Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

Quarter Horse

Arabian

Severe combined immunodeficiency

Related conditions: SCID; lymphopenia; lymphoid hypoplasia

Outline: Severe combined immunodeficiency is an autosomal recessive trait in Arabian horses and is characterised by the complete absence of functional white blood cells of two types - functional B and T lymphocytes - which have a vital function in the body’s adaptive immune system. Affected foals are more susceptible to infectious diseases and are less able to recover from infections. The common clinical signs relate to infections and include nasal discharge, coughing, intermittent fever, pneumonia, colic (abdominal pain), weight loss and diarrhoea. Treatment is usually supportive and may prolong life, but affected foals invariably cannot survive and usually die within the first 6 months of life.


Summary of Information

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1. Brief description

Severe combined immunodeficiency is characterised by the complete absence of functional B and T lymphocytes; B and T lymphocytes are subtypes of white blood cells, which have an important function in the adaptive immune system. These cells recognise “non-self” antigens in the body – molecules such as chemicals, bacteria, viruses or pollen inducing an immune response to destroy the foreign molecules. B cells produce antibodies that destroy bacteria or viruses outside of cells whereas T cells are involved in cell-mediated immune responses, and act to destroy infected or damaged cells, such as virus-infected cells, cells with intracellular bacteria and cancer cells displaying tumour antigens. Affected horses have a mutation in an enzyme which is responsible for the differentiation of B and T lymphocytes, resulting in absence of mature types of these cells. Such horses are therefore more susceptible to infectious diseases and are less able to recover from infections.

The most common clinical signs relate to those caused by the infection, and include nasal discharge, coughing, intermittent fever, pneumonia, colic (abdominal pain), weight loss and diarrhoea. Infection of the pancreas may result in loss of functional endocrine tissue leading to stunted growth and weight loss. Affected horses are also susceptible to secondary bacterial infection.

2. Intensity of welfare impact

The welfare impact of this disease depends upon the type, frequency and severity of infection that the affected horse suffers from. Most commonly, infections occur in the respiratory tract and cause nasal discharge, coughing, breathlessness (dyspnoea), pneumonia or respiratory distress. Infections in other bodily areas may result in intermittent fever, colic (abdominal pain), weight loss and diarrhoea.

Treatment is usually supportive, such as the use of antibiotics to treat secondary infections, and this can prolong life, but affected animals invariably have a shortened lifespan. Though a diagnosis is difficult, if foals are suspected of having severe combined immunodeficiency, euthanasia might be considered to prevent further suffering.

3. Duration of welfare impact

The age of onset of clinical signs depends on environmental challenges and the adequacy of passive transfer of immunity – which occurs when the new born foal first suckles and consumes colostrum, a type of milk produced by the mare for the first 2-3 days after birth, which contains antibodies that the foal absorbs through its gut and which gives it some immunity. Usually, horses with severe combined immunodeficiency become susceptible to infections by 6 to 10 weeks after birth.

The prognosis for affected foals is poor, and they usually die or are euthanised within the first 6 months of age.

4. Number of animals affected

Severe combined immunodeficiency affects both males and females equally commonly. In the USA, the frequency of heterozygous carriers of the condition in Arabian horses - which have inherited one copy of the mutated gene - was just under 9%, while a study in the UK found a prevalence of heterozygous carriers of just under 3%.

5. Diagnosis

Diagnosis is not straightforward as the typical clinical signs of the disease result from the infections that the animal acquires and these may be common in foals regardless. Consequently, the underlying immunodeficiency may not therefore be initially suspected until the foal has suffered frequent and persistent infections, and a diagnosis may be made post-mortem. The most sensitive test for severe combined immunodeficiency is the gene probe which detects the mutation responsible (ie DNA testing). Diagnosis can also be made based on the lack of serum IgM in foals over 4 weeks of age, accompanied by persistently low levels of lymphocytes in the blood (lymphopenia; with less than 1000 lymphocytes per ml).

6. Genetic

Severe combined immunodeficiency is an autosomal recessive trait in Arabian horses. Horses with two copies of the defective gene, one from each parent (homozygous), will be clinically affected by the condition. If a horse has inherited only one copy of the mutation, from one parent, it will not be affected by immunodeficiency and will show no sign of the condition itself, but will be a genetic carrier (heterozygous) and can pass on the mutated gene to some of its offspring. These carriers may also have an increased risk of developing tumours, which may or may not be malignant (cancerous).

7. How do you know if an animal is a carrier or likely to become affected?

A genetic test is available for the detection of the genetic defect causing severe combined immunodeficiency in horses. It can distinguish between homozygous affected horses (those that have two copies of the mutated gene) and heterozygous carriers (those with only one copy of the mutation), as well as non-affected horses (no gene mutation).

8. Methods and prospects for elimination of the problem

Homozygous affected animals are unlikely to be used for breeding since they do not generally reach sexual maturity. Genetic screening of animals before breeding is recommended for Arabian horses. Heterozygous carriers should not be bred from, where possible.


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1. Clinical and pathological effects

Severe combined immunodeficiency is characterised by the complete absence of functional white blood cells of two types - the B and T lymphocytes (Perryman 2004). Lymphocytes are subtypes of white blood cells, which have an important function in the immune system. Lymphocytes include natural killer cells, B and T cells. Natural killer cells provide rapid response to destroy viral-infected cells, and thus have an important role in cell-mediated cytotoxic innate immunity. B and T lymphocytes function as part of adaptive immunity, which is highly specialised and can provide life-long protection by creating immunological memories of specific pathogens (Tizard 2012). Both B and T cells are produced by stem cells in the bone marrow, and are formed from a common lymphoid progenitor. The differentiation of mature B and T lymphocytes from lymphoid precursors requires the rearrangement and expression of genes encoding T-cell receptors and immunoglobulin receptors. Both B and T cells recognise “non-self” antigens – molecules such as chemicals, bacteria, viruses or pollen which are foreign to the body and which induce an immune response. Once a foreign molecule has been recognised, the cells generate tailored responses to eliminate specific pathogens or pathogen-infected cells. B cells play a large role in the humoral immune response, responding to antibodies and other proteins found in extracellular fluids. They express B cell receptors on their cell membrane and these allow them to bind to a specific antigen, against which it will then initiate the production of specific antibodies which destroy the bacteria or virus. T cells mature in the thymus and are involved in cell-mediated immune responses, acting to destroy infected or damaged cells, such as virus-infected cells, cells with intracellular bacteria and cancer cells displaying tumour antigens (Tizard 2012). T helper cells produce cytokines that regulate the immune responses. Another subtype, cytotoxic T cells induce cell death (apoptosis) of cells recognised as foreign. Once activated, T and B cells form memory cells, which “remember” specific pathogens encountered and enable a strong and rapid response if the pathogen is detected again throughout the lifetime of an animal.

Horses with severe combined immunodeficiency have a complete absence of functional B and T lymphocytes (Perryman 2004). Therefore, affected horses fail to produce antigen-specific immune responses, and as a result are more susceptible to infectious diseases and are less able to recover from infections than unaffected individuals. Infectious diseases of the respiratory tract are common in such animals, for example pneumonia caused by viral (Adenovirus), bacterial (Rhodococcus equi), fungal (Pneumocystis carinii) or protozoal (Cryptosporidium) organisms (McGuire & Poppie 1973, Wiler et al 1995).

Affected individuals lack DNA-dependent protein kinase (PK) activity (Wiler et al 1995). Recombinase-activating agents, expressed in lymphoid tissues, and DNA protein kinase act sequentially within B - and T - lymphocyte precursor cells to cut, rearrange, and forge DNA that encodes B-lymphocyte surface immunoglobulin receptors and T-lymphocyte antigen-specific receptors. Failure to properly complete these gene rearrangement events results in the absences of lymphocyte precursors and consequently of mature, functional B- and T lymphocytes. Lymph tissue is underdeveloped (lymphoid hypoplasia) and germinal centres – sites where mature lymphocytes mature – are absent (McGuire & Poppie 1973).

The most common clinical signs relate to those caused by the infection, including nasal discharge, coughing, intermittent fever, pneumonia, colic (abdominal pain), weight loss and diarrhoea. Infection of the pancreas may result in loss of functional endocrine tissue leading to stunted growth and weight loss. Affected foals are also susceptible to secondary bacterial infection.

Horses which carry only one copy of the gene mutation responsible for severe combined immunodeficiency (ie heterozygous) are not affected by an increased rate of infections and have clinically normal levels of B and T lymphocytes (Swinburn et al 1999). However, heterozygous carriers have been found to have an increased risk of tumours. One study found that in horses with tumours the carrier frequency was significantly increased compared to horses without tumours (Ding et al 2002). In such individuals, the types of tumour were largely sarcomas but melanomas and other tumour types were also found. A sarcoma is a tumour that arises from mesenchymal cells, that form the lymphatic and circulatory systems or connective tissues and these may or may not be malignant (cancerous). Sarcomas (sarcodis) are the most common tumour of the horse and usually appear as fibroblastic, wart-like skin lesions that are often invasive and recurrent (Goodrich et al 1998). Predisposition of horses to sarcoids is linked to the functioning of the major histocompatibility complex (Lazary et al 1985), which is essential for the adaptive immune system. It is thought that DNA-dependent protein kinase may suppress the development of tumours through functional repair of DNA (Perryman 2004), hence in affected horse that lack protein kinase activity, tumour development is more likely.

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2. Intensity of welfare impact

The welfare impact of this disease depends upon the type, frequency and severity of infection that the affected horse suffers from. Most commonly infections occur in the respiratory tract and cause nasal discharge, coughing, breathlessness (dyspnoea), pneumonia or respiratory distress. Other clinical signs may reflect infection in other bodily areas, and include intermittent fever, colic (abdominal pain), weight loss and diarrhoea.

Treatment is usually supportive, eg the use of antibiotics to treat secondary infections - and this may prolong life, but affected animals invariably have a shortened lifespan.  Transplantation of normal histocompatible bone marrow cells has successfully corrected the immunodeficiency in foals (Perryman et al 1987); however, this procedure is currently considered experimental and not widely available. The procedure itself may cause pain and distress, and there may be associated risks if the transplant fails.

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3. Duration of welfare impact

Antibodies from the mother are transferred to the new born foal through colostrum, a type of milk produced by the mare for the first 2-3 days after birth that is rich in immunoglobulins, which the foal then absorbs through the gut. This protection means that affected foals are therefore clinically normal, have a passively functioning immune system, at birth. The age of onset of clinical signs of the disease depends on the environmental challenges faced by the foal – eg the number of pathogens it is exposed to in its environment - and the adequacy of passive transfer of immunity.  Usually, horses with severe combined immunodeficiency become susceptible to infections by 6 to 10 weeks after birth.

The prognosis for affected foals is poor, and whilst treatments may prolong life, most affected horses die or are euthanased within the first 6 months of life.

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4. Number of animals affected

Severe combined immunodeficiency was recognised in Arabian horses in the early 1970’s (McGuire & Poppie 1973) and it affects both males and females equally.

In two USA studies, of 508 un-related Arabian horses tested for the gene mutation responsible for severe combined immunodeficiency, 44 horses (8.7%) were heterozygous carriers for the condition- ie had inherited one copy of the mutated gene and were able to pass it on (Bernoco & Bailey 1998, Ding et al 2002). In the UK, 106 Arab horses were tested for the gene mutation, 3 (2.8%) were carriers for the condition (Swinburne et al 1999). These studies did not use records of foal deaths and therefore do not reflect the frequency of homozygous affected animals (those that inherited two copies of the mutated gene). In reality, data on the number of homozygous affected animals is difficult to obtain, since foals die very young and a conclusive diagnosis may not have been reached.

Heterozygous carriers have an increased risk of tumours; in one study, 41 of 295 (14%) horses with tumours carried the mutant allele for severe combined immunodeficiency (Ding et al 2002). The tumours were largely sarcomas (19/102, 18.6%) but melanomas and other tumour types were also found in lower frequencies.

 

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5. Diagnosis

Diagnosis is not straightforward as the clinical signs of the disease are associated with the infection that the animal has and these may be common in foals; the underlying immunodeficiency may not therefore be initially suspected until a foal has suffered repeated and frequent infections and shown a poor response to treatment of those infections. A diagnosis may therefore commonly be made post-mortem. The most sensitive test for severe combined immunodeficiency is the gene probe which detects the mutation responsible (ie DNA testing). Diagnosis can also be made based on the lack of serum IgM in foals over 4 weeks of age, accompanied by persistently low levels of lymphocytes in the blood (lymphopenia;  with less than 1000 lymphocytes per ml), and underdevelopment of lymph tissue (lymphoid hypoplasia).

A post-mortem examination may reveal a small thymus and/or absent lymph nodes. Histologically, lymph node follicles and germinal centres are absent with severe cellular hypoplasia of the thymus and lymph nodes.

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6. Genetics

Severe combined immunodeficiency is an autosomal recessive trait in Arabian horses (Wiler et al 1995, Shin et al 1997).

Horses that have inherited two copies of the defective gene, one from each parent (homozygous), will be clinically affected by the condition. If a horse only has one copy of the mutation, inherited from one parent, it will not be affected by immunodeficiency but it will be a genetic carrier (heterozygous) and will pass on the mutated gene to some of its offspring. Heterozygous carriers also have an increased risk of developing tumours, particularly sarcomas, which may lead to cancer (Ding et al 2002). If two heterozygous horses, each carrying one copy of the mutated gene, are mated together, there is a 25% chance of their offspring being clinically affected with immunodeficiency (ie homozygous) and a further 50% chance of heterozygous carriers of the condition.

The condition is caused by a deletion in the gene responsible for producing DNA-dependent protein kinase, involved in gene rearrangement activities for the differentiation of lymphocytes into T and B cells (Wiler et al 1995). The deletion causes the protein to be unstable.

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7. How do you know if an animal is a carrier or likely to become affected?

A genetic test is available for the detection of the genetic defect causing severe combined immunodeficiency in horses. The test is usually conducted with blood samples, but can be done non-invasively, using saliva or hairs with roots. It can detect homozygous affected horses (those with two copies of the mutation) and heterozygous carriers (those with only one copy of the mutation), as well as non-affected horses (with no gene mutation).

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8. Methods and prospects for elimination of the problem

Homozygous affected animals are unlikely to be used for breeding since they do not generally reach sexual maturity. The condition can be unknowingly spread in the population by the breeding of heterozygous carrier horses that carry only one copy of the defective gene; the breeding of two carriers together is likely to produce 25% homozygous affected horses and 50% heterozygous carriers amongst their offspring. Genetic screening of animals before breeding is therefore recommended for Arabian horses.

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9. Acknowledgements

UFAW thanks Dr Emma Buckland (BSc PhD), Dr David Brodbelt (MA VetMB PhD DVA DipECVAA MRCVS) and Dr Dan O’Neill (MVB BSc MSc PhD MRCVS) for their work in compiling this section.

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10. References

 

Bernoco D and Bailey E (1998) Frequency of the SCID gene among Arabian horses in the USA. Animal Genetics 29: 41–42

Ding Q, Bramble L, Yuzbasiyan-Gurkan V, Bell T and Meek K (2002) DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia. Gene 283: 263–269

Goodrich L, Gerber H, Marti E and Antczak D (1998) Equine sarcoids. The Veterinary Clinics of North America: Equine Practice 14: 607-623

Lazary S, Gerber H, Glatt P and Straub R (1985) Equine leucocyte antigens in sarcoid-affected horses. Equine Veterinary Journal 17: 283-286

McGuire TC and Poppie MJ (1973) Hypogammaglobulinemia and thymic hypoplasia in horses: a primary combined immunodeficiency disorder. Infection and Immunity 8: 272–7

Perryman LE (2004) Molecular pathology of severe combined immunodeficiency in mice, horses, and dogs. Veterinary Pathology 41: 95–100

Perryman LE, Bue CM, Magnuson NS, Mottironi VD, Ochs HS and Wyatt CR (1987) Immunologic reconstitution of foals with combined immunodeficiency. Veterinary Immunology and Immunopathology 17: 495–508

Shin EK, Perryman LE and Meek K (1997) Evaluation of a test for identification of Arabian horses heterozygous for the severe combined immunodeficiency trait. Journal of the American Veterinary Medical Association 211: 1268–70

Swinburne J, Lockhart L, Scott M and Binns MM (1999) Estimation of the prevalence of severe combined immunodeficiency disease in UK Arab horses as determined by a DNA-based test. Veterinary Record 145: 22–23

Tizard IR (2012) Veterinary Immunology, 9th edition. Saunders Elsevier, Missouri

Wiler R, Leber R, Moore BB, VanDyk LF, Perryman LE and Meek K (1995) Equine severe combined immunodeficiency: a defect in V(D)J recombination and DNA-dependent protein kinase activity. Proceedings of the National Academy of Sciences 92: 11485–11489

© UFAW 2016


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