Immunological aspects of immunodeficiency diseases part 66

DEFECTS IN LEUCOCYTE MIGRATION

To reach the sites of inflammation, neutrophils need to migrate across the endothelium into sites of inflammation. For this process to be initiated, sialyl Lewis, which is expressed on the surface of lecocytes, needs to interact with E selectin, which is expressed on the luminal surface of the endothelial cells. Leucocytes, which are transiently arrested by the previous interaction, need to bind tightly to the endothelial surface by a second set of interaction. This is between the protein lymphocyte function-associated antigen-1(LFA-1)LFA-1 expressed on the leucocyte surface and its ligand intercelluler adhesion molecule 1 expressed on the luminal surface of activated endothelial cells. Leucocyte emigration into the tissues follows these adhesion events. LFA-1 is one of a set of three cell surface heterodimers composed of a common β chain (CD18) with three separate α chains called CD11a, b and c. CD18-CD11a heterodimers form LFA-1, CD18/CD11b heterodimers form complement receptor 3, and CD18 combined to CD11c forms complement receptor 4. LFA-1 is required for leucocyte adhesion to endothelial cells while CR3 and CR4 act as receptors for activated complement, aiding ingestion of opsonized microorganisms. Mutation of the gene encoding CD18 (resulting in the lack of expression of LFA-1, CR3 and CR4) results in an inherited primary immunodeficiency called leucocyte adhesin deficiency type 1 (LAF1). Mutations of the enzyme GDP-fucosyl transferase prevents post transcriptional fucocylation of proteins. Such individuals cannot synthesize sialyl Lewis. This condition is called  lecocyte adhesion deficiency type 2. Leucocytes of the patient with LAD1 and 2 exhibit impaired ability to adhere to endothelial walls and therefore cannot migrate into infected sites.