Subsets of Human Dendritic Cells and their Role in Allergy
Author
Summary, in English
The immune system has evolved to protect the human body against harmful invaders. At the same time, development of tolerance against self-derived and innocuous foreign antigens is of vital importance in order to avoid detrimental immune disorders. In allergic conditions, hypersensitivity is developed against harmless antigens, such as pollen. Dendritic cells (DCs) serve as a link between the innate and adaptive immune system and orchestrate the activity of T-cells. This thesis, based on four original papers, deals with distinct subtypes of DCs and their role in allergy, as well as mechanisms underlying DC regulation of ongoing allergic responses.
By transcriptional profiling of DC subsets identified in blood and tonsils we demonstrated subset-selective gene expression, including many genes associated with immune responses. In addition, the resemblance between myeloid DC (mDC) subsets in tonsils suggests that they are highly susceptible to microenvironmental factors. Blood DC subsets were further investigated regarding characteristics associated with allergic responses and the data suggest a prominent role of one specific mDC subset in grass pollen allergy. Thus, functional studies of this subset may give important insights into the regulation of allergic responses in humans and identify novel targets for allergy therapy.
In order to understand DC regulation of ongoing allergic responses, we assessed the influence of IgE antibodies as well as histamine and histamine receptor (HR) 1 and 4 on DC function and subsequent T-cell responses. Due to DC scarcity, these extensive functional studies were performed on DCs derived in vitro from monocytes. We demonstrated that HR4, similarly to HR1, mediated histamine-induced DC activation and HR4 on DCs also influenced T-cell activation in response to grass pollen allergen. Thus, HR4 may be involved in the maintenance of allergic responses and is a potential novel target in allergic conditions. Our assessment of DC modulation by IgE antibodies showed that IgE, in contrast to IgG1 and IgG4, augmented DC-induced allergic T-cell responses to grass pollen allergen. Thus, the production of IgE antibodies during allergic responses may result in a positive feedback loop via their influence on DCs.
In conclusion, the work within this thesis has pinpointed subset-specific characteristics within the DC lineage, supporting individual roles in immune responses and further suggests that one specific myeloid DC subset has a prominent role in allergic rhinitis. Furthermore, mechanisms underlying DC-mediated perpetuation of allergic responses were identified. These insights may lead to development of novel allergy therapeutics which targets key mechanisms involved in DC regulation of allergic responses.
By transcriptional profiling of DC subsets identified in blood and tonsils we demonstrated subset-selective gene expression, including many genes associated with immune responses. In addition, the resemblance between myeloid DC (mDC) subsets in tonsils suggests that they are highly susceptible to microenvironmental factors. Blood DC subsets were further investigated regarding characteristics associated with allergic responses and the data suggest a prominent role of one specific mDC subset in grass pollen allergy. Thus, functional studies of this subset may give important insights into the regulation of allergic responses in humans and identify novel targets for allergy therapy.
In order to understand DC regulation of ongoing allergic responses, we assessed the influence of IgE antibodies as well as histamine and histamine receptor (HR) 1 and 4 on DC function and subsequent T-cell responses. Due to DC scarcity, these extensive functional studies were performed on DCs derived in vitro from monocytes. We demonstrated that HR4, similarly to HR1, mediated histamine-induced DC activation and HR4 on DCs also influenced T-cell activation in response to grass pollen allergen. Thus, HR4 may be involved in the maintenance of allergic responses and is a potential novel target in allergic conditions. Our assessment of DC modulation by IgE antibodies showed that IgE, in contrast to IgG1 and IgG4, augmented DC-induced allergic T-cell responses to grass pollen allergen. Thus, the production of IgE antibodies during allergic responses may result in a positive feedback loop via their influence on DCs.
In conclusion, the work within this thesis has pinpointed subset-specific characteristics within the DC lineage, supporting individual roles in immune responses and further suggests that one specific myeloid DC subset has a prominent role in allergic rhinitis. Furthermore, mechanisms underlying DC-mediated perpetuation of allergic responses were identified. These insights may lead to development of novel allergy therapeutics which targets key mechanisms involved in DC regulation of allergic responses.
Department/s
Publishing year
2009
Language
English
Document type
Dissertation
Topic
- Immunology in the medical area
Keywords
- allergy
- Dendritic cells
- histamine
- antibody mediated allergen-presentation
- Dendritic cell subsets
Status
Published
Supervisor
ISBN/ISSN/Other
- ISBN: 978-91-628-7846-7
Defence date
28 August 2009
Defence time
10:15
Defence place
Room Lundmarksalen, Astronomicentrum, Sölvegatan 27, Lund University Faculty of Engineering
Opponent
- Frode Jahnsen (MD PhD)