Michael J. Day, BSc, BVMS(Hons), PhD, DSc, DECVP, FASM, FRCPath, FRCVS
The four major forms of immune-mediated disease are hypersensitivity, autoimmunity, immunodeficiency and immune system neoplasia. These are all examples of disturbance of normal immune system homeostasis. Immune-mediated diseases are multifactorial and their clinical expression depends upon the optimum interaction of a range of predisposing and triggering factors.
Genetic Basis for Immune Disease
Immune-mediated diseases have distinct predispositions in particular races of man, and are inherited through families. A similar situation exists for breeds of dog - but in cats such associations are rarely documented. Examples of familial canine autoimmunity, hypersensitivity and immunodeficiency are also documented, and there are anecdotal reports of pedigrees of dog in which lymphoma occurs frequently. One factor underlying this phenomenon is likely to be the degree of inbreeding which over the past two centuries has led to the development of many of the pure breeds of dog.
Relatively little is understood of the precise genetic basis for immune-mediated disease. Some gene clusters have strong associations with immune-mediated disease, either because the protein products of the genes are integrally involved in the aberrant immune-response, or because the genes are 'markers' of poorly defined causative 'disease genes'. An example of this is the association between particular genes of the Major Histocompatibility Complex (MHC) and autoimmunity. There are now two versions of the canine genome and a partial version of the feline genome. Modern genomic technology has led to a reawakening of interest in comparative genomics and the genetic basis of canine disease.
The most exciting development in canine genomics has been the European LUPA project (www.eurolupa.org) which has received major European Union funding to permit a genomic investigation of canine diseases that may model similar human conditions. From 2008–2011, consortia of investigators in European veterinary schools collected blood samples from dogs with well-phenotyped breed-associated disease. These were subject to genome-wide association studies (GWAS) using microarray technology to identify single nucleotide polymorphisms (SNPs) in genes that may underlie these diseases.
The Genetic Basis for Canine Autoimmunity
It is now widely recognized that autoimmunity is multifactorial in aetiology. One of the most significant predisposing factors is genetic background. In man (but not dogs) there is a strong hormonal influence with a marked female predisposition. Lifestyle factors such as stress and diet also play a role. Additionally, a wide range of environmental influences play a part in triggering autoimmunity and these include: exposure to infectious agents, drugs, vaccines or UV light.
In man, particular autoimmune diseases occur more frequently in certain races and may be familial. Similarly, particular breeds of dog more often develop autoimmune diseases and these clearly run through pedigrees. The genes most closely associated with genetic predisposition to autoimmune disease are those clustered on a single chromosome to form the MHC. The class I, II and III genes of this complex are integral to immune function and are often termed 'immune response genes.'
MHC-disease associations have now been documented for canine immune-mediated haemolytic anaemia, lymphocytic thyroiditis, diabetes mellitus, Addison's disease and rheumatoid arthritis. Similar associations have been shown to underlie immunological susceptibility or resistance to infection by Leishmania and the susceptibility of German shepherd dogs to anal furunculosis. Both protective and susceptibility haplotypes for some of these diseases have been documented.
GWAS involving microchip scanning of SNPs across the canine genome are now proving informative. One published study has defined genomic associations with the SLE-like autoimmune disease of the Nova Scotia duck tolling retriever.
The Genetic Basis for Canine Allergy
There are clear breed predispositions for the development of type I hypersensitivity diseases in the dog. The most widely recognized of these is the susceptibility of West Highland white terriers (WHWT), golden retrievers/Labradors and German shepherds for atopic dermatitis. Husky dogs have a predisposition to the development of eosinophilic bronchopneumopathy.
To date, there has not been extensive investigation of inheritance of canine allergy at the molecular level. However, as the immunopathogenesis of these diseases is now well-defined, there are numerous 'candidate gene' polymorphisms that might be studied and some of these have recently been described in a gene expression microarray study.
The Genetic Basis for Canine Immunodeficiency
Primary, congenital immunodeficiency disease is most widely recognized in the dog, where approximately 20 distinct entities are documented. There is only a small number of canine immunodeficiency diseases for which the inherited defect is characterized, and for which molecular diagnostic tests have been developed. These include: X-linked severe combined immunodeficiency (X-SCID) in the Bassett, Corgi and Jack Russell Terrier, cyclic neutropenia in the grey Collie and canine leukocyte adhesion deficiency (CLAD) in the Irish Setter. These disorders are autosomal recessive with heterozygous carriers and homozygous affected animals.
The Genetic Basis for Canine Immune System Neoplasia
There is clear clinical evidence that particular canine breeds are more susceptible to certain types of immune system neoplasia. For example dogs of the boxer breed have elevated risk of developing lymphoma or mast cell tumour and the range of histiocytic neoplasms are well-documented in Bernese Mountain dogs and flat coat retrievers. These tumours are also known to arise within particular pedigrees of these breeds.
For many immune-mediated diseases, distinct age predispositions are recognized. Examples include the higher prevalence of autoimmunity in middle aged to older dogs, and the frequent onset of atopic dermatitis in dogs < 3 years of age. One of the proposed mechanisms by which increasing age is related to the development of autoimmune or neoplastic disease is that of 'immunosenescence.'
The role of environmental factors is now recognized to be of major importance in the expression of immune-mediated disease. These environmental factors may work at different levels. In the case of allergy, there is an obvious association between exposure to allergen (e.g., pollens, flea saliva, and dust mite) and development of hypersensitivity but other effects are also at play. Allergy is a disease of industrialized western civilization and relates to numerous aspects of lifestyle, including diet, indoor environment, environmental pollution and stress.
A major area of research in human clinical immunology has been the 'hygiene hypothesis' which has been proposed to account for the increasing incidence of allergic and autoimmune disease in western society. The hygiene hypothesis suggests that reduced exposure to infectious agents in modern life leads to reduced induction and activity of regulatory or suppressor T cells (Treg) that are responsible for preventing inappropriate activation of allergen- or autoantigen-specific lymphocytes. Failure to develop adequate regulatory T cells leads to increased susceptibility to allergic and autoimmune disease. This hypothesis is supported by epidemiological and immunological studies which show protective effects (from developing immune-mediated disease) if children are brought up in a rural versus urban environment, have exposure to pets in the home, attend nursery or are part of large families or receive BCG vaccination. Exposure of the pregnant mother to such influences may also be able to direct programming of the developing fetal immune system towards resistance to allergic disease.
Environment is also now known to play a key role in the development of autoimmune disease, in particular through exposure to microbes. Viruses are widely implicated as the trigger of many human 'autoimmune' diseases. In companion animal medicine we also now appreciate that infectious agents might underlie diseases that were previously considered 'autoimmune' in nature. The largest group of such organisms is the arthropod-transmitted agents which appear to have a propensity for interacting with the host immune response to trigger secondary immune-mediated phenomena. Drugs and vaccines are also known to be triggers of autoimmunity in man and animals.
Environmental pollutants have been implicated in the pathogenesis of immune system neoplasia. Canine lymphoma does not have a retroviral aetiology, but numerous carcinogens have been implicated and a recent study has shown an association with living near to waste dumps. Feline lymphoma is now no longer automatically assumed to be retroviral in aetiology, and affects an older cohort of cats with a predominantly alimentary distribution. Preceding inflammatory disease (lymphoplasmacytic IBD) is a well-documented precursor to alimentary lymphoma in cats, and there are other examples of pre-neoplastic inflammatory change in this species. One recent intriguing association is that between exposure to cigarette smoke and lymphoma in the cat.