immune-mediated disease

• Immune-mediated diseases in dogs constitute a large group of disorders with the common attribute that they are caused by dysfunctions in the immune system. They can be subdivided into: 

  • Immunodeficiency disorders – reduced immune system function
  • Allergies – hypersensitivity reactions towards an external substance
  • Autoimmune diseases – autoantibodies present (against self, or something within self cells)
• Autoimmunity = a failure of self-tolerance. Self-reactive T and B lymphocytes become active and may cause tissue damage and clinical autoimmune disease.
• Normally, the body is self-tolerant, ie doesn’t react to itself, but it is when this process goes wrong that autoimmune problems can arise. Autoimmunity is multifactorial and can have several predisposing factors, or triggers:

  • Immunological imbalance – the normal self-tolerance mechanism goes wrong.
  • Genetics  – there is a clear genetic predisposition for some diseases.
  • Predisposing factors
  • more common in middle to older age
  • neutered animals are more likely to get autoimmune diseases
  • Lifestyle
  • Diet
  • environmental factors e.g., vaccinations, drugs and infectious disease
• "IgE mediated reaction that occurs within 1 hour" which hypersensitivity reaction has been described?

  type I
• "IgG or IgM cytotoxic mediated reaction which can take hours to days"which hypersensitivity reaction has been described?

  type II
• ""immune complex mediated reaction which takes 1-3 weeks" which hypersensitivity reaction has been described?

  type III
• "a t-cell mediated reaction which occurs within days to weeks" which hypersensitivity reaction has been described?

  type IV
• Most AI diseases are organ-specific and target autoantigens in a single system, but some are multisystemic.
• which hypersensitivity reactions are involved in autoimmune disease?

  Type II, III and IV
• autoimmune hemolytic anaemia involves RBC destruction mediated via IgG or IgM autoantibody and the classical pathway of complement (type II hypersensitivity).
• Lymphocytic thyroiditis involves the destruction of thyroid follicular epithelium by cytotoxic T lymphocytes (type IV hypersensitivity).
• Primary idiopathic autoimmune disease arises in a genetically susceptible individual in the absence of a known trigger.  Secondary autoimmune disease occurs due to a recognised underlying trigger. 
• There are lots of known triggers for autoimmune disease. They will not cause AI disease in all cases but have been shown to predispose an animal to these conditions...

  • Neoplasia or chronic disease
  • Environmental triggers
  • Drugs and vaccines as triggers - Antimicrobial drugs are the most implicated.
  • Infectious triggers - The infection may occur immediately before the onset of the autoimmune disease, or there can be a long lag period.
• The most recognised example of a drug trigger to autoimmune disease in dogs is trimethoprim-sulphonamides (TMPS) triggering IMHA, IMTP or IMNP. Dobermann’s are especially predisposed

  • In cats, methimazole/carbimazole for the treatment of hyperthyroidism) is also known as an IMHA/ IMTP and serum ANA production trigger.
• Autoimmunity occurs in canine babesiosis. The RBCs are parasitised by Babesia spp and can develop IMHA secondarily. It is thought that antibodies associated with erythrocytes are true autoantibodies with specificity for RBC membrane antigens. It is possible that a Babesia antigen carries an epitope that acts as a molecular mimic for an epitope within an RBC population. 
• Immunodeficiency is a functional problem with the immune system, making the animal more susceptible to infections. Overall, the immune system is underactive. They are different to immune-mediated diseases where the immune system works but acts inappropriately against itself.  
• Immunodeficiency = failure of part/s of the immune system due to inherited gene mutations (primary immunodeficiency) or acquired suppression of immune function (secondary immunodeficiency).
• Primary immunodeficiency disorders are rare, or rarely recognised unless they are severe. Usually, there is a congenital defect affecting the formation or function of cells and/or proteins of the innate and/or adaptive immune system. This might, for example, affect neutrophils or lymphocytes.  Markers for these disorders include:

  • repeated infections in a young animal post-weaning or after the loss of maternal antibody
  • purebred puppy or several puppies from a litter experiencing problems
• While primary immunodeficiency is rare, secondary immunodeficiency is comparatively common and can affect animals of any breed. Some form of physiological or pathological change affects an animal that has previously had normal immune function, resulting in immunodeficiency. 
• Immunosenescence = age-related decline in immune function; normal in ageing animals. 
• Medical immunosuppression – this might be induced purposefully when a veterinarian chooses to use immunosuppressive therapies or chemotherapeutic agents. While the effect on the pathological process is desired, the secondary immunosuppression and susceptibility to infections are unlikely to be. 

  • Commonly prednisolone
• FIV – A T-lymphotropic retrovirus that infects lymphocytes. The acute phase sees reductions in CD4+ T cells; the chronic phase sees further reductions and then recurrence of mild illnesses before more severe, terminal diseases (chronic and multisystemic including gingivostomatitis; respiratory tract infection; enteritis; dermatitis; weight-loss; pyrexia; lymphadenomegaly; lymphoma; secondary infections)
• the major immune-mediated diseases are...

  • IMHA
  • IMTP
  • Immune-mediated neutropenia
  • Endocrine e.g., Hypothyroidism and Hypoadrenocorticism
  • Canine dermatomyositis
  • Discoid lupus erythematosus (DLE) 
  • Pemphigus-pemphigoid complex
  • Musculoskeletal/neuromuscular e.g., Polyarthritis (erosive and non-erosive) or Myasthenia gravis (neuromuscular)
  • Granulomatous meningoencephalitis (GME)
  • Gastrointestinal e.g., inflammatory bowel disease/chronic enteropathy (IBD/CE) or pancreatitis
  • Glomerulonephropathies (many)
  • Multi-systemic involvement e.g., Systemic lupus erythematosus (SLE)
• IMHA most commonly affects young adults and middle-aged dogs.  IMHA in dogs and cats is an antibody-mediated disease. It’s a classic example of a cytotoxic (type II) immune-mediated reaction in which antibodies and complement attach to the surface of RBCs leading to haemolysis. 
• Although it has no obvious identifiable cause, primary IMHA is associated with an inherited predisposition in dogs, most commonly cocker spaniels, springer spaniels, and poodles. 

  • Secondary IMHA is where the trigger or cause is an underlying condition and this is more common in cats
• IMHA in cats is often secondary to infections: 

  • FIP
  • Mycoplasma haemofelis
  • FeLV
  • Chronic bacterial infections
• haemolysis can be extravascular or intravascular
• Extravascular haemolysis is where antibody-coated RBCs are recognized and phagocytosed by macrophages in organs such as the spleen. Spherocytes are formed if partial phagocytosis occurs.

  • In cats, phagocytosis can occur due to:  intracellular rbc parasites or Heinz bodies (oxidative damage)  

  Haemoglobin is released inside macrophages and eventually metabolized to bilirubin. Excessive bilirubin production can sometimes overwhelm hepatobiliary metabolic pathways leading to hyperbilirubinemia and jaundice.
• how do you identify hepatomegaly on radiography?

  the liver should end at the point of the last rib
• Intravascular haemolysis is where antibodies and complement on the RBC surface lead to direct cell lysis within the circulation.

  • This is less common than extra vascular haemolysis but more acute

  intracellular haemoglobin is released directly into the circulation, leading to hemoglobinemia, haemoglobinuria, and potentially kidney damage caused by haemoglobinuric nephrosis. ( red/pink plasma +/- red/pink urine)
• The anaemia generated by RBC destruction in IMHA is usually regenerative. However, occasionally the auto-immune reaction also affects erythroid precursors in the bone marrow, or chronic inflammation also results in a functional iron-deficiency. In both of these cases, the anaemia may be minimally-regenerative or non-regenerative. 
• Typically, IMHA signs are progressive over 1-2 weeks and include lethargy, anorexia, vomiting and exercise intolerance. More acutely the animal may be weak, collapsed, pyrexic and showing symptoms such as haemoglobinuria.  On CE or testing, animals may exhibit several other findings:

  • Pale mucous membranes; tachycardia, systolic HM, hyperdynamic pulses; tachypnoea
  • Jaundice, icterus, haemoglobinaemia, haemoglobinuria
  • Pyrexia
  • Splenomegaly, hepatomegaly; lymphadenopathy
• IMHA laboratory findings include

  • Anaemia (often regenerative)
  • Blood smear shows spherocytes, ghost cells (IMHA); schistocytes, acanthocytes (neoplasia, vasculitis)
  • Autoagglutination
  • Indicators of triggering disease eg RBC parasites or a positive infectious disease result
  • Inflammatory leucogram (sometimes very high neutrophil counts with a left-shift.
  • Thrombocytopaenia (mild or marked)
  • Hyperbilirubinaemia, bilirubinuria
  • Elevated liver parameters
  • Haemoglobinaemia
  • Hypophosphataemia – can be a trigger for IMHA
• The most common send-out test used to confirm a diagnosis of IMHA is the Coombs’ test, or direct antiglobulin test (DAT), which detects antibodies and/or complement bound to RBC membranes. This uses a mix of antibodies directed against IgG, IgM, and complement. This test results in agglutination in samples that would otherwise not have true autoagglutination. Test sensitivity is therefore increased compared with slide agglutination, albeit with potentially decreased test specificity.
• Thrombocytopaenia (marked, <50,000 plt/uL) is less common in IMHA and may be due to IMTP combined with IMHA = Evans syndrome.
• treatment of IMHA involves treating the underlying trigger or disease and then immunosuppression
• Glucocorticoids alone may not be sufficient to control immune disease in patients with severe or refractory IMHA. Even when glucocorticoids are initially effective, a second immunosuppressive agent is often added to the therapeutic regimen to either increase the chances of initial remission or enable more rapid tapering of glucocorticoid doses for patients experiencing unacceptable steroid side effects. these additional drugs include azathioprine, mycophenolate mofetil, cyclosporin and leflunomide
• In cats, because IMHA commonly occurs secondary to M. haemofelis infection and because this organism can be hard to identify on blood smears, treatment with doxycycline or pradofloxacin, in addition to glucocorticoids, is often commenced at presentation while confirmatory PCR results are pending.
• Leflunomide is a pyrimidine synthesis inhibitor that is not widely used for IMHA
• Azathioprine is a purine synthesis inhibitor that inhibits lymphocyte proliferation, has long been used to treat IMHA in dogs. It is usually well tolerated, but a reversible hepatopathy develops in up to 15% of treated dogs so monitor liver parameters. 

  • This is dangerously myelosuppressive in cats; so do not use in this species