Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1).
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.
Uzel
Gulbu
G
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
Tng
Emilia
E
Rosenzweig
Sergio D
SD
Hsu
Amy P
AP
Shaw
Jacqueline M
JM
Horwitz
Mitchell E
ME
Linton
Gilda F
GF
Anderson
Stacie M
SM
Kirby
Martha R
MR
Oliveira
Jaõ B
JB
Brown
Margaret R
MR
Fleisher
Thomas A
TA
Law
S K Alex
SK
Holland
Steven M
SM
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*
D018821:CD18 Antigens; D016827:CD8 Antigens; D039001:Integrin alpha Chains; D018089:Superantigens