Immune-Mediated Intestinal Disease
World Small Animal Veterinary Association World Congress Proceedings, 2007
Edward J. Hall, MA, VetMB, PhD, DECVIM-CA, MRCVS
Department of Clinical Veterinary Science, University of Bristol
Langford, Bristol, England

Genes may affect the development of inflammatory intestinal diseases by one or more of their influences on the:

 Recognition of bacteria

 Mucosal permeability

 Antigen presentation

 Regulation of the mucosal immune system

These diseases include food allergy and idiopathic inflammatory bowel disease, as intestinal inflammation is the final common pathway by which many intestinal diseases are manifested. The mucosal immune system may be responding to eliminate an infectious agent that has triggered this inflammation, but may also be the culprit in actually causing disease. In both scenarios the genetic make-up of the animal may be important.

Genetic susceptibility to infection may occur through immunodeficiency or through the expression of receptors that microbes use for attachment and invasion of the host, although environmental factors and simple opportunity are perhaps more important factors in whether an animal becomes diseased.

Immune-mediated diseases may also have a genetic susceptibility, and certainly breed-related intestinal diseases are noted and suggest an inherited transmission:

Basenji

lymphocytic/plasmacytic enteritis, IPSID

German shepherd

SIBO, IBD (LPE, EGE)

Irish setter

gluten-sensitive enteropathy

Lundehund

lymphangiectasia

SCWT

PLE/PLN

Shar pei

inflammatory bowel disease, (IgA deficiency)

Siamese cat

inflammatory bowel disease, adenocarcinoma

Finally, it is important to recognise that an apparent genetic basis to an intestinal disease may actually be the result of an opportune infection. Gastric carcinoma in humans is related to Helicobacter infection, and it has recently been recognised that histiocytic ulcerative colitis of Boxer dogs is associated with infection with an atypical adherent and invasive E. coli.1 However, it is not clear whether infection is merely related to opportunity (e.g., infection from the bitch in the perinatal period) or whether there is actually a genetic susceptibility to infection.

Food Allergy

Food allergy is a reproducible adverse reaction to a specific food or food additive with a proven immunological basis. In dogs and cats it is a well-recognized cause of pruritic skin disease. Evidence for food allergy causing GI disease is less compelling, but even skin disease has to involve antigen presentation via the intestine.

Genetic predisposition to the development of food allergies may reflect inherent defects in the mucosal barrier and/or the gut-associated lymphoid tissue. Yet environmental factors, such as viral infections may be necessary to sensitize an animal by temporarily disrupting the mucosal barrier and/or immune system, and allow an allergic reaction to be triggered at the next exposure.

Food allergies have traditionally been considered to be IgE-mediated type 1 immediate hypersensitivity reactions, and remote, pruritic, skin disease fits such a model. However acute vomiting and diarrhoea and even urticaria and anaphylaxis immediately following ingestion of specific foods are rarely reported. In chronic GI disease, more complex delayed reactions seem more likely.

A number of histological changes in the gut have been proposed as markers of food allergy:

 Villus atrophy

 Lymphoplasmacytic infiltrate

 Eosinophilic infiltrate

 Intraepithelial lymphocyte infiltration

They resemble some of the histological changes seen in idiopathic inflammatory bowel disease (IBD), as they merely represent the final common pathway for intestinal inflammation. Therefore, it may be appropriate to perform a diet trial on every suspected case of IBD, before treating with immunosuppressive agents, in case it is actually a food allergy.

The literature suggests that in dogs the most frequent foods incriminated are beef, dairy products and gluten (wheat), whilst in cats, beef, dairy products and fish are apparently significant causes. The prevalence of allergy to different food substances may also be subject to geographic variation, reflecting the nature of the foods most commonly fed. Many proposed breed predilections are largely anecdotal, and it is likely that there are geographic variations, reflecting differences in the gene pool.

Idiopathic Inflammatory Bowel Disease (IBD)

"Inflammatory bowel disease (IBD) is ..... a disease of modern living, where over-vaccination , dysfunction of gut-associated lymph tissue, dietary intolerance, and nutritional imbalance combine to overwhelm the essential process of digestion."2

Such views, to be found commonly on the world-wide web, do contain some grains of truth and are read by our clients. And so we need to improve our understanding of the aetiology of IBD to be able to counter ignorance, improve our diagnostic accuracy and provide more effective treatments. The WSAVA-sponsored GI Standardisation Group hopes to develop a consensus statement on the histological definition of IBD. Furthermore, recent molecular research has begun to shed light on the function of the intestinal immune system, its interaction with the intestinal flora, and the mechanisms of intestinal inflammation, and to open up the possibility of novel therapies beyond immunosuppression.

Idiopathic IBD is probably the most common cause of chronic vomiting and/or diarrhoea in dogs and cats. However, the cause of idiopathic IBD is, by definition, unknown, and so extensive diagnostic investigations must be performed to exclude the known causes of intestinal inflammation before IBD can be deemed idiopathic. Chronic intestinal inflammation caused by food allergy and infections or associated with primary GI diseases such as lymphoma and lymphangiectasia must be ruled out. Yet even idiopathic IBD itself is probably not a single condition, but a collective term used to describe disorders associated with persistent or recurrent gastrointestinal signs and characterised by histological evidence of intestinal inflammation with no discernible cause. Unfortunately, the various histological descriptions of the intestinal inflammation do not give the clinician a clue as to their aetiology. Such descriptions merely report the predominant cell type present, and in fact in most cases a mixed population is actually present. Lymphocytic-plasmacytic enteritis (LPE) is considered to be the most common form of IBD in dogs and, particularly, in cats. Immunophenotyping and functional studies of the immune response of the cellular infiltrate are likely to yield more significant information.

There is no confirmed sex predilection for IBD but certain breeds are predisposed to certain types of IBD (see above). The disease is seen most frequently in middle-age dogs and cats although there is often a history of previous intermittent signs that may have been controlled, at least in part, by dietary manipulation. A diagnosis of idiopathic IBD before the age of one year is unlikely, and the clinician should look again for an underlying cause (e.g., diet or infection) before accepting that the condition is truly idiopathic and beginning immunosuppressive treatment.

IBD in dogs and cats is still poorly understood, and although the disease bears little resemblance histologically to IBD of humans (i.e., Crohn's disease and ulcerative colitis), commonalities in causation may exist. The infiltration of the lamina propria in IBD may reflect an immune response to dietary, microbial or self antigens, and certainly some cases are successfully managed with an exclusion diet or antibiotics. However, idiopathic cases usually require treatment with immunosuppressive drugs suggesting that there is an underlying immune defect that causes intestinal inflammation, but that luminal antigens drive the condition.

Abundant data have incriminated intestinal bacteria in the initiation and amplification of intestinal inflammation. Thus the central hypothesis for the development and persistence of IBD is the loss of tolerance to intestinal microfloral antigens. In rodent models of IBD either interference with the mucosal barrier (e.g., the N-cadherin dominant negative chimaeric mouse)3 or with the gut associated lymphoid tissue (e.g., mice deficient in interleukin [IL]-10 or T-cell receptor αβ, severe combined immunodeficiency [SCID] and CD3-ε transgenic mice, and HLA-B27 transgenic rats)4-7 produces intestinal inflammation only in the presence of an intestinal flora. However, in IL-2 deficient germ-free mice, non-pathogenic Escherichia coli mpk but not Bacteroides vulgatus induce colitis,8 and Bacteroides co-administration is protective.9 This suggests that bacterial virulence factors may influence expression of disease, and provides a rationale for the potential efficacy of probiotics.

Whilst the importance of intestinal bacteria in driving intestinal inflammation is recognised, it seems likely that inherent abnormalities in an individual's intestinal immune system may influence the manifestation and persistence of the inflammation. The NOD2/CARD15 bacterial peptidoglycan recognition gene is implicated in the susceptibility to Crohn's disease.10-12 Studies of steroid-responsive diarrhoea in dogs (presumed idiopathic IBD) have demonstrated a marked inflammatory response with increased CD4+ T cells, MHC class II positive cells, and L1+ cells (macrophages) with domination by IgG plasma cells and IgG expression.13 A semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) technique was used to identify altered cytokine mRNA expression in duodenal biopsies. It demonstrated up-regulation of the expression of pro-inflammatory cytokine mRNA: namely IL-2, IL-5, IL-12p40, IFNγ, TNFα, TGFβ.13 Equivalent semi-quantitative results have also been demonstrated in canine lympho-plasmacytic and histiocytic ulcerative colitis, and feline LPE by others.14-17 However, analysis using real-time RT-PCR to provide truly quantitative data has now been applied; similar results were not obtained.18

German shepherd dogs (GSDs) are prone to a number of chronic enteropathies. Dogs with antibiotic-responsive diarrhoea (ARD, also known as small intestinal bacterial overgrowth) show similar changes in cytokine mRNA expression to LPE, but no gross histological evidence of inflammation and a predominance of IgA plasma cell expression.13 As the average age of GSDs with IBD is much older than those with ARD, it has been speculated that ARD occurs first, and that prolonged stimulation by the intestinal flora in genetically predisposed individuals ultimately causes IBD. For a long time the predisposition of the GSD to a variety of intestinal diseases has focused on suspected IgA deficiency, although conflicting evidence concerning serum IgA concentrations in GSDs exists in the literature. However, serum concentrations do not reflect mucosal IgA secretion,19 and evidence of reduced fecal concentrations, and reduced secretion in intestinal explant cultures, despite increased IgA plasma cell numbers, have been reported.21 However, no changes in the expression of the polymeric immunoglobulin receptor (pIgR), IgA alpha chain or J chain have been found. Recently it has been shown that dogs can express at least four allotypes of IgA.21 Intriguingly all GSDs examined so far express just one of these allotypes. Variations in the allotype molecules occur at the hinge region, which could potentially influence the ability of the IgA molecules to bind antigens and their susceptibility to proteolysis, and hence their efficacy in immune exclusion of luminal antigens.

In conclusion, genetic susceptibility to immune-mediated intestinal diseases may exist, but the role of the intestinal flora is also important.

References

1.  Simpson KW, et al. Infect Immun 2006;74:4778

2.  Kruesi WK. http://www.crvetcenter.com/IBD.htm, 2000.

3.  Hermiston ML, et al. Science 1995;270:1203.

4.  Sellon RK, et al. Infect Immun 1998;66:5224.

5.  Dianda L, et al. Am J Pathol 1997;150:91.

6.  Veltkamp C, et al. Gastroenterol 2001;120:900.

7.  Taurog JD, et al. J Exp Med 1994;180:2359.

8.  Rath, HC, et al. Infect Immunol 1999;67:2969.

9.  Waidmann M, et al. Gastroenterol 2003;125:162.

10. Girardin SE, et al. J Biol Chem 2003;278:41702.

11. Inohara N, et al. J Biol Chem 2003;278:5509.

12. Hisamatsu T, et al. Gastroenterol 2003;124:993.

13. German et al. J Vet Intern Med 2001;15:14.

14. Jergens AE, et al. Am J Vet Res 1996;57:697.

15. Jergens AE, et al. Am J Vet Res 1999;60:515.

16. Mayoral I, et al. Zentralbl Veterinarmed B 1996;43:613.

17. Ridyard AE, et al. Vet Immunol Immunopath 2002;86:205.

18. Peters IR, et al. Vet Immunol Immunopath 2005;103:101.

19. German AJ, et al. Vet Immunol Immunopath 1998;64:107.

20. German AJ et al. Vet Immunol Immunopath 2000;76:25.

21. Peters IR et al. Immunogenetics 2004;56:254.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Edward J. Hall, MA, VetMB, PhD, DECVIM-CA, MRCVS
University of Bristol
Bristol, England


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