Immune-mediated disease - overview Flashcards
What is the spectrum of immune-mediated disease?
- organ specific to non-organ specific (vasculitis)
- primary (‘idiopathic’) vs secondary
What underlying factors should be eliminated when considering immune-mediated disease?
- drug use
- neoplasia
- infxn
Example - non-organ specific immune dz
SLE
Example: organ specific immune dz
Myasthenisa gravis (MG)
What goes wrong in immune-mediated dz?
Immune system (I.S.) overreacts to normal body tissues or harmless exogenous protein. aka loss of tolerance
- humoral and cellular mechanisms
- loss of self-tolerance needed to perpetuate +/- start dz
Trigger factors - immune-mediated dz
- release of sequestered Ag
- abnormal immunoregulation
- molecular mimicry
- polycloncal activation of BCs and TCs
- exposure of cryptic epitopes or haptenisation of foreign molecules to self antigens
What is haptenisation?
small molecules bind to larger carreir molecules and these complexes elicit an immune response, directed against the carrier molecule.
How is infxn thought to influence autoimmune dz?
- breakdown of vascular/cellular barriers allowing exposire of self-antigens
- promotion of cell death by necrosis, causes inflammation –> bystander sactionation
- polyclonal activation of TCs by bacterial superantigens
- molecular mimicry leading to cross-reactivity
- vector-borne pathogens may be important in some parts of the world (r/o by different tests)
Name 3 main vector-borne pathogens that can be important in influencing autoimmune dz
- protozoa
- rickettsia
- bacteria
Aetiology - autoimmune dx
- of many is unclear, likely mutlifactorial often
- genetic, infectious, hormonal influences
Give canine autoimmune dz examples of aetiology
- SLE: genetics (DLA-A7, C4,4), c-type viruses (retroviruses)
- IMHA: vaccinal Ag?
- IMPA: vaccinal Ag?
Signalment - idiopathic immune-mediated disease
- over-represented in juvenile to middle-aged patients
- any age or dog/cat though
- SLE: Dogs 2mo-13yo, GSD, shelties, collies, beagles, poodles. Cats 1-11 yo, Siamese, Persian, Persian-related breeds
Hx and PE - immune-mediated dz characteristics
- remission and exacerbation
- lameness, mucocutaneous lesions, lethargy, dyspnoea, wt loss, PUPD, +/- seizures or behavioural changes
- effusive, painful joint, cutaneous erythema, macules, papules, pustules, erosion etc, pallor +/- petechiae, cardiac arrhythmias, lymphadenomegaly +/- splenomegaly
- Hx and PE are PIVOTAL to a DIAGNOSIS
How can CBC/coags tests help make diagnosis? 4
- ANAEMIA: regenerative (IMHA) or non-regenerative (ifxn, uraemia, chronic bleeding, attack of precursors)
- THROMBOCYTOPAENIA: I-M thrombocytopaenia
- LEUCOPAENIA? anti-leukocyte Abs (e.g. SLE, I-M neutropaenia)
- COAGULATION ABNORMALITIES: increased APTT, PT, anticoagulant Ab (SLE), DIC
On a blood smear, what is the hallmark of extravascular haemolysis?
spherocytes
What do chromatophils suggest on smear?
rengerative anaemia
What is rubricytosis?
- presence of immature RBCs
- suggests regenerative anaemia
What do ghost cells represent on a smear?
intravascular haemolysis
How can biochem. help make I-M dz diagnosis? 5
- AZOTAEMIA, increased inorganic phosphate (chronic glomerular lesions)
- HYPOALBUMINAEMIA, HYPERCHOLESTEROLAEMIA: e.g. PLN
- HYPERBILIRUBINAEMIA: pre-hepatic/ haemolysis
- HYPERGLOBULINAEMIA; inflammatory disease, polyclonal BC activation
- INCREASED CK and (LACTATE DEHYDROGENASE); polymyositis and/or myocarditis
How can UA make an I-M diagnosis?
- PROTEINURIA: with PLN r/o UTI and occult infections
- HAEMATURIA, POLYURIA, ERYTHROCYTE CASTS: r/o UTI and occult infxn, compatible with membranoproliferative glomerulonephritis (GN)
Features - radiography for I-M dz
- erosive lesions suggest an overlap syndrome
- arthritis is not always clinically obvious
Define pauciarthropathy
where a few joints are affected, >1 but
How common are joint lesions in polysystemic I-M dz?
- common
- usually a non-erosive pauciarthropathy
Describe synovial fluid of I-M dz
- increased WBC
- increased neutrophil %
+/- increased protein content - decreased viscosity
- poor mucin clot formation
Describe synovial fluid of I-M dz
- increased WBC
- increased neutrophil %
+/- increased protein content - decreased viscosity
- poor mucin clot formation
Which joint space do you aim for in carpus?
- antebrachial joint as this is the 1st joint space and this is the largest joint space
- aim for middle (to avoid nn, tendons, BVs)
List some tests for specific I-M dz
- coomb’s test
- anti-platelet Ab
- rheumatoid factor
- T3, T4, TG autoAb
- ACh receptor autoAb
- 2M myofibre autoAb
- ANA
- biopsies
What to do if IMHA is suspected
- in-saline agglutination and ostmotic fragility tests to be performed
- Ab associated with surface of RBC may also be detected with Coomb’s test
- primary reagent: polyvalent anti-dog or anti-cat IgG, IgM and C3 antiserum (direct antiglobulin test)
- false positive and negatives may occur
What is the commonest I-M neuromuscular disorder?
Acquired MG (various forms: focal, generalised, acute fulminating, paraneoplastic)
Gold standard diagnosis for acquired MG
- documentation of nicotinic AChR autoAb by immunoprecipitation RIA
Sensitivity/specificity of nicotinic AChR autoAb by immunoprecipitation radioimmunoassay (RIA)
- false positives v rare: 2% dogs with generalised MG may be seronegative
What part of PE may cause you to suspect MG?
you will be able to fatigue the palpebral response in MG patients after 10-20 stimulations
Outline antinuclear antibodies (ANA)
- serum ANA = hallmark of human/canine/feline SLE, occasional ANA-negative cases
- indirect immunofluorescene or immuno-peroxidase test
- substrate tissues have included rat liver, vero and Hep-2 cells: various patterns of staining
- false positives /negatives may occur
How are biopsies useful for I-M dz?
- often signal immune mediation of lesionsin organ-specific and polysystemic diseases
- mucocutaneous lesions should be sampled across interface with normal tissue
- lesions may not be specific for one disease but helps you localise lesion (e.g. dermis vs. epidermis)
- immune deposits in lesional tissue may be demonstrated by immunoperoxidase or immunofluorescence techniques.
T/F: I-M dz are a major cuse of morbidity and mortality in SA
True
T/F: various vector-borne dz have immunopathological sequelae
True
Define anergy
the absence of a normal immune response to a particular Ag
What determines central tolerance?
thymic selection
What determines peripheral tolerance?
- intrinsic and extrinsic components
What can be the physiological response to degranulation?
- inflammatory mediators
- pruritus
- bronchoconstriction
- vasodilation
- oedema
- eosinophil chemotaxis
Define MMM
Masticatory Muscle Mysositis
What is MMM?
CS?
Dx?
- idiopathic I-M dz of 2M myofibres, directed specifically at myosin
- CS include swelling +/- eventual atrophy of mm of mastication
- Dx by demonstrating autoAb against 2M myofibres of temporalis mm in immunocytochemical assay
What is the anti-platelet Ab test?
- considered when I-M thrombocytopaenia is a ddx
- indirect immuofluorescence test: substrate comprises PLTs from healthy donor
- reagent is fluoresceinated and goat anti-dog or anti-cat IgG antiserum: micrscopic and flow cytometric assays are described
- false positive/negatives may occur
What is rheumatoid factor?
- considered when erosive arthritis documented
- RF is a non-specific autoAb to IgG that may be found at low titre in animals with a range of infectious, inflammatory neoplastic diseases
- high titres characterise RA
- assayed by ELISA or Rose-Waaler test, in which RF agglutinates IgG-coated substrate RBCs
What are T3, T4 and thyroglobulin autoAb used for?
- lymphocytic thyroiditis thought to represent an autoimmune disease: Ab against thyroid Ag are released during ensuing inflammation
- 50-60% hypothyorid dogs have TG-autoAb
- 20% euthyroid dogs with TG-autoAb develop additional signs within a year
- T3-autoAb observed in 33% hypothyroid dogs, T4-autoAb observed in 15% cases
Define TT4
total T4
Define fT4d
free T4 by dialysis (baseline)
What is suggested with normal FT4D and TSH
healthy euthyroid
What is suggested with low TT4 or FT4D with increased TSH
hypothyroidism
What is suggested by TG-autoAb with no other abnormalities?
impending hypothyroidism?
What does low TT3 suggest?
it is of limited diagnositic value, except in sight hounds, which have low TT4 and FT4D based on generic canine reference ranges
What can be the physiological response to degranulation?
- inflammatory mediators
- pruritus
- bronchoconstriction
- vasodilation
- oedema
- eosinophil chemotaxis
Define MMM
Masticatory Muscle Mysositis
What is MMM?
CS?
Dx?
- idiopathic I-M dz of 2M myofibres, directed specifically at myosin
- CS include swelling +/- eventual atrophy of mm of mastication
- Dx by demonstrating autoAb against 2M myofibres of temporalis mm in immunocytochemical assay
