A novel form of integrin dysfunction involving β1, β2, and β3 integrins
Alison McDowall, … , Nigel Klein, Nancy Hogg
Alison McDowall, … , Nigel Klein, Nancy Hogg
Published January 1, 2003
Citation Information: J Clin Invest. 2003;111(1):51-60. https://doi.org/10.1172/JCI14076.
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Article Vascular biology

A novel form of integrin dysfunction involving β1, β2, and β3 integrins

Abstract

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.

Authors

Alison McDowall, David Inwald, Birgit Leitinger, Alison Jones, Ri Liesner, Nigel Klein, Nancy Hogg

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Figure 7

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Comparison of the affinity and avidity state of integrins. (a) Control (...
Comparison of the affinity and avidity state of integrins. (a) Control (black line) and patient (gray region) T cells incubated with mAbs 24 (β2 integrin activation reporter) or HUTS 21 (β1 integrin activation reporter) at 25 μg/ml, or ICAM-1Fc (300 μg/ml) or VCAM-1Fc (2 μg/ml) for 20 minutes at 37°C in the presence of 0.5 mM MnCl2; control (dotted line) and patient (dashed line) T cells incubated with mAbs or soluble ligand as above for 20 minutes at 4°C in the presence of 1 mM EDTA. Data are from one representative experiment (n = 3). (b) T cells were either unstimulated or treated with 5 mM Mg2+/1 mM EGTA, 50 nM PdBu, or 5 μM thapsigargin then labeled with LFA-1 mAb G25.2 and analyzed by confocal microscopy. A false color scheme is employed, which depicts the intensity of the fluorescent signal from blue (low) to yellow (high) (2). One optical section is shown at midheight of the cells. Data are representative of four experiments. The total fluorescent signal was quantified and averaged over four experiments as follows: no treatment, control 61.5 ± 5.0, patient 98.8 ± 4.9; Mg2+/EGTA, control 59.5 ± 3.5, patient 105.5 ± 6.8; PdBu, control 78.8 ± 2.9, patient 101.0 ± 1.8; thapsigargin, control 81.0 ± 3.4, patient 96.5 ± 6.6.