Immune mediated diseases Flashcards
Give examples of immune mediated diseases with multi-system involvement
- Systemic lupus erythematosus (SLE), very rare
- Sjogren’s syndrome, poorly defined, Cocker spaniels (involves mouth and joints)
Give examples of cutaneous immune mediated diseases
- Canine dermatomyositis
- Discoid lupus erythematosus
- Pemphigus pemphigoid complex
Give examples of musculoskeletal/neuromusclar immune mediated diseases
- Polymyositis/polyneuritis
- Myasthenia gravis
- Polyarthritis (erosive and non-erosive)
Give examples of haemolymphatic immune mediated diseases
- Immune mediated haemolytic anaemia
- Immune mediated thrombocytopaenia
- Immune mediated neutropaenia
Give examples of renal immune mediated diseases
Glomerulonephropathies (many)
Give examples of immune mediated diseases of the CNS
- Steroid responsive meningitis/encephalitis
- Grannulomatous meningoencephalitis
Give an example of an immune mediated GI disease
- Inflammatory bowel disease
- Unsure if immune mediated
What causes the development of primary immune mediated diseases?
- MHC class (accounts for some breed predispositions)
- May be true auto-immunity (but not referred to as autoimmune)
Give examples of things that immune mediated disorders may occur secondary to
- Vaccination
- Neoplasia (esp. lymphoproliferative)
- Inflammatory disease (pancreatitis, prostatitis)
- Infection
- Drugs/toxins (MPS< carprofen, cephalosporins, griseofulvin, zinc)
- Hormones (oestrogen)
- Seasonality
Outline the diagnosis of immune mediated disorders
- Recognition of signalment, history and physical examination
- lab tests and biopsy
- Fulfilment of specific diagnostic criteria e.g. those for SLE
- Haematology, biochem and urinalysis as minimum database
- Diagnostic tests should be carried out before starting therapy
Describe the major signs of SLE
- Skin lesions
- Polyarthritis
- Haemolytic anaemia
- Glomerulonephritis
- Polymyositis
- leukopaenia
- Thrombocytopaenia
Describe the minor signs of SLE
- Fever of unknown origin
- CNS signs, seizures
- Oral ulceration
- Lymphadenopathy
- Pericarditis
- Pleuritis
Describe the serology for SLE
- ANA
- Not specific to SLE
Describe the diagnostic criteria for SLE
- Definitely SLE: 2 major signs with positive serology OR 1 major and 2 minor signs with positive serology
- Probably SLE: 1 major sign with positive serology OR 2 major signs with negative serology
List the potential causes of immune mediated haemolytic anaemia and identify the main one
- Autoantibody to RBC membrane antigen
- Cross-reacting antibody against infectious agent
- Antibody against drug adherent to RBC
- Drug or infection modifies RBC antigen or exposes a hidden antigen
- Idiopathic (majority of cases in dogs and cats)
- Alloantibody
Outline the pathogenesis of IMHA
- Phagocytosis of opsonised RBCs mainly in the spleen (extravascular) but also in blood by monocytes (intravascular)
- Usually IgG, sometimes IgM or C3 complement implicated
- IgM: intravascular mainly
- Complement: immediate lysis
Explain how IMHA can cause death
- Thrombus formation
- DIC
- Marked systemic immune response
- Rarely from hypoxia unless limited ability to access blood for transfusion
Outline the signalment for IMHA
- Cocker, Mini Schnauzer, Springer spaniel, poodle, old english sheepdog increased risk
- Usually youngmiddle aged
- F>M
- May be more prevalent in summer
Discuss the approach to vaccination in a patient with IMHA
- Unconfirmed link with vacc
- Use titre test to identify if need vaccinating
- If immunity not very robust, discuss with owner re. risk of infection vs risk of immune mediated disease recurrence
Describe the clinical presentation of IMHA
- Variable in severeity and chronicity
- Lethargy, depression, tachypnoea, tachycardia, weakness, anorexia
- Collapse, pale MM (>75% of cases)
- Haemic heart murmur due to altered blood viscosity
- Jaundice
- Hepatosplenomegaly
- may have concurrent IMTP
Explain why jaundice may occur in IMHA and compare the 2 types of IMHA
- Pre-hepatic
- Increased bilirubin from RBC breakdown, usually from extravascular IMHA
- Intravascular IMHA usually leads to haemoglobinaemia (red plasma)
Discuss IMTP that is concurrent with IMHA
- = Evan’s syndrome
- IMTP immune mediated thrombocytopaenia
- More difficult to stabilise due to bleeding tendency with IMTP
Outlinen the methods for the diagnosis of IMHA
- Haematology and smears
- Auto-agglutination
- Coomb’s test
Describe the common findings on haematology/blood smear in a case of IMHA
- Regenerative anaemia (degree depends on magnitude of anaemia)
- Spherocytes (partial phagocytosis by cells of RES)
- leukocytosis
- Hyperbilirubinaemia
- Elevated liver enzymes
Describe the use of auto-agglutination in the diagnosis of IMHA
- 1-3 drops of saline to one drop EDTA blood, mix by rocking
- Look for clumping under microscope
- Must use anticoagulated blood otherwise will mistake normal clotting as abnormal auto-agglutination
Describe the Coomb’s test for IMHA
- Add Coomb’s reagent
- Anti-canine Fc antibody
- binds to red cells with antibodies attached leading to agglutination if IMHA
Outline the principles of treatment for IMHA
- aim to induce rapid remission from ongoing haemolysis
- Slower aim to enable recovery from anaemia
- halt ongoing immune mediated damage to allow recovery
- Corticosteroids +/- adjuncts
- Blood transfusions
- Oxyglobin
- Thromboprophylaxis
- Splenectomy in refractory cases
- therapeutic plasmapharesis
- Gastroprotectants
Explain the reasons for the use of corticosteroids in the treatment of IMHA
- reduce egress of inflammatory cells into tissues
- Reduce inflammatory mediators
- Suppress macrophage and neutrophil function
- Lymphocytotoxic
- Reduce macrophage Fc receptor expression
- Inhibition of complement
Describe the use of corticosteroids in the treatment of IMHA
- Licensed
- Some significant side effects, some mild, others less so
- Rarely may get thromboembolic complications
- Effects usually see within 24-36hours
- Dex injectable thought to be more significantly ulcerogenic than prednisolone
Compare the relative immunosuppressive potencies, dose and duration of action of prednisolone, methylpred, dex, betamethasone
Pred: 1, 2.0-4.0mg/kg/d, 12-26h
Methyl pred: 1.25, 2.0-4.0mg/kg/d, 12-26h
Dex and beta: 7-10, 0.2-0.5mg/kg/d, >48h
Discuss the use of azathioprine in the treatment of IMHA
- Unlicensed
- Tablets cannot be split, typically dosed q48h (base frequency so that dose per day works, not dose to make frequency fit)
- use lowest dose possible and remove as soon as possible
- Usually well tolerated in dogs
- Delayed onset of activity, use as adjunct, use early for optimal onset
Outline the side effects of azathioprine
- Irreversible myelosuppression if used at higher than recommended dose
- Progressive hepatopathy
- Metabolites produced in dogs more toxic than those in people
- Not recommended in cats, rapid lethal bone marrow suppression
Discuss the use of ciclosporin in the treatment of IMHA
- Licensed for atopy, not IMHA
- Suppresses formation of cytokines in innate and adaptive immune system
- Anecdotally useful
- Various formulations (microemulsion capsule and liquid preparations)
Outline the side effects of ciclosporin
- May increase risk of infection
- Linked with increased incidence of lymphoma
Discuss the use of cyclophosphamide in the treatment of IMHA
- UNlicensed
- Alkylating agent
- Assocaited with neutral or negative impact on survival in IMHA therefore not recommended use in immune mediated disease
Discuss the use of chlorambucil in the treatment of IMHA
- Unlicensed
- Alkylating agent
- Slow acting, low toxicity
- Give on empty stomach as food reduces absorption
- Can use as adjunct to steroids in IMHA (also IMTP, immune mediated polyarthritis and IBD)
Discuss the use of mycophenolate mofetil in the treatment of IMHA (mech of action, use, side effects)
- Unlicensed
- Antimetabolite agent inhibiting purine synthesis in lymphocytes
- Steroid adjunct
- Limited evidence for efficacy, some evidence for IMHA (and myasthenia gravis)
- Can have GI side effects
Discuss the use of IV immunoglobulin in the treatment of IMHA (mech of action, use)
- Unlicensed
- Purified preparation of polyspecific IgG from human blood donors: ethics
- Very expensive, inconsistent availability
- Multiple actions: block Fc receptors, neutralise autoantibodies
- Used in IMHA, IMTP, some skin diseases as adjunct
- Variable efficacy
Discuss the use of vincristine in the treatment of IMHA
- Use to treat concurrent IMTP
- Stimualtes thrombopoiesis in bone marrow, inhibits platelet phagocytosis by monocytes
Outline the monitoring required in a case of IMHA
- Abscence of spherocytes, lack of reticulocytes once PCV normalised, acute phase proteins
- Check CRP before changing drug dose
- Monitor steroid neutrophilia
What does it indicate if PCV is normal but reticulocytes are high in a case of IMHA?
Disease is not under control
Outline the general protocol for the of therapy for IMHA
- Start with single agent pred at 1-2mg/kg PO q24h (dogs), cats 2mg/kg q12h
- Maintain dose until induction of remission (often 3-4 weeks)
- Once have remission, taper corticosteroids over 3-4 months at 20-25% reduction per month (based on side effects, maintenance of remission, APP concentration, re-check dose 2 weeks after)
- If poor response after 3-4 weeks, add additional therapy
- Monitor for recurrence (common)
Outline the prognosis for IMHA
- 50-88% survival to discharge from hospital
- Death/euthanasia due to ongoing IMHA or complications e.g. thromboembolic disease
- Variable median survival times
- Relapse common
- Survive past 14 days most the survive to a year
What are the negative prognostic indicators for IMHA?
- Icterus
- Severe agglutination
- Thrombocytopaenia
- Hypoalbuminaemia
- Elevated urea
Explain the cause of immune mediated thrombocytopaenia
- Usually from destruction of circulating platelets
- Occasionally immune mediated attack at level of precursors in teh bone
- Mediated by IgG against platelet membrane protein
Which breeds are predisposed to immune mediated thrombocytopaenia?
Cockers, poodes, Old english sheep dogs
- NB CKCS and cairn terriers low platelet count as normal
What platelet count would be indicative of IMTP?
<30x10^9/l
Describe the clinical signs of IMTP
- Spontaneous bleeding
- Pyrexia prior to thrombocytopaenia
- Mucosal and skin haemorrhage (petechiae, ecchymoses)
- Hyphaema/retinal haemorrhage/epistaxis
- GI haemorrhage (melaena, haematemesis)
- Death through severe bleeding
Why may pyrexia occur with IMTP?
Release of pyrogenic cytokines from platelet breakdown
Describe the diagnosis of IMTP
- Low platelet count
- Exclusion of other causes of bleednig
- Determine between primary and secondary IMTP
- Severe thrombocytopaenia with absence of disease elsewhere is the main method of diagnosis
Give examples of alloimmune haemolytic anaemias
- Neonatal isoerytrholysis in cats and dogs
- Delayed haemolytic transfusion reaction in dogs
Describe alloantibodies/isoantibodies
- Specific antibodies directed against erythrocyte antigens from the same species but not from the individual producing the antibody
How are alloantibodies produced?
- Occur naturally in cats
- Produced through sensitisation by birth of foal with mismatched blood group (horses)
- Produced through sensitisation with mismatched blood transfusion (dog)
Describe neonatal isoerythrolysis
- Transfer of maternal antibodies in colostrum against the blood cells of the offspring
- NI develops several hours to days after colostrum ingestion
- Natural alloantibodies in cats, sensitisation required in horses
- Haemolysis is main mechanism of pathogenesis, also agglutinating antibodies
Explain how neonatal isoerythrolysis occurs in horses
- Sensitisation to blood antigen with first foal
- Second and subsequent mismatched foals at risk due to production of alloantibodies to stallion’s blood due to blood leakge through placenta during pregnancy or delivery
- OR sensitisation occurred prior to pregnancy through blood transfusions or administration of vaccines containing equine tissue products, through which first foal can be at risk
Explain feline neonatal isoerythrolysis
- Caused by maternal anti-A alloantibodies in colostrum of blood group B queens
- Immune mediated haemolysis of type A and type AB erythrocytes
- Major cause of fading kitten syndrome
Outline the proportion of type B queens in different breeds
- UK BSH: high prevalence type B queens
- DSH: low prevalence type B queens
Describe the clinical signs of feline neonatal isoerythrolysis
- Within hours of feeding or after a few days
- Haemoblobinuria
- Fading kitten syndrome
Describe the treatment of feline neonatal isoerythrolysis
- Blood transfusion
- Fostering type A queen or milk replacer
- Supportive therapy
- Rarely successful due to acute disease course
Outline the prevention of feline neonatal isoerthrolysis
- Blood typing queen and tom and mating only type B with type B
- Foster nursing type A and AB kittens born to type B queen
Which antibodies are implicated in equine neonatal isoerythrolysis?
- 90% to blood groups Aa and Qa,
- None to Ca
Describe the clinical signs of equine neonatal isoerythrolysis
- Progressive lethargy, weakness, depressed
- Pale mucous membrane, later icteric
- Severe anaemia, marked haemoglobinaemia and haemoglobinuria
- Breathing may become shallow, rapid, laboured
- +/- tachycardia
- Severe hypoxia can lead to convulsions, coma, death
- Shock leads to rapid death (within 6-8hrs postpartum)
Describe the treatment of equine neonatal isoerythrolysis
- Immediately stop further ingestion of colostrum
- Supportive care needed until foal recovers
- IV fluid therapy
- Transfusions - whole blood if suitable donor available or washed RBCs from dam
Describe the prevention of equine neonatal isoerythrolysis
- Avoid mismatched matings
- Prevent colostrum ingestion until crossmatch performed between mare’s serum and offspring RBC (Jaundice Foal Agglutination JFA test)
- Feed stored suitable colostrum
- Once colosturm gone, rest of milk ok
Describe the clinical signs of bovine neonatal pancytopaenia
- Calves <1mo
- Pyrexia
- Unexplained haemorrahge from nose, gums, ear tag sites, injection sites, GIT etc.
- Recumbency, pale MM, dyspnoeic, colic, sudden death
- mortality 90%
Describe the aetiology of bovine neonatal pancytopaenia
- Destruction of bone marrow cells
- Some evidence for immunopathological reaction due to alloreactive antibodies which are transferred to calves via colostrum
- Greater risk 2nd and 3rd partum cows with multiple vacc (BVD vacc implicated)
Describe the diagnosis of bovine neonatal pancytopaenia
- Multiple internal and external haemorrhages
- Thrombocytopaenia
- Leukocytopaenia
- Bone marrow depletion
Describe the treatment of bovine neonatal pancytopaenia
- Gentle handling to prevent further haemorrhage/haematoma formation
- Blood transfusion (whole blood) often only gives transient improvement of clinical signs
Describe the prevention of bovine neonatal pancytopaenia
- Avoid use fo pooled colostrum
- Newborn calves to previous cow with BNP calf should receive colostrum from another cow with no BNP calf
- No colostrum or blood from cows on farms with BNP history should be used for commercial purposes
Describe the aetiology of immune mediated diseases
- Loss of self tolerance, allowing formation of antibodies to subset of normal proteins in the body
- Lack of regulation leads to development of progressive inflammation and damage
- Usually not global immunodeficiency
- Specificity of loss appears to be determined in part by genetic background
- Role of hormones unclear
- More common in younger vs older
What are primary immunodeficiencies?
Inherited defects of innate or adaptive immunity rather than antibodies attacking host cells. Usually global effect of 0 innate immune cells, B and T lymphocytes. Rare, except fell pony immunodeficiency syndrome
What is Fell pony immunodeficiency syndrome?
- Autosomal recessive disoder
- Majorly impaired adaptive immune system, molecular basis unknown
What condition causes foals to appear normal at birth, but then fail to thrive and die within 3 months, and have prodound anaemia, B-lymphopaenia and fail to produce immunoglobulins?
Fell pony immunodeficiency syndrome, autosomal recessive disease common in UK
What causes Arab horse SCID?
Autosomal recessive disorder leading to no functional B or T cells, no adaptive immunity
What condition of horses causes foals to be normally initially, then succumb to opportunistic infections within the first 4-6 months of life?
Arab horse SCID
Which dog breeds are susceptible to severe combined immunodeficiency?
- Jack Russel terrier
- Basset Hounds and cardigan Welsh Corgi (x-SCID)
Which rare condition causes lymphopaenia, agammaglobulinaemia, thymic and lymphoid aplasia in Jack Russel terriers?
SCID
How does SCID of JRTs cause disease?
Defect in DNA dependent protein kinase => blocks gene splicing and recombination of T cell receptors
What condition causes stunted growth, increased susceptibility to infection, absence of lymph nodes, and a partially developed thymus in Basset Hunds and Cardigan Welsh Corgis?
X-SCID (mutation in common gamma chain, defect of receptors for IL-2, IL-4, IL-7, IL-9 and IL-15)
