Year: 2014
Type: dissertation
Abstract: The adhesion molecules of blood cells are of great importance in the regulation of many of the most central processes of the human body, e.g. haematopoiesis, immune functions, haemostasis and wound healing, and the delivery of oxygen to the tissues. Leukocyte β2 integrins, VLA-4 integrin and members of the immunoglobulin superfamily like ICAMs (intercellular adhesion molecules) and VCAM (vascular cell adhesion molecule) are the most essential adhesion molecules of blood cells. The adhesion molecules on blood cells have many requirements that they need to fulfil in order to maintain a physiological system: they need to stay in an inactive, non-binding state for most of the time, and to be activated and thus become adhesive only when needed. In addition, they should specifically recognise their binding partners or ligands, as unnecessary binding could lead for example to clogging of the blood vessels, autoimmune diseases or allergic reactions. Still one important feature of blood cell adhesion is the ability to let go and release the adhesion, when the cell needs to move forward or continue patrolling the circulation. In my thesis work I have analysed the properties of leukocyte integrins and their ligands as well as the regulation of their interactions. We observed that the red cell adhesion molecule ICAM-4 can bind to CR4, a leukocyte integrin expressed on monocytes and macrophages, and that the I domain is the ICAM-4 binding site on leukocyte integrins (LFA-1, Mac-1 and CR4). We also characterised the phosphorylation of the cytoplasmic tail of CR4, and found that αX chain is phosphorylated on Ser1158, and that this phosphorylation is essential for CR4 inside-out activation, adhesion and phagocytosis but not for outside-in signaling initiated by CR4. Finally we analysed the regulation of VLA-4 mediated adhesion to VCAM-1 that is controlled by the β2 integrins. The findings of my studies show how leukocyte integrins are involved in numerous blood cell functions and that their functions are tightly regulated. Due to their multifold roles, they also offer attractive targets for therapeutic use. The specificity of phosphorylations or ligands may serve as distinctive factors between different integrins, even members of the same family.
Source: Työväentutkimus Vuosikirja
Author: Liisa M. Uotila
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Helsingin Yliopisto
OpenAlex ID: W2144789082