The adhesion receptors known as integrins perform key functions for hematopoietic cells. The platelet integrin αIIbβ3 is critical in hemostasis, and the β1 and β2 integrins on leukocytes have many roles in cell-mediated immunity. Mutations in the β2 subunit lead to integrin nonexpression and to an immune deficiency, leukocyte adhesion deficiency-1. Mutations in either the α or β subunit of αIIbβ3 usually lead to integrin nonexpression and a bleeding tendency termed Glanzmann thrombasthenia. Here we describe a unique patient with clinical features of both Glanzmann thrombasthenia and leukocyte adhesion deficiency-1. The patient has normal expression of β1, β2, and β3 integrins, but all are dysfunctional. The key findings are that “inside-out” signaling pathways leading to integrin activation are defective and that this is associated with abnormal integrin clustering. The integrins themselves are intact and capable of function following extracellular stimulation. T cell motility is normal, as are the expression levels and electrophoretic characteristics of all cytoskeletal and signaling proteins tested, except PKC-α, which has enhanced expression in the patient’s cells. To our knowledge, this is the first description of a dysfunction affecting three classes of integrins. We propose that it is caused by a lesion in an intracellular factor or signaling pathway essential for integrin activation in hematopoietic cells and results in lack of regulation of clustering, an essential component of integrin-mediated adhesion.
Alison McDowall, David Inwald, Birgit Leitinger, Alison Jones, Ri Liesner, Nigel Klein, Nancy Hogg