Leukocyte Adhesion Deficiency-III in an African-American Patient
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia 30322, USA. Pediatric Blood & Cancer
(Impact Factor: 2.39).
07/2010; 55(1):180-2. DOI: 10.1002/pbc.22386
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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Available from: Markus Sperandio
- "The reason why some patients reveal an osteopetrosis and others do not is not yet elucidated. However, allogeneic bone marrow transfer abrogated the bone defects (Sabnis et al., 2010; McDowall et al., 2010; Malinin et al., 2009). So far, the only curative treatment of LAD-III patients is allogeneic hematopoietic stem cell transplantation, which has been successfully performed in several patients alleviating all major symptoms. "
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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 · 2.97 Impact Factor
Available from: Michael W. Hess
- "Several LAD-III patients have displayed increased bone mineral density (Kilic and Etzioni, 2009; Malinin et al., 2009; McDowall et al., 2010; Sabnis et al., 2010), which points to the possibility that kindlin-3 plays a role in bone homeostasis. "
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ABSTRACT: The blood cell-specific kindlin-3 protein is required to activate leukocyte and platelet integrins. In line with this function, mutations in the KINDLIN-3 gene in man cause immunodeficiency and severe bleeding. Some patients also suffer from osteopetrosis, but the underlying mechanism leading to abnormal bone turnover is unknown. Here we show that kindlin-3-deficient mice develop severe osteopetrosis because of profound adhesion and spreading defects in bone-resorbing osteoclasts. Mechanistically, loss of kindlin-3 impairs the activation of β1, β2, and β3 integrin classes expressed on osteoclasts, which in turn abrogates the formation of podosomes and sealing zones required for bone resorption. In agreement with these findings, genetic ablation of all integrin classes abolishes the development of podosomes, mimicking kindlin-3 deficiency. Although loss of single integrin classes gives rise to podosomes, their resorptive activity is impaired. These findings show that osteoclasts require their entire integrin repertoire to be regulated by kindlin-3 to orchestrate bone homeostasis.
The Journal of Cell Biology 02/2011; 192(5):883-97. DOI:10.1083/jcb.201007141 · 9.83 Impact Factor
Available from: Gerben Bouma
- "Restoring Kindlin - 3 protein expression in affected cells of patients with LAD - III restored integrin - mediated adhesion and migration defects , directly implicating Kindlin - 3 mutations in this disease ( Svensson et al , 2009 ) . Bone marrow transplantation ( BMT ) can be curative in LAD - III although it remains to be clarified whether engraft - ment failure and post BMT mortality are specifically prob - lematic ( Kuijpers et al , 2009 ; Elhasid et al , 2010 ; Jurk et al , 2010 ; Sabnis et al , 2010 ) . "
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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 · 4.71 Impact Factor
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