Leukocyte Adhesion Deficiency-III in an African-American Patient
ABSTRACT Leukocyte adhesion deficiency-III (LAD-III) is a rare disorder characterized by abnormal signaling to beta integrins, leading to defective leukocyte adhesion and chemotaxis and platelet aggregation. Here we present the first case of an African-American female infant with this disorder. She had history of multiple infections, bleeding, and leukocytosis since birth. She was successfully treated with allogeneic bone marrow transplant using a reduced intensity-conditioning regimen. Mutations in KINDLIN-3 have been described in LAD-III but the mutations in KINDLIN-3 in her case are unique.
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ABSTRACT: The innate immune system responds to inflammation, infection and injury by recruiting neutrophils and other leukocytes. These cells are able to leave the intravascular compartment in a process called leukocyte recruitment. This process involves several distinct steps: selectin-mediated rolling, firm adhesion via integrins, postarrest modifications including adhesion strengthening and leukocyte crawling and finally transmigration into tissue. Genetic defects affecting the different steps of the cascade can result in severe impairment in leukocyte recruitment. So far, three leukocyte adhesion deficiencies (LAD I-III) have been described in humans. These LADs are rare autosomal recessive inherited disorders and, although clinically distinct, exhibit several common features including recurrent bacterial infections and leukocytosis. In LAD-I, mutations within the β2-integrin gene result in a severe defect in β2 integrin-mediated firm leukocyte adhesion. Defects in the posttranslational fucosylation of selectin ligands dramatically reduce leukocyte rolling and lead to LAD-II. Finally, LAD-III, also known as LAD-I variant, is caused by impaired integrin activation due to mutations within the kindlin-3 gene. This review provides an overview on the molecular basis of leukocyte adhesion and its deficiencies.Molecular Immunology 12/2012; 55(1). DOI:10.1016/j.molimm.2012.11.006 · 3.00 Impact Factor
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ABSTRACT: Neutrophils are amongst the first immune cells to arrive at sites of infection and play an important role as the host's first line of defence against invading pathogens. Defects of neutrophil number or function are usually recognized clinically by recurrent infections that often are life-threatening. Over the last few years, a number of genetic mutations have been discovered to be the basis for congenital neutropenia, adding to our understanding of the molecular basis of these diseases. While many genetic mutations that cause severe congenital neutropenia result in a differentiation block at the promyelocyte stage, defects of neutrophil function are more heterogeneous on clinical, genetic and mechanistic levels. In this review we discuss recent advances in our understanding of the genetic and molecular basis of human neutrophil disorders.British Journal of Haematology 11/2010; 151(4):312-26. DOI:10.1111/j.1365-2141.2010.08361.x · 4.96 Impact Factor
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ABSTRACT: Disabling mutations in integrin-mediated cell signaling have been a major focus of interest over the last decade for patients affected with leukocyte adhesion deficiency-III (LAD-III). In this study, we identified a new C>T point mutation in exon 13 in the FERMT3 gene in an infant diagnosed with LAD-III and showed that KINDLIN-3 expression is required for platelet aggregation and leukocyte function, but also osteoclast-mediated bone resorption. After allogeneic bone marrow transplant, all overt symptoms disappeared. This newly identified mutation along with its novel role in dysregulation of bone homeostasis extends our understanding of KINDLIN-3 in humans. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.Pediatric Blood & Cancer 04/2015; DOI:10.1002/pbc.25537 · 2.56 Impact Factor