Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.

Autor: Dang TS; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Willet JD; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Griffin HR; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK., Morgan NV; School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK., O'Boyle G; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Arkwright PD; Department of Paediatric Allergy & Immunology, Royal Manchester Children's Hospital, University of Manchester, Manchester, UK., Hughes SM; Department of Paediatric Allergy & Immunology, Royal Manchester Children's Hospital, University of Manchester, Manchester, UK., Abinun M; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Tee LJ; School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK., Barge D; Blood Sciences Flow Cytometry Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Engelhardt KR; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Jackson M; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Cant AJ; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Maher ER; School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.; Department of Medical Genetics, University of Cambridge, Cambridge, UK., Koref MS; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK., Reynard LN; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Ali S; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK., Hambleton S; Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. sophie.hambleton@newcastle.ac.uk.; Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. sophie.hambleton@newcastle.ac.uk.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2016 Feb; Vol. 36 (2), pp. 117-22. Date of Electronic Publication: 2016 Jan 22.
DOI: 10.1007/s10875-016-0232-2
Abstrakt: Purpose: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency.
Methods: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting.
Results: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding.
Conclusion: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.
Databáze: MEDLINE
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