21Canine leukocyte adhesion deficiency (CLAD) in Irish setters is caused by genetic 22 defects of leukocyte integrin CD18 leading to recurrent bacterial infections. We report 23 clinical features and analysis of neutrophil function from two mixed-breed canine 24 littermates (one female and one male dog) similar to CLAD. The symptoms of pyogenic 25 infection were first recognized at 3 months of age and since then the patients suffered 26 from recurrent bacterial infections. These clinical findings were strongly suggestive of 27 genetic phagocyte dysfunction. Neutrophil function tests revealed a marked reduction of 28 serum-opsonized zymosan-mediated superoxide production in the two littermates. 29Neutrophils of the male dog revealed impaired integrin-mediated adherence and 30 phagocytic activity, whereas ability of serum opsonization was normal. There was also a 31 profound decrease of surface expression of CD11b/CD18 and 2-integrin transcript 32 level, detected by real-time RT-PCR without missense mutations unlike CLAD. 33Immunoblot analysis indicated that protein expression of cytochrome b 558 component 34 gp91 phox , the cytosolic components p47 phox and p67 phox of NADPH oxidase components 35 increased profoundly in the male. Our study suggests that decreased transcriptional 36 levels of 2-integrin without mutations, lead to downregulation of surface expression, 37 resulting in multiple defects in adhesion-related neutrophil functions and consequently, 38 recurrent bacterial infections from puppyhood. 39 40

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ABSTRACT. This study reported detailed clinical effects of bovine lactoferrin on 2 canine littermates (1 female and 1 male) with familial neutrophil dysfunction and an investigation of their genetic background. Clinical signs caused by severe upper respiratory bacterial infections were observed in these dogs. Oral administration of bovine lactoferrin for a long duration improved their clinical signs (severe uveitis in the female dog and coughing from pneumonia in the male dog). Their backcross dogs that have the same father didn't show clinical signs of bacterial infection. Neutrophil function tests revealed that the backcross dogs didn't have any disorders. It is likely that abnormal clinical signs are associated with neutrophil dysfunction in the colony, and the mother dog of these cases might be the genetic carrier of this dysfunction. KEY WORDS: bovine lactoferrin, familial canine neutrophil dysfunction, genetic background.

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