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Canine Granulocytopathy Syndrome an Inherited Disorder Ofleukocyte Function

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Canine Granulocytopathy Syndrome an Inherited Disorder Ofleukocyte Function Canine Granulocytopathy Syndrome An Inherited Disorder ofLeukocyte Function Harland W. Renshaw, DVM, PhD, and William C. Davis, PhD A disease closely resembling the human neutrophil dysfunction syndromes has been identified in a colony of dogs. The syndrome, referred to as the canine gran- ulocytopathy syndrome, is characterized by recurrent life-threatening bacterial infec- tions and a greatly shortened life span. The disease is genetically determined, being transmitted as an autosomal recessive trait. The increased susceptibility to pyogenic infections and shortened life span is related to an impairment of leukocvte function at the cellular level. Preparations of neutrophils from affected animals exhibit impaired in ritro killing of Escherichia coli. The defect in bactericidal activity is associated with reduced glucose oxidation by the hexose monophosphate shunt and an increased capac- ity to reduce nitroblue tetrazolium dye. The data obtained thus far indicate the canine granulocytopathy syndrome will be of considerable value as a model for the study of granulocytopathy syndromes in man. (Am J Pathol 95:731-744, 1979) STUDIES OF LEUKOCY-TE structure and function in host defense failure syndromes of man and animals have provided dramatic evidence for the necessitv of adequate neutrophil function for normal host resis- tance.`6 A group of human diseases, characterized clinically bv enhanced susceptibilitv to pyogenic infections, has been related to impaired killing of microorganisms by neutrophils and monocytes.7-12 A direct correlation has been demonstrated between defective intraneutrophilic microbicidal capacitv and enhanced susceptibilitv to infections in Chediak-Higashi syndrome (C-HS) of humans,12 chronic granulomatous disease (CGD) of childhood,13-15 mveloperoxidase (MPO) deficiencv,'-'8 glucose-6-phos- phate dehydrogenase (G-6-PD) deficiencv,"" congenital abnormalities of specific granules,22 and lysozvme and lactoferrin deficiency with con- genital absence of specific granules.2 Evidence from detailed clinical and laboratory studies of the affected patients and their relatives supports the hypothesis that several, if not all, of these diseases are genetically deter- mined clinical svndromes.5,1324,25 From the Department of Veterinary Microbiology and Parasitology. College of Veterinary Medi- cine. Texas A&M Uni-ersity. College Station. Texas. and the Department of Veterinary Microbiology and Pathology. College of Veterinan Medicine. Washington State University. Pullman. Washington Supported in part by US Public Health Service Grants AI-15952-01 and AI-12826402 from the National Institute of Allergy and Infectious Diseases. Accepted for publication January 222 1979. Address reprint requests to Harland WV Renshaw. DVM. PhD, Department of Veterinarv Micro- biology and Parasitology. College of Veterinary Medicine. Texas A&MN University. College Station. TX 77843 0002-9440/79/0607-0731 $01.00 731 © 1979 American Association of Pathologists 732 RENSHAW AND DAVIS American Journal of Pathology Recently, we observed a spontaneously occurring disease in a male Irish setter dog, which had clinical features closely resembling those observed in human neutrophil dysfunction syndromes.26 Increased susceptibility to infection in the affected animal was associated with defective bactericidal capacity of neutrophil-rich leukocyte preparations. Affected canine neu- trophils appear normal ultrastructurally with no morphologically identi- fiable alteration in lysosome formation.27 Results of preliminary studies of this condition, tentatively designated the canine granulocytopathy syn- drome (CGS), suggest that it is similar to, but uniquely different from, any neutrophil dysfunction syndrome described thus far in man or ani- mals. Because this new disease could have considerable value in com- parative biology studies, controlled breeding experiments were conducted to determine whether the CGS is a genetically determined metabolic dis- order. In this report, we present the results of the breeding experiments and describe studies that indicate that the increased disease susceptibility of affected dogs is associated with impaired in vitro killing of bacteria and a metabolic anomaly in hexose monophosphate shunt (HMPS) activ- ity by their neutrophils. Materials and Methods Subjects The subjects used in this study were obtained from two sources: 1) a series of controlled breeding experiments involving matings of the propositus, his clinically normal dam, an unrelated clinically normal female, and breedings of some of the resultant clinically normal offspring (Text-figure 1); and 2) a population of clinically normal unrelated mongrel dogs. Healthy animals were maintained under conventional conditions in ken- nels. A combination of clinical and laboratory evidence was used to arrive at a diagnosis of CGS. Affected animals were treated with antibiotics as soon as signs of the disease were evident. Representative Case Report Data Prominent clinicopathologic features of the CGS are omphalophlebitis after birth, suppurative skin lesions, gingivitis, lymphadenopathy, pododermatitis, and, in most ad- vanced cases, osteomyelitis. Hematologic studies, even in very young affected puppies, reveal a persistent leukocytosis with a regenerative left shift. Normal dogs usually have a total leukocyte count of 8000 to 14,000/cu mm with 55 to 75% neutrophils. In affected dogs that have been stabilized with antibiotic therapy total leukocyte counts are usually in the range of 25,000 to 65,000/cu mm with 75 to 90% neutrophils. During exacerbations the counts will rise to 120,000 to 540,000 with a corresponding increase in immature forms. Mature neutrophils contain nuclei that are often hypersegmented and both peroxidase- positive lysosomes and specific granules. Neither immature nor atypical lymphocytes or undifferentiated nongranular neutrophil forms are observed in Wright's-stained blood smears. Most affected animals have a moderate normocytic, normochromic anemia. The syndrome is often associated with hypergammaglobulinemia. The major classes of canine immunoglobulins are present. Histopathologic examination of necropsy or biopsy material Vol. 95, No. 3 CANINE GRANULOCYTOPATHY- - - . - - . - .. SYNUHUME 733 May 1979 O -0Z E > LEE E-, E U |0X 0 0 *~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~o 0{ o.c| bc C @00 s CC l> ~~~~~~~~.... .0 g3 wc;}ht; w-N t~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~OC~~~~~w_W It -t-c-3 -CD qu:=--.--W.... r <-; - ...... > rEE tY~~~~~~~~~~~~~~~~~~~...... q3 -t_§~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.*-~~~~~~~~~~~~~~~~~~~~.-...... .........t.__ ..~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~. ... E -. ......... ._'. ,-. ...,, ,,,., .... , S,:.,.''',, ,j_..,|,.... ...'...- t,,- ,*.,j _;-;:S,j,,~~~~~~~~~~~~~~~~~~~~~~~~~~~~.,.,..............W.,,....,v 734 RENSHAW AND DAVIS American Journal of Pathology reveals granular brown-staining pigment (lipofuscin) in reticuloendothelial cells through- out the lymphoid tissues with an absence of granulomatous lesions. Radiographic examina- tion of head, thorax, abdomen, and limbs reveals no visceral or skeletal abnormalities except those associated with cases of osteomyelitis. Serum glutamic transaminase and alkaline phosphatase activities are generally normal, as are results of blood urea nitrogen determinations, urinalysis, and the direct Coomb's test. Between episodes of severe infections, the animals eat and drink well and are alert. However, during exacerbations of the disease, anorexia, weight loss, dehydration, and severe depression accompany periods of pyrexia and extreme neutrophilia. By 1 month of age, the affected animals are usually only slightly greater than half the size and weight of their clinically normal littermates. Continuous therapy with a broad-spectrum antibiotic appears to be necessary to keep affected individuals alive for more than a few weeks. Even with antibiotic therapy and extensive supportive therapy, the affected dogs have a greatly shortened life span. Leukocyte Preparation Heparinized blood (15 U/ml) specimens were collected from affected and clinically normal dogs of the same ages. Mixed cell preparations of peripheral blood leukocytes were isolated from the heparinized blood by lysing the erythrocytes in three volumes of 0.87% NH4C1.28 The leukocytes were pelleted by low-speed centrifugation at 200g for 5 minutes at 22 C and suspended in sterile saline for counting. Preparations containing an enriched population of polymorphonuclear neutrophils (PMN) were obtained using a modification of the IsopaqueFicoll density gradient centrifu- gation technique of B6yum.29 The heparinized blood was mixed with an equal volume of heparinized (15 U/ml) Eagle's minimal essential medium (MEM). The heparinized blood- MEM mixture (30 ml) was layered on 20 ml of Isopaque-Ficoll separation fluid (density 1.077 g/ml), and centrifugated at 450g for 40 minutes at 22 C. The mononuclear cells banded at the interface region were removed and discarded. The bottom fraction contain- ing erythrocytes and leukocytes was resuspended and the erythrocytes lysed in 3 volumes of 0.87% NH,C1. Leukocytes were collected by centrifugation at 200g for 5 minutes at 22 C and suspended in sterile saline for counting. Cell viability, determined by 0.1% trypan blue dye exclusion, was > 95% for all mixed cell preparations and > 90% in all PMN preparations. Total and differential leukocyte counts were performed with a hemacytometer and by examination of Wrights's-stained smears, respectively.
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