Immune-mediated hematological disease in dogs is associated with alterations of the fecal microbiota: a pilot study.

BACKGROUND: The dog is the most popular companion animal and is a valuable large animal model for several human diseases. Canine immune-mediated hematological diseases, including immune-mediated hemolytic anemia (IMHA) and immune thrombocytopenia (ITP), share many features in common with autoimmune hematological diseases of humans. The gut microbiome has been linked to systemic illness, but few studies have evaluated its association with immune-mediated hematological disease. To address this knowledge gap, 16S rRNA gene sequencing was used to profile the fecal microbiota of dogs with spontaneous IMHA and ITP at presentation and following successful treatment. In total, 21 affected and 13 healthy control dogs were included in the study. RESULTS: IMHA/ITP is associated with remodeling of fecal microbiota, marked by decreased relative abundance of the spirochete Treponema spp., increased relative abundance of the pathobionts Clostridium septicum and Escherichia coli, and increased overall microbial diversity. Logistic regression analysis demonstrated that Treponema spp. were associated with decreased risk of IMHA/ITP (odds ratio [OR] 0.24-0.34), while Ruminococcaceae UCG-009 and Christensenellaceae R-7 group were associated with increased risk of disease (OR = 6.84 [95% CI 2-32.74] and 8.36 [95% CI 1.85-71.88] respectively). CONCLUSIONS: This study demonstrates an association of immune-mediated hematological diseases in dogs with fecal dysbiosis, and points to specific bacterial genera as biomarkers of disease. Microbes identified as positive or negative risk factors for IMHA/ITP represent an area for future research as potential targets for new diagnostic assays and/or therapeutic applications.

Companion animals in comparative oncology: One Medicine in action.

Comparative oncology is poised to have a far-reaching impact on both animals and human beings with cancer. The field is gaining momentum and has repeatedly proven its utility in various aspects of oncology, including study of the genetics, development, progression, immunology and therapy of cancer. Companion animals provide many advantages over both traditional rodent models and human beings for studying cancer biology and accelerating the development of novel anti-cancer therapies. In this review, several examples of the ability of companion animals with spontaneous cancers to fill a unique niche in the field of oncology are discussed. In addition, potential caveats of the use of companion animals in research are reviewed, as well as ethical considerations and efforts to standardize veterinary clinical trials.

Prognostic significance of clinical presentation, induction and rescue treatment in 42 cases of canine centroblastic diffuse large B-cell multicentric lymphoma in the United Kingdom.

Canine lymphoma is a heterogeneous group of diseases and many previous studies have evaluated the response of a mixed population of lymphoma cases to one specific treatment protocol. The aim of this retrospective study was to describe the outcome and prognostic factors in 42 cases of multicentric centroblastic diffuse large B-cell lymphoma treated with either a COP-type (35%) or CHOP-type (64%) induction chemotherapy. The objective response rate to induction therapy was 94%; entire dogs had a greater rate of complete vs partial remissions than neutered dogs (P = .017). Median progression-free survival for the first remission (PFS1) was 182 days; absence of anaemia at diagnosis (P = .002) and pretreatment neutrophil:lymphocyte ratio (NLR) below 9.44 (P = .015) were independently predictive of longer PFS1. Fifty-eight percent of dogs received rescue protocols with an objective response rate of 81%; 31% of dogs received further rescue protocols (up to a total of 5) and the median number of protocols administered were 2. Median overall survival (OS) was 322 days, the 1-year survival rate was 38% and the 2-year survival rate was 9%. Lymphocyte:monocyte ratio above 1.43 (P = .031), NLR below 11.44 (P = .009), the combination of induction and rescue therapy (P = .030) and the total number of doxorubicin doses used (P = .002) were independently predictive of longer OS. Use of a COP-type protocol induction compared with CHOP did not undermine OS providing doxorubicin was used as rescue therapy.

Characterization of Paroxysmal Gluten-Sensitive Dyskinesia in Border Terriers Using Serological Markers.

BACKGROUND: Paroxysmal gluten-sensitive dyskinesia (PGSD) in border terriers (BTs) results from an immunologic response directed against transglutaminase (TG)2 and gliadin. Recent evidence suggests that PGSD is only one aspect of a range of possible manifestations of gluten sensitivity in the breed. HYPOTHESIS/OBJECTIVES: Gluten sensitivity in BTs is a heterogeneous disease process with a diverse clinical spectrum; to characterize the phenotype of PGSD using TG2 and gliadin autoantibodies as diagnostic markers. ANIMALS: One hundred twenty-eight client-owned BTs with various disorders. METHODS: Prospective study. BTs with paroxysmal episodes and a normal interictal examination were phenotyped using footage of a representative episode and assigned to 3 groups: idiopathic epilepsy (IE), paroxysmal dyskinesia (PD), or other. Owners of each dog completed a questionnaire to obtain information regarding clinical signs. Healthy BTs formed a control group. Serum antibodies against TG2 and AGA were measured in all dogs. RESULTS: One hundred twenty-eight BTs were enrolled; 45 with PD, 28 with IE, 35 with other conditions, and 20 controls. Three overlapping phenotypes were identified; PD, signs suggestive of gastrointestinal disease, and dermatopathy. AGA-IgG concentrations were increased in PD, compared with IE (P = 0.012), controls (P < 0.0001) and other (P = 0.018) conditions. Anti-canine TG2-IgA concentrations were increased in PD, compared with IE (P < 0.0001), controls (P < 0.0001) and other (P = 0.012) conditions. Serological markers are highly specific for PGSD but lack sensitivity. CONCLUSIONS: PGSD appears part of a syndrome of gluten intolerance consisting of episodes of transient dyskinesia, signs suggestive of gastrointestinal disease, and dermatological hypersensitivity.

Prevalence of FoxP3+ Cells Does Not Correlate With Ki67 Expression in Canine Diffuse Large B-cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of canine lymphoma and survival times are currently <1 year. Manipulation of the tumour microenvironment, of which the regulatory T cell (Treg) is a principal player, represents a potentially exciting way to curb the rapid proliferation of neoplastic cells. Tregs, characterized by the stable expression of the transcription factor FoxP3, suppress innate and adaptive arms of the immune response and represent a potential therapeutic target within neoplastic lymph nodes. This retrospective study explored the hypothesis that Tregs promote the proliferation of neoplastic large B cells, employing immunohistochemistry to assess both FoxP3 and Ki67 expression within canine lymph nodes. Fifty-seven biopsy samples of canine nodal DLBCL were examined. There were significantly fewer FoxP3+ cells in lymph nodes effaced by DLBCL than in reactive lymph nodes (27 versus 369 cells/mm2; Mann-Whitney U = 16, P = 0.011). There was no relationship between the number of intratumoural FoxP3+ cells and neoplastic cell proliferation (Spearman's rank r = 0.058, P = 0.670, 95% confidence interval). The results of this study show that FoxP3+ cells are reduced in lymph nodes effaced by DLBCL and that this change is unrelated to the expression of Ki67. This study also describes a robust digital method to standardize cell counts and facilitate future comparative studies.

European canine lymphoma network consensus recommendations for reporting flow cytometry in canine hematopoietic neoplasms.

BACKGROUND: Flow cytometry (FC) is assuming increasing importance in diagnosis in veterinary oncology. The European Canine Lymphoma Network (ECLN) is an international cooperation of different institutions working on canine lymphoma diagnosis and therapy. The ECLN panel of experts on FC has defined the issue of reporting FC on canine lymphoma and leukemia as their first hot topic, since a standardized report that includes all the important information is still lacking in veterinary medicine. METHODS: The flow cytometry panel of the ECLN started a consensus initiative using the Delphi approach. Clinicians were considered the main target of FC reports. A panel of experts in FC was interrogated about the important information needed from a report. RESULTS: Using the feedback from clinicians and subsequent discussion, a list of information to be included in the report was made, with four different levels of recommendation. The final report should include both a quantitative part and a qualitative or descriptive part with interpretation of the salient results. Other items discussed included the necessity of reporting data regarding the quality of samples, use of absolute numbers of positive cells, cutoff values, the intensity of fluorescence, and possible aberrant patterns of antigen expression useful from a clinical point of view. CONCLUSION: The consensus initiative is a first step toward standardization of diagnostic approach to canine hematopoietic neoplasms among different institutions and countries. This harmonization will improve communication and patient care and also facilitate the multicenter studies necessary to further our knowledge of canine hematopoietic neoplasms. © 2016 International Clinical Cytometry Society.

Conformity and controversies in the diagnosis, staging and follow-up evaluation of canine nodal lymphoma: a systematic review of the last 15 years of published literature.

Diagnostic methods used in the initial and post-treatment evaluation of canine lymphoma are heterogeneous and can vary within countries and institutions. Accurate reporting of clinical stage and response assessment is crucial in determining the treatment efficacy and predicting prognosis. This study comprises a systematic review of all available canine multicentric lymphoma studies published over 15 years. Data concerning diagnosis, clinical stage evaluation and response assessment procedures were extracted and compared. Sixty-three studies met the eligibility criteria. Fifty-five (87.3%) studies were non-randomized prospective or retrospective studies. The survey results also expose variations in diagnostic criteria and treatment response assessment in canine multicentric lymphoma. Variations in staging procedures performed and recorded led to an unquantifiable heterogeneity among patients in and between studies, making it difficult to compare treatment efficacies. Awareness of this inconsistency of procedure and reporting may help in the design of future clinical trials.

A rapid method for labelling CD4+ T cells with ultrasmall paramagnetic iron oxide nanoparticles for magnetic resonance imaging that preserves proliferative, regulatory and migratory behaviour in vitro.

A number of techniques have been developed to track the migration of T cells in vivo, but they all suffer significant shortcomings, including the examination of selected organs rather than the organism as a whole--thus precluding longitudinal studies--or limitations imposed by poor spatial resolution and the application of ionizing radiation. By conjugating the HIV tat peptide to ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles in a reaction yielding a mean valence of 45, a magnetic resonance (MR) contrast agent was synthesised that allowed T cells to be efficiently labelled within just 5 min. The USPIO nanoparticles were incorporated into both the cytoplasm and nucleus of labelled cells, which retained normal in vitro proliferative responses to a polyclonal stimulus; suppressive responses mediated by labelled CD4(+) CD25(+) regulatory T cells; chemotactic responses to the chemokine CXCL-12; and transmigration of an activated endothelial monolayer. We believe that this rapid, efficient and essentially non-toxic approach to labelling both murine and human T cells for MRI holds considerable promise, paving the way for the wider immunological application of this exciting technology.

Complications of Percutaneous Endoscopic Gastrostomy in Dogs and Cats Receiving Corticosteroid Treatment.

BACKGROUND: Corticosteroid treatment is commonly required in veterinary patients for treatment of inflammatory, immune-mediated, neurologic, and neoplastic diseases, which also may require assisted enteral nutrition via percutaneous endoscopic gastrostomy (PEG). OBJECTIVE: To evaluate complications associated with PEG use in dogs and cats receiving corticosteroid treatment. ANIMALS: Forty-two animals were included in the study: 12 dogs and 2 cats in the steroid group and 26 dogs and 2 cats in the control group. METHODS: Medical records, between January 2006 and March 2015, were reviewed. Patients were included if the PEG tube was in use for at least 24 hours and if complete medical records were available. Patients were assigned to the control group if they were not treated with corticosteroids during PEG use or to the steroid group if they had received corticosteroids during PEG tube use. Complications were classified as minor, moderate, and major in severity. Maximum severity complication rate was compared between groups. RESULTS: The general prevalence of complications was found to be similar between groups (P = .306), but in the steroid group, 43% of the cases developed a major severity complication compared with 18% of the control group (P = .054). CONCLUSION AND CLINICAL IMPORTANCE: Owners of dogs and cats receiving corticosteroids, in which PEG is planned, should be counseled about possible complications beyond those associated with PEG tube usage alone.

Cytological Findings of 140 Bile Samples from Dogs and Cats and Associated Clinical Pathological Data.

BACKGROUND: Cholecystocentesis can be part of the diagnostic workup of hepatobiliary disease in small animals, but literature on cytological evaluation of bile is scant. OBJECTIVES: To determine the diagnostic utility of cytological assessment of bile aspirates. ANIMALS: Fifty-six and 78 client-owned dogs and cats, respectively, with bile collected by cholecystocentesis and submitted to our diagnostic laboratory between 1999 and 2014. METHODS: Retrospective study describing cytological findings of bile, concurrent bacterial culture results, hematological and serum biochemical data, gallbladder biopsy results, as well as final diagnosis and complications after cholecystocentesis. RESULTS: Infectious agents were found in 30% of canine and 22% of feline bile aspirates, and inflammation in 5% and 19% respectively. Presence of microorganisms was more often detected on cytological examination (24%) than by culture (21%). The most common bacterial isolates were Escherichia coli and Enterococcus spp., isolated from 14.8% and 6.7% of cultured samples respectively. Only increased canine pancreatic lipase immunoreactivity concentration (cPLI) was significantly associated with the presence of microorganisms, inflammatory cells, or both in bile. Clinically relevant complications of cholecystocentesis occurred in 2 dogs. The majority of the animals undergoing cholecystocentesis suffered from hepatic, pancreatic, gastrointestinal disease, or a combination thereof. CONCLUSIONS AND CLINICAL IMPORTANCE: Cytological examination of bile is inexpensive and straightforward, and yields diagnostically relevant information that precedes and complements bacterial culture.

A presumptive case of gluten sensitivity in a border terrier: a multisystem disorder?

Paroxysmal gluten-sensitive dyskinesia (previously termed canine epileptoid cramping syndrome) is a condition of Border terriers in which the leading manifestation is neurological. The authors describe a case they believe to represent the first report of a Border terrier with a combination of neurological signs, atopy, positive serological results for anti-transglutaminase 2 (TG2 IgA) and anti-gliadin (AGA IgG) antibodies, and signs suggestive of gastrointestinal disease with pathological changes in the gastrointestinal tract-seemingly responsive to a gluten-free diet. As such, the authors suggest that gluten sensitivity in Border terriers may manifest as a multisystem disease in a similar manner to that seen in human beings.

Prevalence of FoxP3(+) Cells in Canine Tumours and Lymph Nodes Correlates Positively with Glucose Transporter 1 Expression.

Hypoxia and regulatory T cells (Tregs) in tumours are both known to be negative prognostic factors in cancer, and this study demonstrated a correlation between the two factors in canine neoplasia. Samples of 57 canine tumours and 29 canine lymph nodes categorized as tumour-draining, with or without metastasis, or reactive and not tumour-associated, were examined. Sequential sections were labelled by immunohistochemistry for glucose transporter 1 (Glut1) and FoxP3 as markers of hypoxia and Tregs, respectively. Up to 21 regions of interest (ROI) were selected in each section in a representative pattern and were assigned a semiquantitative score based on Glut1 labelling. The number of FoxP3(+) cells within each ROI was counted. A generalized estimating equation with negative binomial log link function was used to determine an association between Glut1 expression and FoxP3(+) cell count. Higher Glut1 immunoreactivity was correlated with significantly higher numbers of FoxP3(+) cells in the total tumour sample pool and total lymph node sample pool. Analysis of various subcategories of tumours and lymph nodes showed that this correlation was also present within samples characterized as malignant, haemopoietic mesenchymal tumours, non-haemopoietic mesenchymal tumours, epithelial tumours, lymphoma, lymph nodes containing metastases and reactive lymph nodes. These results indicate that hypoxia in canine tumours may result in an increased infiltration by Tregs.

A prospective, randomized, blinded, placebo-controlled pilot study on the effect of Enterococcus faecium on clinical activity and intestinal gene expression in canine food-responsive chronic enteropathy.

BACKGROUND: Canine chronic enteropathies (CE) are believed to be caused by an aberrant immune response towards the intestinal microbiome. Administration of probiotics can alleviate colitis in people. In vitro effects of the probiotic Enterococcus faecium NCIMB 10415 E1707 (EF) previously have been evaluated using canine cells (e.g., whole blood, intestinal biopsies), but data on in vivo efficacy are lacking. HYPOTHESIS/OBJECTIVES: Administration of EF to dogs with food-responsive CE will improve clinical outcome and decrease the intestinal inflammatory profile. ANIMALS: Dogs diagnosed with CE were prospectively recruited to receive a hydrolyzed elimination diet plus either a synbiotic product containing EF or placebo for 6 weeks. Both veterinary staff and owners were blinded to the treatment. METHODS: Clinical severity index (CCECAI), clinicopathological data and gene expression using intestinal biopsies (TLR2/4/5/9, IL-17A, IL-22, IL-23p19, RORC, IL-2, IL-12p35, TNFα, IL-4, IFNy, IL-10, TGFß, IL-1ß, IL-18, NLRP3, casp-1, TFF1, TFF3 and PPARy) before and after 6 weeks of treatment were analyzed using linear mixed modeling. RESULTS: Of the 45 cases recruited, 12 finished the clinical trial. Seven received the synbiotic and 5 the placebo product. There was no difference between groups or treatments regarding clinical efficacy, histology scores or expression of any of the investigated genes. CONCLUSIONS AND CLINICAL IMPORTANCE: Standard dietary treatment induced rapid clinical response in all cases. Because the study was underpowered, it was not possible to determine whether or not EF had an additional effect within the time period of 6 weeks.

The Clinical and Serological Effect of a Gluten-Free Diet in Border Terriers with Epileptoid Cramping Syndrome.

BACKGROUND: Canine epileptoid cramping syndrome (CECS) is a paroxysmal movement disorder of Border Terriers (BTs). These dogs might respond to a gluten-free diet. OBJECTIVES: The objective of this study was to examine the clinical and serological effect of a gluten-free diet in BTs with CECS. ANIMALS: Six client-owned BTs with clinically confirmed CECS. METHODS: Dogs were prospectively recruited that had at least a 6-month history of CECS based on the observed phenomenology (using video) and had exhibited at least 2 separate episodes on different days. Dogs were tested for anti-transglutaminase 2 (TG2 IgA) and anti-gliadin (AGA IgG) antibodies in the serum at presentation, and 3, 6, and 9 months after the introduction of a gluten-free diet. Duodenal biopsies were performed in 1 dog. RESULTS: Serum TG2 IgA titers were increased in 6/6 BTs (P = .006) and AGA IgG titers were increased in 5/6 BTs at presentation compared to those of controls (P = .018). After 9 months, there was clinical and serological improvement in all BTs with CECS strictly adhering to a gluten-free diet (5/5). One dog had persistently increased antibody titers. This dog scavenged horse manure. On the strict introduction of a gluten-free diet this dog also had an improved clinical and serological response. The diet-associated improvement was reversible in 2 dogs on completion of the study, both of which suffered a relapse of CECS on the re-introduction of gluten. CONCLUSIONS: Canine epileptoid cramping syndrome in BTs is a gluten-sensitive movement disorder triggered and perpetuated by gluten and thus responsive to a gluten-free diet.

Silent polymorphisms within the coding region of human sodium/hydrogen exchanger isoform-1 cDNA in peripheral blood mononuclear cells of leukemia patients: A comparison with healthy controls.

We have examined the sequence of the cDNA encoding the sodium/hydrogen exchanger isoform 1 (NHE1), from 23 bases upstream of the start codon to 28 bases downstream of the stop codon. Template was prepared from (1) peripheral blood mononuclear cells (PBMC) isolated from 10 healthy unrelated Caucasian volunteers; (2) PBMCs isolated from 6 leukemic patients (acute lymphoblastic leukemia [ALL], n = 3; chronic lymphocytic leukemia [CLL], n = 1; chronic myelogenous leukemia [CML], n = 2); and (3) samples of 4 leukemic cell lines (ALL: CEM, MOLT4; AML: KG1a; CML: K562). NHE1 cDNA in normal PBMCs showed silent polymorphism of nucleotides 112 (N1: T, frequency 0.70; C, frequency 0.30; prevalence of heterozygosity 0.42); 2248 (N2: G, frequency 0.90; A, frequency 0. 10; heterozygosity 0.18); and 2493 (N3: G, frequency 0.90; A, frequency 0.10; heterozygosity 0.18). Deduced primary structure of NHE1 protein in all normal volunteers was identical to that previously published for NHE1 from renal and cardiac tissue. Similar to normal PBMCs, NHE1 cDNA from leukemic cells showed polymorphism of nucleotides N1, N2, and N3, but failed to demonstrate leukemia-specific sequence differences. We conclude that the coding region of NHE1 cDNA shows a greater level of polymorphism than is currently recognized, but that sequence mutation of NHE1 is not a key event in the pathogenesis of leukemia.

In situ hybridization as a technique for the immunological investigation of canine intestine: jejunal expression of IFNgamma and IL10 in Irish setters and beagles.

In situ hybridization (ISH) has found numerous applications in biology and medicine. However, its use to demonstrate expression of cytokines within the canine small intestine has not been described. Digoxigenin-labelled riboprobes complementary to mRNA encoding canine IFNgamma and IL10 were used to demonstrate expression of these cytokines within formalin-fixed, paraffin-embedded sections of jejunum obtained from healthy control Irish setter (IS) dogs (n = 4), gluten-sensitive IS in remission (n = 7), and beagles with high enteric bacterial populations (n = 5). Proportional areas of cells within the lamina propria showing one of three mutually exclusive staining intensities were measured, as well as the total stained area. Intensity categories were chosen arbitrarily to represent cells showing weak, moderate or dense staining (grades 1-3 respectively), reflecting increasing expression of mRNA. Control and gluten-sensitive IS showed similar total and grade-by-grade areas of expression of IFNgamma and IL10 in the lamina propria (p>0.05), in contrast to beagles, which showed greater total and grade 1 areas of expression of IFNgamma, and greater total, grade 1 and grade 2 areas of expression of IL10, than both groups of IS (p<0.05). Epithelial expression of both cytokines was demonstrated in beagles and IS, but differences between groups for each cytokine were not apparent (p>0.05). This study has validated the use of in situ hybridization for the detection of IFNgamma and IL10 mRNA within canine intestinal biopsies, andhas shown heightened jejunal expression of both cytokines in beagles with high enteric bacterial populations.

Reference range and repeatability of a combined intestinal permeability and function test in clinically healthy Irish setter dogs.

A reference range was determined for a combined test of differential sugar permeability, using lactulose (L) and rhamnose (R), and intestinal function, using D-xylulose (X) and 3-O-methylglucose (G), in clinically healthy adult Irish setter dogs. Urinary L/R ratios in 48 Irish setters from one to 12 years old varied from 0.03 to 0.18, with a mean (SEM) of 0.10 (0.01); X/G ratios varied from 0.46 to 0.81, with a mean (SEM) of 0.59 (0.01). There were no significant differences between L/R or X/G ratios of dogs of different sex (P > 0.2) or age (P > 0.5), using analysis of covariance. Lactulose/rhamnose ratios of > or = 0.18 and X/G ratios > or = 0.43 were considered normal, defined by the respective mean +/- 2SD. Repeatability was established by performing three permeability and function tests at monthly intervals in twelve of the dogs. Analysis of repeated L/R and X/G ratios by means of linear models procedure revealed no significant differences between measurements made on successive occasions (P > 0.15), confirming the repeatability of this test.

Intestinal permeability of Irish setter puppies challenged with a controlled oral dose of gluten.

A combined test of intestinal permeability using lactulose (L) and rhamnose (R), and absorptive function using xylose (X) and 3-O-methylglucose (G), was carried out at four, six, eight and 16 weeks of age in 22 healthy control and six gluten-sensitive Irish setter (IS) dogs fed a diet containing a controlled dose of gluten from weaning. Comparisons were made with two groups of 12 healthy control dogs of breeds other than IS, one fed the same diet as the setters and the other fed a gluten-free diet. Gluten-sensitive IS showed a rise in permeability (mean [SEM] urinary L/R) from 0.23 (0.07) at four weeks to 0.39 (0.05) at eight weeks, remaining at 0.36 (0.04) at 16 weeks. These results were significantly higher in gluten-sensitive than control IS at six, eight and 16 weeks, compatible with jejunal biopsy lesions characteristic of gluten-sensitive enteropathy demonstrated in affected dogs at 16 weeks. Urinary L/R ratios of control dogs of breeds other than IS peaked at six weeks 0.27 (0.02), and were significantly higher than those of control IS at six and eight weeks, demonstrating differences in permeability between Irish setter dogs and other breeds at this age. There were no significant differences in urinary X/G ratios at six, eight and 16 weeks of age between any of the groups of dogs challenged with gluten. Urinary L/R and X/G ratios were similar in the control dogs of breeds other than IS fed gluten-containing and gluten-free diets. These findings indicate that intestinal permeability testing of puppies during controlled oral gluten challenge provides a practical screening test for gluten sensitivity in Irish setter dogs at an early age.

Inheritance of gluten-sensitive enteropathy in Irish Setters.

OBJECTIVE: To establish a model for inheritance of gluten-sensitive enteropathy (GSE) in Irish Setters. ANIMALS: 44 dogs of a 6-generation family of Irish Setters with GSE and 7 healthy Irish Setters. PROCEDURE: Phenotype of each dog was determined after oral administration of gluten in the weaning diet, using morphometric evaluation of jejunal biopsies (all generations) and measurement of small intestinal permeability by use of a lactulose-rhamnose permeation test (generations 1, 2, and 3). Overall probability for each of 4 genetic models of inheritance (autosomal recessive, autosomal dominant, sex-linked recessive, and sex-linked dominant) accounting for segregation of partial villus atrophy within the entire family was calculated. RESULTS: The autosomal recessive model was most tenable and was 56,250 times more likely to account for segregation of partial villus atrophy than the autosomal dominant model, assuming disease prevalence of 0.8%. Both sex-linked models were untenable. These conclusions were robust to the error attached to estimation of disease prevalence. High intestinal permeability without morphometric jejunal abnormalities in 4 of 20 dogs in the 3 youngest generations suggested heterogeneity of lesions associated with GSE. CONCLUSIONS: Genetic transmission of GSE is under the control of a single major autosomal recessive locus.

Gastrointestinal immunity in health and disease.

The gastrointestinal lymphoid tissue (GALT) is under constant antigenic challenge from bacteria and food and must be able to distinguish between benign and pathogenic organisms. Recent advances in understanding the organization and function of GALT reveal how it is able to direct appropriate immune responses according to the nature of the antigen and how inappropriate immune responses can lead to local and systemic immunopathology and/or infection. The interaction of the normal bowel flora and GALT is critical to normal local and systemic immune function and plays a major role in the pathogenesis of some immune-related diseases. This review draws upon information from veterinary, human, and laboratory animal studies to provide an update of mechanisms and consequences of function and dysfunction in the gastrointestinal immune system.