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Benign Disorders of Leukocytes
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Gene L. Gulati, Zoran Gatalica, Bong H. Hyun
Leukocyte adhesion protein deficiency (LAD) is a rare autosomal recessive disorder of leukocyte adhesion and chemotaxis. Leukocytes from patients with LAD adhere poorly to endothelial cells and exhibit defective margination and chemotaxis, leading to recurrent severe infections. Leukocyte adhesion deficiency 1 (LAD1) is caused by defects in CD18 gene, which codes for the common beta-2 subunit of the leukocyte integrins LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), and pl50,95 (CD11c/CD18). Patients with LAD2 exhibit normal expression of CD18 but lack sialyl Lewis X antigen (selectin ligand) and similarly do not adhere to endothelial cells. Neutrophil adherence and aggregation deficits in general population are most commonly drug induced (glucocorticoids, alcohol, etc.), or acquired (hemodialysis, myelodysplastic syndromes, etc.). Patients with LAD have persistent leukocytosis (15–20 × 109/fL), but the leukocytes appear morphologically normal. The laboratory diagnosis of LAD is generally made by flow cytometric analysis of blood neutrophils using antibodies specific for CD11 or CD18 antigens.
Inflammatory bowel disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Giovanni Monteleone, Markus F. Neurath, Britta Siegmund
The pathophysiology of IBD, especially Crohn's disease, is currently undergoing a significant reassessment, because genetic studies have led to the identification of several susceptibility genes associated with innate immune dysfunction, suggesting that these may be central to disease pathogenesis. Another source of support for this idea comes from clinical observations showing that rare congenital disorders of innate immunity (and, in particular, phagocyte function) can associate with noninfectious bowel inflammation that shows similarities to Crohn's disease, and that some patients with various neutropenias (namely, leukocyte adhesion deficiency-1, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, chronic granulomatous disease, and Chediak-Higashi syndrome) have been reported to develop chronic intestinal inflammation that looks similar to Crohn's disease. These results have been extrapolated to suggest that Crohn's disease is caused by a defect in macrophage function and that adaptive immune responses, as described later, are a secondary event. In reality, the situation is more complex in that there is unlikely to be a single unifying problem with macrophages in Crohn's disease; instead, a combination of subtle effects in innate immunity, differing between individuals, may allow the accumulation of sufficient microbial antigens in the gut wall to trigger T-cell activation. Therefore, although the rare phagocyte defects show that an inability to handle antigens from the gut microflora properly can result in disease that resembles Crohn's disease, it is unlikely that this is the complete story, and it is equally likely that some patients also have altered thresholds of T-cell activation.
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).
Dexmedetomidine modulates mitochondrial dynamics to protect against endotoxin-induced lung injury via the protein kinase C-ɑ/haem oxygenase-1 signalling pathway
Published in Biomarkers, 2022
Kai Song, Jia Shi, Lina Zhan, Qiaoying Gao, Jing Yang, Shuan Dong, Yuan Zhang, Jianbo Yu
It was found that there was an increase of plasma levels of TNF-a, IL-6 and IL-1β in group L, LAD1, LAD2 and LDP when compared with those in group C (p < 0.01 for all), indicating an inducing effect of LPS on lung inflammation. In contrast, administration of DEX reduced these inflammatory cytokine levels under LPS condition (p < 0.01 for all; LAD1 OR LAD2 versus L). However, the anti-inflammatory function of reducing levels of TNF-a, IL-6 and IL-1β was suppressed via PKC-ɑ inhibitor CHE (p < 0.01 for all; LDP versus LAD1 OR LAD2). (Figure 3(A–C))