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Also known as: '''''CLAD — Canine Granulocytopathy Syndrome

| Also known as:

|'''CLAD'''<br>

'''Canine Granulocytopathy Syndrome'''

==Description==

==Introduction==

Leucocyte adhesion deficiency (LAD) is caused by a defect in a surface molecule expressed by neutrophils which usually allows this type of cell to attach to vessel walls and move into tissues. The disease was first reported in a dog in 1987<ref>Giger U, Boxer LA, Simpson PJ, Lucchesi BR, Todd RF 3rd. '''Deficiency of leukocyte surface glycoproteins Mo1, LFA-1, and Leu M5 in a dog with recurrent bacterial infections: an animal model.''' ''Blood. 1987 Jun;69(6):1622-30.''</ref> and it bears similarities to leucocyte adhesion deficiencies in mice and humans. The surface molecule, the integrin subunit CD18, is affected by a mis-sense mutation of Cys-38-Ser and this results in a failure to express multiple integrin molecules as CD18 is a common subunit in several heterodimeric complexes. The disease is inherited in an autosomal recessive manner, with heterozygous carriers showing no signs of disease.

Leucocyte adhesion deficiency (LAD) is caused by a defect in a surface molecule expressed by neutrophils which usually allows this type of cell to attach to vessel walls and move into tissues. The disease was first reported in a dog in 1987<ref>Giger U, Boxer LA, Simpson PJ, Lucchesi BR, Todd RF 3rd. '''Deficiency of leukocyte surface glycoproteins Mo1, LFA-1, and Leu M5 in a dog with recurrent bacterial infections: an animal model.''' ''Blood. 1987 Jun;69(6):1622-30.''</ref> and it bears similarities to leucocyte adhesion deficiencies in mice and humans. The surface molecule, the integrin subunit CD18, is affected by a mis-sense mutation of Cys-38-Ser and this results in a failure to express multiple integrin molecules as CD18 is a common subunit in several heterodimeric complexes. The disease is inherited in an autosomal recessive manner, with heterozygous carriers showing no signs of disease.

Since stimulatory cytokines are still released from inflamed tissues, neutrophils are produced in greater numbers from the bone marrow and released into the circulation. As these cells are unable to enter tissues, affected animals develop a persistent [[Neutrophilia|neutrophilia]]. Neutrophils from affected animals also show defects in chemotaxis and phagocytosis.

Since stimulatory cytokines are still released from inflamed tissues, neutrophils are produced in greater numbers from the bone marrow and released into the circulation. As these cells are unable to enter tissues, affected animals develop a persistent [[Neutrophilia|neutrophilia]]. Neutrophils from affected animals also show defects in chemotaxis and phagocytosis.

==Signalment==

==Signalment==

==Diagnosis==

==Diagnosis==

LAD is a very rare disease and should only be seriously considered in Irish setters with relevant genetic history.

LAD is a very rare disease and should only be seriously considered in Irish setters with relevant genetic history.

===Clinical Signs===

===Clinical Signs===

Affected animals show signs of recurrent infections without neutrophilic exudates. Signs which have been described include<ref>Trowald-Wigh G, Ekman S, Hansson K, Hedhammar A, Hård af Segerstad C. '''Clinical, radiological and pathological features of 12 Irish setters with canine leucocyte adhesion deficiency.''' ''J Small Anim Pract. 2000 May;41(5):211-7.''</ref>:

Affected animals show signs of recurrent infections without neutrophilic exudates. Signs which have been described include<ref>Trowald-Wigh G, Ekman S, Hansson K, Hedhammar A, Hård af Segerstad C. '''Clinical, radiological and pathological features of 12 Irish setters with canine leucocyte adhesion deficiency.''' ''J Small Anim Pract. 2000 May;41(5):211-7.''</ref>:

*'''Pyrexia'''

*'''Pyrexia'''

*'''Skin lesions''' including pyoderma, furunculosis and ulceration

*'''Skin lesions''' including pyoderma, furunculosis and ulceration

===Other Tests===

===Other Tests===

Genetic tests are now available to screen for the mutation in the CD18 gene in Irish setters<ref>Verfaillie T, Verdonck F, Cox E. '''Simple PCR-based test for the detection of canine leucocyte adhesion deficiency.''' ''Vet Rec. 2004 Jun 26;154(26):821-3.''</ref>.  Carrier animals can then be prevented from breeding in future. A study of Irish setters in Germany revealed a carriage rate of 11%<ref>Pfeiffer I, Brenig B. '''Frequency of the canine leucocyte adhesion deficiency (CLAD) mutation among Irish red setters in Germany.''' ''J Anim Breed Genet. 2005 Apr;122(2):140-2.''</ref>.

Genetic tests are now available to screen for the mutation in the CD18 gene in Irish setters<ref>Verfaillie T, Verdonck F, Cox E. '''Simple PCR-based test for the detection of canine leucocyte adhesion deficiency.''' ''Vet Rec. 2004 Jun 26;154(26):821-3.''</ref>.  Carrier animals can then be prevented from breeding in future. A study of Irish setters in Germany revealed a carriage rate of 11%<ref>Pfeiffer I, Brenig B. '''Frequency of the canine leucocyte adhesion deficiency (CLAD) mutation among Irish red setters in Germany.''' ''J Anim Breed Genet. 2005 Apr;122(2):140-2.''</ref>.

==Treatment==

==Treatment==

Supportive therapy may be attempted with antibiotics for specific infections but this is associated with a poor success rate.

Supportive therapy may be attempted with antibiotics for specific infections but this is associated with a poor success rate.

More recently, various forms of stem cell therapy have been attempted to introduce cells capable of expressing CD18. Typically, CD34 positive (pluripotential) stem cells are transformed with a viral vector expressing CD18 before being transfused into puppies suffering from CLAD. The technique has achieved success when foamy virus or gamma retroviral vectors were used to transfect the stem cells<ref>Hai M, Adler RL, Bauer TR Jr, Tuschong LM, Gu YC, Wu X, Hickstein DD. '''Potential genotoxicity from integration sites in CLAD dogs treated successfully with gammaretroviral vector-mediated gene therapy.''' ''Gene Ther. 2008 Jul;15(14):1067-71. Epub 2008 Mar 27.''</ref><ref>Bauer TR Jr, Allen JM, Hai M, Tuschong LM, Khan IF, Olson EM, Adler RL, Burkholder TH, Gu YC, Russell DW, Hickstein DD. '''Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors.''' ''Nat Med. 2008 Jan;14(1):93-7. Epub 2007 Dec 23.''</ref>.

More recently, various forms of stem cell therapy have been attempted to introduce cells capable of expressing CD18. Typically, CD34 positive (pluripotential) stem cells are transformed with a viral vector expressing CD18 before being transfused into puppies suffering from CLAD. The technique has achieved success when foamy virus or gamma retroviral vectors were used to transfect the stem cells<ref>Hai M, Adler RL, Bauer TR Jr, Tuschong LM, Gu YC, Wu X, Hickstein DD. '''Potential genotoxicity from integration sites in CLAD dogs treated successfully with gammaretroviral vector-mediated gene therapy.''' ''Gene Ther. 2008 Jul;15(14):1067-71. Epub 2008 Mar 27.''</ref><ref>Bauer TR Jr, Allen JM, Hai M, Tuschong LM, Khan IF, Olson EM, Adler RL, Burkholder TH, Gu YC, Russell DW, Hickstein DD. '''Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors.''' ''Nat Med. 2008 Jan;14(1):93-7. Epub 2007 Dec 23.''</ref>.

==Prognosis==

==Prognosis==

Affected animals are unlikely to survive beyond six months of age as they are unable to control widespread bacterial infections.

Affected animals are unlikely to survive beyond six months of age as they are unable to control widespread bacterial infections.

==References==

==References==

[[Category:Primary Innate Immunity Deficiencies]]

[[Category:Primary Innate Immunity Deficiencies]]

[[Category:To Do - James]][[Category:Dog]][[Category:To Do - Review]]

[[Category:To Do - James]][[Category:Dog]][[Category:Expert Review]]