title: Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1).
abstract: Leukocyte adhesion deficiency type-1 (LAD-1) is an autosomal recessive immunodeficiency caused by mutations in the beta2 integrin, CD18, that impair CD11/CD18 heterodimer surface expression and/or function. Absence of functional CD11/CD18 integrins on leukocytes, particularly neutrophils, leads to their incapacity to adhere to the endothelium and migrate to sites of infection. We studied 3 LAD-1 patients with markedly diminished neutrophil CD18 expression, each of whom had a small population of lymphocytes with normal CD18 expression (CD18(+)). These CD18(+) lymphocytes were predominantly cytotoxic T cells, with a memory/effector phenotype. Microsatellite analyses proved patient origin of these cells. Sequencing of T-cell subsets showed that in each patient one CD18 allele had undergone further mutation. Interestingly, all 3 patients were young adults with inflammatory bowel disease. Somatic reversions of inherited mutations in primary T-cell immunodeficiencies are typically associated with milder clinical phenotypes. We hypothesize that these somatic revertant CD18(+) cytotoxic T lymphocytes (CTLs) may have altered immune regulation. The discovery of 3 cases of reversion mutations in LAD-1 at one center suggests that this may be a relatively common event in this rare disease.
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. guzel@mail.nih.gov
authors: Gulbu
authors: G
authors: Uzel
authors: Emilia
authors: E
authors: Tng
authors: Sergio D
authors: SD
authors: Rosenzweig
authors: Amy P
authors: AP
authors: Hsu
authors: Jacqueline M
authors: JM
authors: Shaw
authors: Mitchell E
authors: ME
authors: Horwitz
authors: Gilda F
authors: GF
authors: Linton
authors: Stacie M
authors: SM
authors: Anderson
authors: Martha R
authors: MR
authors: Kirby
authors: Jaõ B
authors: JB
authors: Oliveira
authors: Margaret R
authors: MR
authors: Brown
authors: Thomas A
authors: TA
authors: Fleisher
authors: S K Alex
authors: SK
authors: Law
authors: Steven M
authors: SM
authors: Holland
mesh_terms: D000328:Adult; D018821:CD18 Antigens / Q000235:genetics*; D016827:CD8 Antigens / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D016130:Immunophenotyping; D039001:Integrin alpha Chains / Q000235:genetics; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics* / Q000276:immunology*; D008297:Male; D009030:Mosaicism; D009154:Mutation; D009503:Neutropenia / Q000235:genetics; D018089:Superantigens / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*
chemical_list: D018821:CD18 Antigens; D016827:CD8 Antigens; D039001:Integrin alpha Chains; D018089:Superantigens