Defect of cellular adhesion molecules resulting in clinical syndromes. It is a combined (B cell) and cellular (T cell) immunodeficiency disorder.
Autosomal recessive
(2020) Inherited Innate Immunodeficiencies (Immunology) Flashcards | Memorang. Retrieved February 07, 2020, from https://www.memorangapp.com/flashcards/29949/Inherited+Innate+Immunodeficiencies/
Classification
Classified as defects in adhesion-dependent functions of myeloid phagocytes (principally polymorphonuclear leukocytes (PMNs; neutrophils) and monocytes):
LAD-I (M/C):
Failure to express CD18 (integrin subunit) → adhesion
LAD-II (rare)
Absence of Sialyl-Lewis X → rolling
LAD-III:
Defect in beta integrins 1, 2, and 3
The LAD syndromes are caused by molecular defects in integrin expression, fucosylation of selectin ligands, or inside-out signaling (‘activation’) of integrins on leukocytes and platelets. The adhesive phenotypes of PMNs from healthy individuals and patients with LAD syndromes, the corresponding functional defects in leukocyte interactions with endothelium, and known mutated genes are shown. In LAD-III, platelet integrin signaling is also defective. In addition to PMNs, monocytes, other myeloid leukocytes, and lymphocytes also basally express integrins and selectin ligands; the patterns of adhesion molecules on human leukocyte subsets are different but overlapping. Similarly, mouse leukocytes display integrins and selectin ligands, and mouse platelets express integrin αIIbβ3 and other integrins. There are murine models of each LAD syndrome. See text for details. Diagnosis of the LAD syndromes is commonly made based on the clinical presentation, PMN phenotype [surface expression of β2 integrins and sialyl Lewis X (sLex), a fucosylated oligosaccharide present on P-selectin glycoprotein 1 and other selectin ligands], and functional analysis of leukocytes and platelets. | LAD, leukocyte adhesion deficiency; PMN, polymorphonuclear leukocyte. | Harris, E. S., Weyrich, A. S., & Zimmerman, G. A. (2013). Lessons from rare maladies: leukocyte adhesion deficiency syndromes. Current Opinion in Hematology, 20(1), 16–25. https://doi.org/10.1097/MOH.0b013e32835a0091
Pathophysiology
The leukocyte adhesion cascade: traditional and new features. PMN interactions are used here to illustrate the leukocyte adhesion cascade; specific molecular interactions vary between leukocytes of different types in leukocyte–endothelial interactions. Early studies established the concept of a cascade of PMN tethering and rolling involving selectins and selectin ligands (1), leukocyte activation and inside-out signaling of β2 integrins (2), tight adhesion and arrest resistant to shear (3), and emigration of adherent leukocytes across the endothelium in response to inflammatory signals. In-vivo experiments complemented in-vitro models and confirmed that similar events occur in postcapillary venules and other vessels. Studies of PMNs from patients and animal models indicate that there is defective rolling in LAD-II (step 1), defective integrin activation and consequent tight adhesion in LAD-III (step 2), and defective tight adhesion in LAD-I (step 3). Each defect impairs the ability of PMNs to transmigrate to sites of extravascular infection or injury (step 4). More recent studies, many involving genetically altered mice, have refined the cascade paradigm, and added nuances to the stepwise events illustrated here. For example, β2 integrins, particularly αLβ2, mediate early slow rolling of PMNs, in addition to later tight adhesion and arrest. Furthermore, there is evidence that engagement of PSGL-1 on PMNs can trigger inside-out signaling of β2 integrins; thus, this is a second mechanism for β2 integrin activation in addition to localized signaling of PMNs by endothelial presentation of activating agonists recognized by G-protein-coupled receptors. This was first indicated by potentiation of β2 integrin activation triggered via G-protein-coupled receptors when selectin ligands on human PMNs were engaged by purified P-selectin and more recently supported by studies in murine models of inflammation. Additional recent experiments demonstrate that PMN rolling on P-selectin or E-selectin can partially activate αLβ2 by engaging PSGL-1. Another new feature of the adhesion cascade is evidence for intraluminal crawling of monocytes and PMNs mediated by binding of αMβ2 to ICAM-1, occuring after rolling and arrest and prior to emigration. Intraluminal gradients of chemokines may form, contributing to differential activation of β2 integrins on PMNs. New facets of extravasation of PMNs and transmigration through subendothelial matrix mediated by β1 and β2 integrins have been identified. Although it is not known that all of these newly identified events occur in the targeting and emigration of human PMNs in clinical infection and inflammation, it is clear that there are intricate features of adhesive interactions mediated by selectin ligands and integrins on PMNs that may be disrupted in a complex fashion in LAD syndromes. The adhesion and signaling paradigms for monocytes and other leukocytes are also likely to be further refined. LAD, leukocyte adhesion deficiency; PMN, polymorphonuclear leukocyte; PSGL-1, P-selectin glycoprotein 1. | Harris, E. S., Weyrich, A. S., & Zimmerman, G. A. (2013). Lessons from rare maladies: leukocyte adhesion deficiency syndromes. Current Opinion in Hematology, 20(1), 16–25. https://doi.org/10.1097/MOH.0b013e32835a0091
