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Overview of Cell Adhesion Molecules and Their Antagonism
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
A relevant consideration in antiadhesion therapy is the potential for adverse effects, particularly increased susceptibility to infection. This is supported by two human immunodeficiencies, leukocyte adhesion deficiency (LAD) types 1 and 2, that are characterized, respectively, by deficiencies of CD11/CD18 and selectin ligand. Moreover, in some animal studies, an increased proclivity for infection has been noted as a sequela of antiadhesion therapy (50). The risk of infection may be affected by the choice of target. For example, it might be expected that targeting ICAM-1, which is up-regulated at inflammatory sites in comparison to normal tissue, might be less immunosuppressive than targeting CD18, which is present on all leukocytes. Support for this comes from knockout animals, where it has been shown that ICAM-1 deficient mice do not appear excessively susceptible to infection. Similarly, targeting VLA-4, which is expressed on all leukocytes with the exception of neutrophils, might conceivably engender less global immune suppression by leaving neutrophil function intact. Nevertheless, heightened vigilance for sequelae of immunosuppression is required for all studies using antiadhesion therapies.
Host Defense I: Non-specific Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
The last group of adhesion molecules is the selectin family (LEC-CAMs). These molecules resemble lectins and bind to carbohydrate ligands. Most of these are important in lymphocyte homing to various tissues and are also known as addressins. L-selectin(CD62L, also called LAM-1), is expressed on T and B cells, NK cells, neutrophils, and monocyte derivatives. On the lymphocyte surface LAM-1 directs cells to HEV of peripheral lymph nodes. P-selectin (CD62P) is a component of platelet and endothelial cell granules and mediates adhesion to neutrophils and monocytes. The carbohydrate CD 15 (Lewisx) expressed on granulocytes is a ligand for CD62P. IL-1 induces endothelial cells to express E-selectin (CD62E, ELAM-1) which binds to the carbohydrate CD15s (sialyl-Lewisx) on granulocyte membranes. Recently, a small group of patients with recurrent bacterial infections were found to have a deficiency of a fucosyltransferase enzyme which is required to generate the sialyl-Lewis X determinant. This has been called leukocyte adhesion deficiency type 2.
Gene Transfer into Human Hematopoietic Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Serguei Kisselev, Tatiana Seregina, Richard K. Burt, Charles J. Link
Leukocyte adhesion deficiency (LAD) is an autosomal recessive disease.122 LAD is due to a defect of the integrin CD 18.123 The defect of leukocyte integrin CD 18 prevents the CD 11 /CD 18 heterodimer formation and blocks migration of leukocytes into the sites of primary infection in patients with LAD.119 Pre-clinical studies indicated that the structural and functional defect in LAD leukocytes could be corrected by CD 18 subunit gene transfer into mobilized CD34+ HSC from the peripheral blood of patients with LAD.118
Treatment challenges and delivery systems in immunomodulation and probiotic therapies for periodontitis
Published in Expert Opinion on Drug Delivery, 2021
Anže Zidar, Julijana Kristl, Petra Kocbek, Špela Zupančič
Cytokines are a very important part of the complex immune communication and thus have a particularly important role in periodontitis pathology, which makes them an attractive target for medical intervention. These potential targets for therapy of periodontal disease include IL-1, IL-17, and tumor necrosis factor (TNF)-α [65]. However, inhibition of a single cytokine has only limited efficacy due to redundant signaling pathways in periodontal inflammation. An example of an effective treatment is subcutaneous injection of the IL-12 and IL-23–neutralizing monoclonal antibody ustekinumab, which significantly improves oral inflammation and healing in patients with leukocyte adhesion deficiency type 1 [66]. On the other hand anti-cytokine therapies can have serious adverse effects on the host immune system, although when applied locally, fewer systemic effects are expected [12,65].
Gene therapy for primary immunodeficiencies: up-to-date
Published in Expert Opinion on Biological Therapy, 2021
Leukocyte Adhesion Deficiency 1 (LAD-1) is an autosomal recessive disorder of impaired neutrophil migration to sites of infection, resulting in severe, recurrent bacterial infections. Pathogenic variants in the ITGB2 gene lead to defective membrane expression of the CD18 integrin subunit on leukocytes, crucial for neutrophil migration. Without curative allogeneic HSCT, children do not survive beyond infancy. Early trials using a γRV vector in two patients without pre-conditioning led to poor outcomes, with no gene marked cells detectable peripherally after two months [74]. Subsequent pre-clinical work undertaken in murine and canine models has been successful, leading to in-human trials using busulfan conditioning for patients without access to an HLA-identical sibling donor [75,76] (NCT03825783, NCT03812263).
Neutrophil phenotypes in chronic lung disease
Published in Expert Review of Respiratory Medicine, 2019
Michael J. Hughes, Elizabeth Sapey, Robert Stockley
A different neutrophil phenotype occurs in leukocyte adhesion deficiency (LAD), where leucocytes lack surface expression or functional expression of the key integrin adhesion molecules CD11 and CD18, inhibiting adhesion to endothelium or insoluble proteins such as fibrinogen [72,73]. Poor neutrophil transmigration gives rise to skin ulcerations without neutrophilic infiltrate despite neutrophil release from the bone marrow in response to infection [72]. LAD type III describes a variant where integrin expression is present, but activation (necessary for adhesion) is dysregulated. Interestingly, the use of a non-phycological reducing agent (dithiothreitol) that forces an activated conformation of integrins on the surface of neutrophils demonstrated normalized adhesion. Physiological activation with formyl-methionyl-leucyl-phenylalanine (fMLP), a bacterial product, also demonstrated normalized adhesion, but significant differences remained when stimulated with LPS [74]. These observations suggest that cell migration into the tissues might be influenced by subtle changes in CD11/18 expression, upregulation and integrin activation, which could lead to an inappropriately high influx of neutrophils and subsequently increased tissue damage. In keeping with this, in COPD, peripheral blood neutrophils have been shown to display increased levels of CD11b on the cell surface, potentially enhancing trans-endothelial migration [75].