.8 Conclusion and Outlook 89
4. Materials and Methods 90
4.1 General materials 90
4.2 Biological samples 90
4.3 Equipment 90
4.4 Databases and Programs 91
4.5 General procedures 91
4.5.1 Agarose gel electrophoresis 91
4.5.2 Transformation of bacteria 91
4.5.3 Isolation and purification of bacterial plasmid DNA 92
4.5.4 Cloning of PCR products 93
4.5.5 Sequencing 93
4.5.6 SDS-PAGE 93
4.5.7 Western blot 94
4.6 Mutation analysis 94
4.6.1 Isolation of total RNA and genomic DNA from blood 94
4.6.2 RNA analysis 95
4.6.2.1 cDNA synthesis 95
4.6.2.2 RT-PCR 96
4.6.3 DNA analysis: standard methods 96
4.6.3.1 Southern blot, CSGE and DHPLC 96
ix
4.6.3.2 PCR amplification of exons in the F8 gene 97
4.6.4 DNA-analysis: methods for inversion/deletion/insertion mutations 97
4.6.4.1 PCR for gross localization of the deletion in the gene F8 97
4.6.4.2 PCR amplification to determine the extent of the MPPl insertion 98
4.6.4.3 Long range PCR across the deletion and inside int22hl 98
4.6.4.4 Quantitative real-time PCR 99
4.6.4.5 Analysis of sequence variations in the intron 22 homology regions 100
4.6.4.6 Long-range PCR for detection of m^2A-related inversions 101
4.6.5 DNA-analysis: identification of unknown flanking sequences 101
4.6.5.1 Whole genome amplification with phi29 DNA polymerase 101
4.6.5.2 Inverse PCR 101
4.6.5.3 Primer walking with the Seegene-Kit 102
4.6.5.4 TAIL-PCR 103
4.6.5.5 Unpredictably primed PCR 104
4.6.6 DNA-analysis: polymorphic markers 104
4.6.7 Cytogenetic methods 105
4.7 Production of recombinant FVIII fragments 105
4.7.1 Vector construction 105
4.7.2 Cell culture 106
4.7.3 Generation of stable cell lines producing recombinant proteins 106
4.7.4 Production and purification of His-tagged FVIII domains 106
4.8 Processing and analysis of plasma samples 107
4.8.1 Bethesda Assay 107
4.8.2 Radio-immunoprecipitation 107
4.8.3 Antibody purification 108
4.8.4 ELISA for total and FVIII-specific immunoglobulins 109
4.9 Phage Display Methods 109
4.9.1 Selection of random peptides displayed by phage 109
4.9.2 Phage titering Ill
4.9.3 Amplification and purification of phage Ill
4.9.4 Plaque amplification and rapid purification of sequencing templates 11'
4.9.5 Evaluation of sequences Ill
4.9.6 Phage binding assays 112
4.9.7 Competitive ELISA with peptides 112
5. References 113
Appendix m 127
Additional tables 127
List of figures ]29
Acknowledgments 130
Curriculum vitae j31
List of publications 132
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| publishDateSort | 2008 |
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| spelling | Mühle, Christiane 1976- Verfasser (DE-588)13588019X aut Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A von Christiane Mühle 2008 XII, 134 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Erlangen-Nürnberg, Univ., Diss., 2008 Langzeitarchivierung Nationalbibliothek gewährleistet Mutation (DE-588)4170883-0 gnd rswk-swf Hämophilie A (DE-588)4243053-7 gnd rswk-swf Gerinnungsfaktor VIII (DE-588)4156835-7 gnd rswk-swf (DE-588)4113937-9 Hochschulschrift gnd-content Hämophilie A (DE-588)4243053-7 s DE-604 Gerinnungsfaktor VIII (DE-588)4156835-7 s Mutation (DE-588)4170883-0 s Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:29-opus-9846 https://open.fau.de/handle/openfau/656 Verlag kostenfrei Volltext https://nbn-resolving.org/urn:nbn:de:bvb:29-opus-9846 Resolvingsystem http://d-nb.info/989638332/34 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016566888&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Mühle, Christiane 1976- Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A Mutation (DE-588)4170883-0 gnd Hämophilie A (DE-588)4243053-7 gnd Gerinnungsfaktor VIII (DE-588)4156835-7 gnd |
| subject_GND | (DE-588)4170883-0 (DE-588)4243053-7 (DE-588)4156835-7 (DE-588)4113937-9 |
| title | Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A |
| title_auth | Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A |
| title_exact_search | Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A |
| title_exact_search_txtP | Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A |
| title_full | Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A von Christiane Mühle |
| title_fullStr | Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A von Christiane Mühle |
| title_full_unstemmed | Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A von Christiane Mühle |
| title_short | Molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor VIII in patients with hemophilia A |
| title_sort | molecular basis and characteristics of the polyclonal antibody response to exogenous coagulation factor viii in patients with hemophilia a |
| topic | Mutation (DE-588)4170883-0 gnd Hämophilie A (DE-588)4243053-7 gnd Gerinnungsfaktor VIII (DE-588)4156835-7 gnd |
| topic_facet | Mutation Hämophilie A Gerinnungsfaktor VIII Hochschulschrift |
| url | https://open.fau.de/handle/openfau/656 https://nbn-resolving.org/urn:nbn:de:bvb:29-opus-9846 http://d-nb.info/989638332/34 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016566888&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT muhlechristiane molecularbasisandcharacteristicsofthepolyclonalantibodyresponsetoexogenouscoagulationfactorviiiinpatientswithhemophiliaa |