- Author
-
P. Tuijnenburg
- Title
- Deconstructing B cell responses
- Subtitle
- Lessons learned from development, drugs and deficiencies
- Supervisors
-
T.W. Kuijpers
- Co-supervisors
-
E.M.M. van Leeuwen
G.J. de Bree - Award date
- 31 January 2020
- Number of pages
- 254
- ISBN
- 9789463756297
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
The human immune system is protecting us from a wide variety of potentially disease-causing pathogens, already starting directly after birth. Inborn errors of immunity or primary immunodeficiency disorders (PIDs) are a group of diseases where any or multiple of these protective components of the immune system fail.
There is a close relationship between how the immune system functions in PIDs and how the immune system works in healthy individuals. The B cells of patients with defects in specific components, i.e. proteins, show how important they really are in humans. By studying the effects of the absence, reduction or modification of these key proteins we could ‘deconstruct’ healthy B cell responses.
Here we add pieces of missing information to how B cell differentiation and antibody responses may work, by investigating monogenic PIDs. We did not focus on these human knock-outs only. We used different approaches and looked at healthy human B cells from different age-ranges in several experimental conditions in order to compare normal and abnormal B cell development and differentiation. A high-throughput compound screen showed us distinct mechanisms to modulate B cell responses and offered new therapeutic targets for diseases with B cell dysregulation (such as antibody-dependent autoimmune diseases).
This thesis reveals important roles for both the canonical and non-canonical NF-κB pathway and the PI3K-AKT-mTOR pathway in the differentiation of naïve B cells to antibody producing plasmablasts and plasma cells. - Persistent Identifier
- https://hdl.handle.net/11245.1/4c933374-f6c6-48f2-8bbb-690889ee3a68
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General Introduction and outline
Chapter 2: Profiling of high IgM-producing cord blood B cells
Chapter 3: Mutations in EXTL3 cause neuro-immuno-skeletal dysplasia syndrome
Chapter 4: A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency
Chapter 5: Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans
Chapter 6: Pathogenic NFKB2 variant in the ankyrin repeat domain (R635X) causes a variable antibody deficiency
Chapter 7: Humoral immunodeficiency with hypotonia, feeding difficulties, enteropathy, and mild eczema caused by a classical FOXP3 mutation
Chapter 8: High-throughput compound screen reveals mTOR inhibitors as potential therapeutics to reduce (auto)antibody production by human plasma cells
Chapter 9: General discussion
Summary; Nederlandse samenvatting voor niet-ingewijden; Curriculum vitae; PhD portfolio; Publications; Dankwoord
Stellingen
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