Leukocyte adhesion deficiency

From Dog
Clinical manifestations of leukocyte adhesion deficiency, showing craniomandibular osteopathy[1]

Canine leukocyte adhesion deficiency (CLAD) is an autosomal-recessive genetic disease of dogs characterized by leucopenia.

This immunodeficiency disease has been reported in the Doberman[2], Irish Setter and Irish Red and White Setter, where carrier rates up to 12% have been reported[3].

CLAD is caused by mutations in the leukocyte integrin ITGB2 gene also known as CD18. Failure to express the CD11-CD18 adhesion complex on the leukocyte cell surface prevents adhesion to the vascular endothelium and migration to sites of infection, resulting in life-threatening infectious complications[4].

Heterozygous carriers are usually unaffected but homozygous CLAD dogs invariably die prematurely from various infections[5] due to rapidly diminishing populations of circulating leucocytes[6].

Concurrent craniomandibular osteopathy and hypertrophic osteodystrophy have also been reported with this condition[1].

Hematological analysis of blood samples usually reveals varying degrees of lymphopenia and neutropenia.

Diagnosis is based on molecular testing by PCR-based DNA assays[7].

A differential diagnosis would include toxins, aplastic pancytopenia, immune-mediated thrombocytopenia and myelosuppression due to lymphoma.

This disease has been successfully treated using reduced intensity allogeneic bone marrow transplantation from normal matched littermates[8] and use of hematopoietic stem cell gene therapy with CD18 cDNA[9].

References

  1. 1.0 1.1 Sokolic RA et al (2005) Nonmyeloablative conditioning with busulfan before matched littermate bone marrow transplantation results in reversal of the disease phenotype in canine leukocyte adhesion deficiency. Biol Blood Marrow Transplant 11(10):755-763
  2. Breitschwerdt EB et al (1987) Rhinitis, pneumonia, and defective neutrophil function in the Doberman pinscher. Am J Vet Res 48(7):1054-1062
  3. Foureman P et al (2002) Canine leukocyte adhesion deficiency: presence of the Cys36Ser beta-2 integrin mutation in an affected US Irish Setter cross-breed dog and in US Irish Red and White Setters. J Vet Intern Med 16(5):518-523
  4. Anderson DC & Smith CW (2001) Leukocyte adhesion deficiencies. In: Scriver CR, Beaudet AL, Sly WS, V D, editors. The metabolic and molecular bases of inherited disease. McGraw-Hill; New York, NY. pp:4829–4856
  5. Bauer TR et al (2011) Treatment of canine leukocyte adhesion deficiency by foamy virus vectors expressing CD18 from a PGK promoter. Gene Ther 18(6):553-559
  6. Donahue RE et al (2011) Leukocyte integrin activation mediates transient neutropenia after G-CSF administration. Blood 118(15):4209-4214
  7. Gu YC et al (2004) The genetic immunodeficiency disease, leukocyte adhesion deficiency, in humans, dogs, cattle, and mice. Comp Med 54(4):363-372
  8. Bauer TR et al (2005) Nonmyeloablative hematopoietic stem cell transplantation corrects the disease phenotype in the canine model of leukocyte adhesion deficiency. Exp Hematol 33(6):706–712
  9. Bauer TR et al (2008) Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors. Nat Med 14(1):93–97