Thomas R Bauer1, Suzanne M Pratt2, Christina M Palena3, Karthik Raj4, Urs Giger4. 1. Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 2. Antech Diagnostics, Portland, OR, USA. 3. Mountain View Veterinary Hospital, Vancouver, WA, USA. 4. Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abstract
BACKGROUND: Leukocyte adhesion deficiency (LAD) or CD18 deficiency is an autosomal recessive immunodeficiency which has been described in people, cattle, dogs, and knockout mice. OBJECTIVES: The study goals were to characterize the clinicopathologic, immunologic, and molecular genetic features of feline LAD (FLAD) in a neutered male adult Domestic Longhair cat with severe leukocytosis and recurrent infections. METHODS: Flow cytometry evaluated surface expression of CD18 on neutrophils. In vitro functional assays assessed CD18-dependent neutrophil adhesion and T-cell proliferation. Genomic DNA and cDNA were used to identify a causative mutation in the coding sequence of the integrin β2 subunit (ITGB2) gene. RESULTS: The affected cat developed periodontitis during the first months of life followed by recurrent infections poorly responsive to antibiotic therapy, accompanied by extreme neutrophilia. Neutrophils from the proband, compared to feline controls, did not express any CD18 on the cell surface. Adhesion of affected neutrophils was severely impaired with and without phorbol-myristate-acetate activation. The proband's T-cells proliferated weakly to 1 pg but normally to 100 pg staphylococcal enterotoxin A, suggesting a CD18-independent T-cell response at higher doses. Molecular genetic analysis of the ITGB2 gene revealed a 24 bp deletion at the exon 2 to intron 2 boundary (c.46_58 + 11del), predicting premature translational termination due to abnormal splicing of exon 1 to exon 3 or 4. CONCLUSIONS: Feline LAD exhibits features similar to LAD in other species. However, clinical episodes in FLAD appeared milder allowing for an extended life expectancy under long-term antimicrobial therapy, possibly due to an alternative, CD18-independent T-cell proliferation pathway.
BACKGROUND:Leukocyte adhesion deficiency (LAD) or CD18 deficiency is an autosomal recessive immunodeficiency which has been described in people, cattle, dogs, and knockout mice. OBJECTIVES: The study goals were to characterize the clinicopathologic, immunologic, and molecular genetic features of feline LAD (FLAD) in a neutered male adult Domestic Longhair cat with severe leukocytosis and recurrent infections. METHODS: Flow cytometry evaluated surface expression of CD18 on neutrophils. In vitro functional assays assessed CD18-dependent neutrophil adhesion and T-cell proliferation. Genomic DNA and cDNA were used to identify a causative mutation in the coding sequence of the integrin β2 subunit (ITGB2) gene. RESULTS: The affected cat developed periodontitis during the first months of life followed by recurrent infections poorly responsive to antibiotic therapy, accompanied by extreme neutrophilia. Neutrophils from the proband, compared to feline controls, did not express any CD18 on the cell surface. Adhesion of affected neutrophils was severely impaired with and without phorbol-myristate-acetate activation. The proband's T-cells proliferated weakly to 1 pg but normally to 100 pg staphylococcal enterotoxin A, suggesting a CD18-independent T-cell response at higher doses. Molecular genetic analysis of the ITGB2 gene revealed a 24 bp deletion at the exon 2 to intron 2 boundary (c.46_58 + 11del), predicting premature translational termination due to abnormal splicing of exon 1 to exon 3 or 4. CONCLUSIONS: Feline LAD exhibits features similar to LAD in other species. However, clinical episodes in FLAD appeared milder allowing for an extended life expectancy under long-term antimicrobial therapy, possibly due to an alternative, CD18-independent T-cell proliferation pathway.
Authors: Dirk Roos; Christof Meischl; Martin de Boer; Suat Simsek; Ron S Weening; Ozden Sanal; Ilhan Tezcan; Tayfun Güngör; S K Alex Law Journal: Exp Hematol Date: 2002-03 Impact factor: 3.084
Authors: J M Kijas; T R Bauer; S Gäfvert; S Marklund; G Trowald-Wigh; A Johannisson; A Hedhammar; M Binns; R K Juneja; D D Hickstein; L Andersson Journal: Genomics Date: 1999-10-01 Impact factor: 5.736
Authors: Waseem Qasim; Marina Cavazzana-Calvo; E Graham Davies; Jeffery Davis; Michel Duval; Gretchen Eames; Nuno Farinha; Alexandra Filopovich; Alain Fischer; Wilhelm Friedrich; Andrew Gennery; Carsten Heilmann; Paul Landais; Mitchell Horwitz; Fulvio Porta; Petr Sedlacek; Reinhard Seger; Mary Slatter; Mary Slatten; Lochie Teague; Mary Eapen; Paul Veys Journal: Pediatrics Date: 2009-03 Impact factor: 7.124