Frequent respiratory tract infections in the canine model of X-linked ectodermal dysplasia are not caused by an immune deficiency
Introduction
In X-linked hypohidrotic ectodermal dysplasia (XHED) in man (MIM #305100; defect in ED1), affected individuals have a developmental disorder characterized by sparse or absent hair, missing and/or malformed teeth, and hypoplastic eccrine glands (Beahrs et al., 1971, Soderholm and Kaitila, 1985, Clarke, 1987, Clarke et al., 1987, Kere et al., 1996). There is significant morbidity and mortality in affected children due to hyperthermia because of their inability to sweat and due to an increased risk of respiratory tract infections (Beahrs et al., 1971, Soderholm and Kaitila, 1985, Clarke et al., 1987, Gilgenkrantz et al., 1989). The human X-linked HED phenotype has been shown to be a result of mutations in the ectodysplasin (ED1) gene (Zonana et al., 1993, Kere et al., 1996, Monreal et al., 1998).
X-linked ectodermal dysplasia has also been described in a variety of dog breeds, cattle and the Tabby mouse and is characterized by hypoplasia of hair and sweat glands, as well as missing and malformed teeth (Drogemuller et al., 2001, Drogemuller et al., 2002, Drogemuller et al., 2003, Moura and Cirio, 2004). Over the past 10 years we have maintained a colony of dogs with XHED derived from an affected male German shepherd that was donated. The XHED male was bred to a Giant Schnauzer and a beagle-cross producing carrier females which in turn have produced all of the dogs in the colony. The affected dogs have all of the classic signs of XHED and the disease is caused by a splice acceptor site mutation in intron 8 of ED1 (Casal et al., 1997, Casal et al., 2004). As in most human patients with XHED, we have found increased morbidity and mortality to other, usually benign, rarely fatal pulmonary infectious diseases. Most affected dogs had chronic nasal and ocular discharge, often accompanied by corneal ulceration, and a small number of the adult dogs had chronic, treatment-resistant demodecosis that in veterinary medicine is associated with a mildly compromised immune system (Caswell et al., 1997).
In humans with XHED, it is thought that the increased occurrences of pulmonary disease are due to the lack of mucous glands in the respiratory tract (Reed et al., 1970, Beahrs et al., 1971, Siegel and Potsic, 1990). To rule out immune system defects as a cause for the increased pulmonary disorders in the XHED dogs, we compared systemic and local immune parameters of clinically healthy, affected dogs to age-matched normal dogs.
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Dogs and tissues
Medical records from 30 XHED dogs (23 males and 7 females – produced by breeding affected males to carrier females) and 59 non-affected littermates (29 males and 30 females) were reviewed for morbidity and mortality rates. The dogs’ genotypes were determined by assessing their phenotype at birth (Casal et al., 1997) and later confirmed by PCR (Casal et al., 2004). Depending on the assays to be performed, three to nine affected dogs and 3–10 age-matched normal dogs were used for each assay. At
Dogs
Of the 89 offspring born to carrier females and normal or affected males, 30 dogs were affected (23 males and 7 females) and 59 were carrier or normal dogs (29 males and 30 carrier females). There was no phenotypical difference between affected males and affected females. About 30% of the affected pups died within the first 3 days of life while only 10% of the non-affected pups died in the perinatal period (normal losses are 7–10%). Two affected pups and one normal pup had severe cleft palates,
Discussion
Significant morbidity, specifically respiratory tract disease, has often been described in humans with X-linked hypohidrotic ectodermal dysplasia (Reed et al., 1970, Beahrs et al., 1971, Soderholm and Kaitila, 1985, Clarke, 1987, Clarke et al., 1987, Gilgenkrantz et al., 1989, Siegel and Potsic, 1990). All but four of our affected dogs have been housed in a closed, climate-controlled environment and yet the percentage of post-weaning dogs with recurrent respiratory tract infections was around
Acknowledgements
The authors wish to thank Margaret Weil, Patty O’Donnell, and the veterinary students of The University of Pennsylvania School of Veterinary Medicine for their excellent XHED colony husbandry and Dr. Mark Haskins for critical advice. This work was supported by NIH grants AR049817, and RR02512 and the National Foundation for Ectodermal Dysplasias.
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