Many of the most common diseases in dogs have an immune or autoimmune component, including many types of cancer (prostate cancer, breast cancer, no-Hodking lymphoma, leukemya, etc), rheumatoid arthritis, hypothyroidism, lupus erythematosus, myasthenia gravis, diabetes, pemphigus vulgaris, Addison's disease, atopic dermatitis, mangue, haemolytic anaemia, leishmaniosis seceptibility, linked severe combined immunodeficiency syndrome, von Willebrand’s disease, narcolepsy, etc. Drugs or vaccines can trigger autoimmune diseases, and that immune response is partially influenced by the genetic background of the subject.
How does the immune system?
The respose of the inmune system can be summarized in the figure below:
The proteins encoded by the MHC are expressed on the surface of cells and display both self antigens (peptide fragments from the cell itself) and nonself antigens as fragments of invading microorganisms, to a type of lymphocytes called T cell, through specific proteins receptors (TCR) that has the capacity to kill or coordinate the killing of pathogens in infected or malfunctioning cells.
The immune system has another and equally important method for identifying an antigen: B lymphocytes called B cells with their membrane bound antibodies, also known as B cell receptors (BCR). However, whereas B cells can bind to antigens without much outside help, but the T cells require "presentation" of the antigen through the help of MHC.
These are the genes that mark virtually all body cells to help the immune system distinguish itself from foreign invaders such as bacteria or viruses. These genes are critical for immune system to differentiate yourself from foreign objects, and for displaying foreign antigens to your immune system. Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. The immune system mistakes some part of the body as a pathogen and attacks it.
The Genetic of MHC
In heterozygous individuals MHC genes are expressed in codominant, so that alleles inherited from both parents have an equivalent effects.
The genetic component of immunity may be especially important in purebred dogs that have a restricted gene pool. The biggest damage caused by inbreeding is an inevitable reduction in the effectiveness of the immune system. Each gene has an unusually large number of alleles (alternate forms of a gene that produce alternate forms of the protein). As a result, in a normal situation of hazard matting it is very rare for two individuals to have the same set of MHC molecules.
Only for the three genes of exon 2 of canine MHC class II (DLA-II): DRB1 (102 alleles), DQA1 (26 alleles) and DQB1 (67 alleles) are 11,036,376 possible genotypes for a heterozygous individual and only 1,379,547 genotypes for a homozygous individual.
The genes of the canine MHC
The major histocompatibility complex (MHC) is the most gene-dense region of the mammalian genome contains genes that encoded proteins expressed on the surface of cells and display both self antigens (peptide fragments from the cell itself) and nonself antigens (e.g., fragments of invading microorganisms) to the T lymphocytes that has the capacity to kill or coordinate the killing of pathogens in infected or malfunctioning cells.
In the canine MHC, called dog leukocyte antigen (DLA) located mainly in the pericentromeric region of the canine 12 chromosome (a minor portion of DLA-I is located in the subtelomeric region of the 38 chromosome) we can distinguish three major areas:
1. DLA class I: Encode membrane proteins (glycoproteines) of almost every cell in an organism. They present antigen fragments to cytotoxic T-cells via the CD8+ receptor on the cytotoxic T-cells.
2. DLA class II: Encode membrane proteins (glycoproteines) on antigen-presenting cells (APC: macrophages, dendritic cells, B lymphocytes). APC present antigen fragments to T-helper cells by binding to the receptor CD4+on the T-helper cells.
3. DLA class III: Encode proteins related to the immune system, such as complement proteins or tumour necrosis factor (TNF) and others none related with the immune response. They have a function very different from that of class I and class II.
A scheme of DLA genes, alleles and functions are in the figure below:
B and T cells and Genetic diversity
Antibodies and TCR specific receptors are similar both in their chemical details of specific antigen recognition. When B and T cells develop, their genomes become modified until the cell can produce one specific type of antibody or TCR specific receptor. If we had a different gene for each antibody our entire genome would be taken up by antibody genes. Nature resolves this apparent contradiction enabling the DNA rearrangement and other mutations in the genome of these types of cells and a small number of genes can recombine to generate multitudes of possible antibodies or TCR specific receptors (VDJ recombination) that are necessary for the recognition of diverse antigens from bacterial, viral, and parasitic invaders, and from dysfunctional cells such as tumor cells.
For example, by a simplified calculation, a DNA chain with 6 gene segments, each of which can be rearranged in 10 different ways (in a real case are many more). These six segments produce:
10 x 10 x 10 x 10 x 10 x 10 = 1 million of different antibodies.
A heterozygous dog can produce 2 millions of antibodies and a homozygous dog for these genes only half (1 million).
Loss of alleles is a common consequence of endogamy. If by a repeated use of inbreeding it loss 1 of the initial 6 gene segments, there is a reduction in the production of antibodies (or TCR specific receptors) to only 100.000 antibodies (loss of 900.000 antibodies).
In an endogamic dog the chromosomes have identical gene segments with respect to immune system cells. When this occurs, the animal begins to lose its ability to fight certain diseases.
Genetic scent signals
Nature has created a special protection against dangerous reduction of genetic variation in the MHC gene system. Again the solution is brilliantly simple. The genes of the MHC system take part in the production of the scent substances called pheromones. The pheromones are important sexual signals and make it possible for animals to "smell" part of the genetic set up of the MHC genes carried by a possible mating partner.
It is important to accept when the bitches distinctly signal that they do not accept a male. The females know better than the breeder if the male carries MHC genes which are favourable for her progeny. Forced mating is an effective way to violate one of the most important protections of genetic variability.
What is the situation in Dobermann?
In the MHC Class II genes has been a wide variation between breeds but a slight variation of haplotypes within each breed (Kennedy et al., Tissue Antigens 2002 59: 194–204
). This study include 82 breeds and 886 genotyped dogs (25 Dobermanns) and authors compare the number of alleles at the alleles frequency and diversity for the locus DLA II -DRB1, DLA II -DQA1 For locus DLA II -DRB1, the Dobermann is the breed with a smaller number of alleles (only 2 of 30 possible alleles) and frequency of one allelle (DLA-DRB1-006) is nearly homozygous (97.5%), the bigger allele frequency of any allele in the nine analyzed pure breeds. For locus DLA II -DQA1 is the second breed, after Poodle, with minor diversity (4 of 17 possible alleles) but the allele DLA II -DQA1-00401 has the higher frequency (85%) between all alleles and breeds in locus DLA II -DQA1.
Dobermann is predisposed for many types of cancer: lymphoproliferative diseases (no-Hodking and leukaemia) (Modiano et al., Cancer Res 2005; 65: (13). July 1, 2005
), osteosarcoma (Terracini et al., The Veterinary Journal, 11998, 156, 31-39
), mammary and prostate cancer (Cadieu & Ostrander, Cancer Epidemiol Biomarkers Prev 2007; 16, 11, 2181-2183
), melanoma …..
Cancer risk is associated with the loss of heterozygosity in the MHC, particularity in the DLA-II involved in the polymorphisms of the T-helper cells. In a study about genetic of hepatitis in 40 Dutch Dobermanns (Mandinguers 2005, Insights in the pathogenesis of Dobermann hepatitis, Thesis Univ. Utrech, p.188
), DNA sequencing of the DLA-II genes: DRB1, DQA1 and DQB1, showed the haplotypes distribution of the table below:
89% of the studied Dobermanns had the same haplotype!! Inappropriate MHC class II expression in hepatocytes and mononuclear cell infiltration suggests an autoimmune nature for chronic hepatitis in Dobermans.
Dobermann and English springer spaniel are the breed with most high risk for mammary cancer (Egenvall et al. Prev Vet Med 2005; 69:109–27
). In a study about Biochemical Markers and Genetic Risk Factors in Canine Tumors (Rivera, 2010, Doctoral Thesis, Uppsala University, p.48
), author has sequenced the same DLA-II genes and he found a statistically significant protective effect for breast cancer in dogs (355 dogs: German Shepherds, English Springer Spaniels, Dobermanns and Boxers) carrying the haplotype:
DLA-II: DRB1-00101/DQA1-00201/DQB1-01303 .
The results indicate also that the DRB1 and DQA1 loci are the major contributors to the negative association with breast cancer and the allele DQA1-00201 is a main contributor to the breast cancer resistance.
Look now to the last table of the work of Mandinguers
with 40 Dutch Dobermanns. Major haplotype (89%) for DLA-II genes is DRB1-00601/ DQA1-00401/DQB1-01303. Was the allele DQA1-00201, the major contributor to the breast cancer resistence? Lost.
In dogs, hormonal cancers as prostate cancer are rare. Some breeds of dog seem to be at a higher risk for the disease, such as the Bouvier de Flanders, Dobermann, Shetland sheepdogs, and the Norwegian Elkhound, specially in castrated males (Cadieu & Ostrander, Cancer Epidemiol Biomarkers Prev 2007; 16, 11, p2181
Relatively shorter lengths of the polymorphic polyglutamine repeat-1 (CAG-1) of the androgen receptor gene have been associated with an increased risk of prostate cancer. A high percentage (64.5%) of the shortest haplotype 10/11 was found in the Doberman (Chen-Li Lai at al. J Vet Intern Med 2008; 22:1380-1384
Hypothyroidism which showed an association of the disease with a haplotype carrying DLA class II allele DQA1-00101, (Kennedy at al. Tissue Antigens 2006: 67: 53–6). The average frequency in Dobermann haplotypes for risk allele in Dobermann is 20% and it’s one of the most risk breed (Angles et al. Diversity of DLA class II alleles in 25 dog breeds Tissue Antigens 2005: 66: 173–184
). MHC haplotype found in association with hypothyroid disease in Dobermans, it is unlikely that the same rare haplotype will be found to be associated with hypothyroid disease in other dog breeds (Kennedy et al., 2006Tissue Antigens 67, 53–56
). Obviously the rare haplotype as breed disease characteristic it is the result of the endogamic practices in the breeding.
Doberman is reported with Golden Retriever, Dalmatian and Dachshund as greater risk breeds for the development of skin disease (Zur et al. 2002; Veterinary Dermatology, 13, 89–102
In a review of immunologic diseases of the dog, Pedersen (Veterinary Immunology and Immunopathology 69 (1999) 251-342)
, Dobermann breed is predisposed for acquired myasthenia gravis, Bullous pemphigoid, Systemic lupus erythematosus, hypothyroidism, chronic active hepatitis, myelomas and cryptococcal infections.
Immune mediated hemolytic anemia secondary to sulphonamide antibiotics administration has been reported in Doberman pinscher dogs, as part of an allergic drug reaction complex, involving both Types II and III hypersensitivity reactions (Giger et al. J AmVet Med Assoc 1985; 186: 479-483
Dobermann is a breed of risk with the Rottweiler for canine parvovirus enteritis (Glickman et al., Journal of American Veterinary Medical Association, v.187, n.6, p.589-94, 1985
Why we must limit the number of litters sired by a male?
The effective size of the population is important in relation to accumulation of inbreeding in a population and as evaluation of genetic diversity.
Calculations formulas are:
For instance, a simulation for a six generation population with a normal progression: 10, 80, 120, 150, 170 y 230 (N=760) individuals with only 5% of males participate in the configuration of the next generation and an average endogamic coefficient of F=0,10. The Ne would be:
Simulation demonstrate that the asymmetric distribution of reproductive population between males and females (top sire syndrome), it’s the main effect on the Ne reduction.
The level of “top sire syndrome” in Dobermann is so high that in a study of the diversity of the Y chromosome, Doberman has a diversity of 0!! (a single haplotype H7 for all 17 dogs of the sample of dogs at least unrelated in the first generation) (Bannasch at. al., 2005. Mammalian Genome, Volume 16, 273–280
The verdict of the facts is more powerful than the eloquence of the views. Individual efforts are laudable but it is impossible to overcome this situation without a collective effort. This also poses an ethical dilemma, but Genetics can not resolve what Ethics is not able to discern.