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Blood, 1 January 2008, Vol. 111, No. 1, pp. 209-218.
Prepublished online as a Blood First Edition Paper on September 17, 2007; DOI 10.1182/blood-2007-04-082552.
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Submitted April 3, 2007
Accepted August 21, 2007
Reversion mutations in patients with leukocyte adhesion deficiency type I (LAD-I)
Gulbu Uzel, Emilia Tng, Sergio D Rosenzweig, Amy P Hsu, Jacqueline M Shaw, Mitchell E Horwitz, Gilda F Linton, Stacie M Anderson, Martha R Kirby, Jao B Oliveira, Margaret R Brown, Thomas A Fleisher, S.K. Alex Law, and Steven M Holland*
Laboratory Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, United States
MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Servicio de Inmunologia, Hospital Nacional de Pediatria J. P. Garrahan, Buenos Aires, Argentina
Department Of Medicine, Duke University Medical Center, Durham, NC, United States
Laboratory of Host Defenses, NIAID, NIH, Bethesda, MD, United States
Genetics and Molecular Biology Branch, NHGRI, NIH, Bethesda, MD, United States
Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, United States
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
* Corresponding author; email: sholland{at}niaid.nih.gov.
Leukocyte adhesion deficiency type-I (LAD-I) is an autosomal recessive immunodeficiency caused by mutations in the  2 integrin, CD18, which 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 three 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 three 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 (CTL) 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.
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