Leukocyte adhesion deficiency III: a group of integrin activation defects in hematopoietic lineage cells. Curr Opin Allergy Clin Immunol 4:485-490

Meyer Children's Hospital, B. Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Current Opinion in Allergy and Clinical Immunology (Impact Factor: 3.57). 01/2005; 4(6):485-90. DOI: 10.1097/00130832-200412000-00003
Source: PubMed


In the last 2-3 years our understanding of leukocyte adhesion cascades has increased, mainly in defining new pathways by which integrin activation occurs on circulating leukocytes recruited to sites of inflammation. While defects in the integrin structure (leukocyte adhesion deficiency (LAD) I) and in the selectin glycoprotein ligand biosynthesis (LAD II) have been described in the past few decades, a newly recognized defect in the activation of integrins (LAD III) was only recently delineated. The clinical manifestations and molecular basis of this syndrome and related cases will be reviewed.
While in LAD I and II the defect in the adhesion cascade is restricted to leukocytes, all four cases of LAD III described to date also had defects in platelet aggregation. These patients suffered from recurrent bacterial infections and a severe bleeding tendency. All cases were reported to have activation defects in all major integrin subfamily members expressed in circulating leukocytes and platelets. In one case there was a defect in Rap1, which is a crucial protein in the inside-out and outside-in (ligand-induced) signaling underlying integrin activation mainly by cytokines. In this case, both chemokines and cytokines were unable to activate Rap1 leading to severe adhesive defects analyzed in vitro.
While in LAD I and II the primary genetic defect is known, in the newly described LAD III the primary event leading to the defect is still unknown, despite a clear biochemical defect in Rap1 activation. The molecular basis or the defect in integrin activation may be different in the various cases described so far. It seems logical, however, to assume that in all reported cases, a key component of inside-out signaling to integrins activation is involved.

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    • "The inability of neutrophils to enter the circulation is seen in neutropenic patients with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome (Zuelzer, 1964). Moreover, the trapping of neutrophils within the blood stream is a hallmark of leukocyte adhesion deficiency (Etzioni and Alon, 2004) and the failure of neutrophils to undergo oxidative burst is associated with chronic granulomatous disease (Baehner and Nathan, 1967). On the other hand, neutrophilic inflammation must be controlled to prevent non-specific damage to host tissues. "
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    • "Neutrophilia is a hallmark of the normal host response to stress or infection (Summers et al., 2010). Neutrophilia is also seen in Leukocyte Adhesion Deficiency (LAD), a primary immunodeficiency characterized by abnormal neutrophil distribution with increased circulating neutrophils and absent recruitment to tissues or infection (Etzioni and Alon, 2004). There are different types of LAD, according to the underlying genetic deficiency. "
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