Immunodeficiency and Hypersensitivity Flashcards
Canine Leukocyte Adhesion Deficiency
(CLAD)
*Innate Immune Deficiency*
Seen in Irish setter dogs.
Missense mutation in CD18, a molecule required for neutrophil migration (it functions as a cell adhesion molecule) and phagocytosis (it also functions as a complement receptor).
Affected dogs suffer from recurrent bacterial infections, despite a marked neutrophilia, since neutrophils are trapped in the bloodsteam and cannot enter tissues to fight infection.
Primary Immune Deficiencies
Inherited Defects in immune response genes
- Sometimes catastrophic!
- Inherited defects in immune response genes- usually start to see these manifest when animals are young (3-4months)
Secondary Immune Deficiencies
- Aquired immune Dysfunction
- generally fine until an adult and then immunodeficient
Missense Mutation
- In genetics, a missense mutation is a point mutationin which a single nucleotide change results in a codon that codes for a different amino acid.
- It is a type of nonsynonymous substitution
Equine Severe Combined Immune Deficiency
(SCID)
*Adaptive Immune Deficiencies*
- Autosomal recessive defect seen in 2-3% of Arabian foals.
- Results from a mutation in a gene coding for a DNA repair enzyme, critically involved in V(D)J recombination for generation of lymphocyte antigen receptors.
- No functional T or B cells produced.
- foals usually start developing signs of infection at around 8-12 weeks of age and often die from bronchopneumonia.
Why Do SCID foals not show signs of infection before 8 weeks of age?
- don’t die immediately after birth because they get maternally derived antibody after birth from their mother
- that keeps them going for about 3-4 months
Foal Immunodeficiency Syndrome
(Fell Pony Syndrome)
- Aka ‘Fell Pony Syndrome’.
- Profound anaemia and immunodeficiency as the result of B cell deficiency and a lack of antibody production ( http://www.aht.org.uk/cmsdisplay/genetics_fis.html )
Canine X-linked SCID
- Basset Hounds and Corgis affected.
- X-linked recessive defect in the IL-2 receptor gene.
- Lymphoid hypoplasia, stunted growth and susceptibility to infection.
- Usually die from pneumonia or sepsis as maternal antibody wanes.
WHAT IS THE NORMAL FUNCTION OF THE IL-2 RECEPTOR EXPRESSED ON RECENTLY ACTIVATED T CELLS?
-what happens in your lymphnode in early adaptive immune response, your T-cells get activated and need to proliferate
–> need the clonal expansion
- that clonal expansion is brought about by that IL-2 production, acting in an autocrine and paracrine manner on its own receptor
- absolutely vital for the expansion and proliferation of naïve T-cells
- Normal IL-2 would bind to the receptor and cause that proliferation signal in the antigen activated T-cell
MUTATION IN THE IL-R2 GENE:
- Sneaky “c’ base has jumped into the code (insertion, mutation of single base)–> knocks reading frame out of sync. Aa’s beyond that insertion are wrong and it all comes to a premature stop
- So now you don’t have a nice receptor waiting for the IL-2 (cytokine).. Corgi mutant.. Binding site is missing. No way of binding to it and therefore no T-cell function
Selective IgA deficiency in German Shepherd Dogs
*Adaptive Immune Deficiency*
- Poorly understood immune defect seen in GSDs.
- This condition has been linked to a number of disease syndromes, including inflammatory bowel disease, anal furunculosis and disseminated aspergillosis.
- in this, they are very poor at producing mucosal Ab
- IgA is very important for infections coming through mucosal epithelium!!
- mucosal defense is bad, but it is not just IgA deficiency!
- They have this pronounce adaptive immune deficiency but also a paralleled innate immunodeficiency
Other suspected primary adaptive immune deficiencies
- Immune deficiency syndrome in Weimaraner dogs.
- Chronic rhinitis / bronchopneumonia syndrome in Irish wolfhounds.
- Pneumocystis pneumonia in dachshunds and Cavalier King Charles spaniels.
SECONDARY IMMUNE DEFICIENCY (ACQUIRED DISEASE)
3 Types and related diseases
- Retrovirus-induced immunosuppression (see POS Virology)
Feline leukaemia virus (FeLV)
Feline immunodeficiency virus (FIV)
- Toxin-induced immunosuppression
- Poisons (e.g. lead)
- Drugs (e.g. corticosteroids, ciclosporin, chemotherapy drugs)
- Miscellaneous
- Malnutrition, chronic disease (neoplasia), stress, immunosenescence
Major Cause of Immunosupression in Veterinary Practice
- Drugs
- Corticosteroids
- Ciclosporin
- Chemotherapy drugs
In the Thymus, when would the T-cells be marked for cell death?
- immature T-cell not binding at all to MHC receptor
- immature T-cell binding TOO tightly to MHC receptor
- When a mature T-cell is responsive to MHC and self antigen
Equine SCID (Equine Severe Combined Immune Deficiency)
- Autosomal recessive mutation – 2-3% Arabian foals
- Defect in a DNA repair enzyme required for antigen receptor gene recombination–> lymphocytes can’t develop any further & die –>No functional T or B cells
- Become agammaglobulinaemic after MDA wanes & develop infections ~2mths old
- Usually die by 4-6 months from bronchopneumonia
Immunodeficiency Summary
- Suspect underlying immunodeficiency if an animal is suffering from repeated infections that relapse following therapy
- Suspect inherited immunodeficiency if animal affected is between 3-12 months of age, especially if a known breed-susceptibility
Tolerance
Tolerance- Strategic targeted immune suppression
• Sometimes the immune system deliberately ignores or suppresses responses to some antigens
Inappropriate Tolerance to
- Foreign pathogen antigen (virus, bacteria, parasite): In this case tolerance= bad, it prevents long term immunity developing so animal becomes persistently infected
- E.g. Bovine Viral Diarrhoea Virus (BVDV)- Pregnant cow infected with ↓ virulence strain foetus becomes tolerant to BVDV PI calf- Mucosal disease can then develop after birth if the persistent virus mutates to become virulent or if infected with more virulent strain
Failure to develop tolerance –> hypersensitivity
- Foreign antigens from harmless environmental components: Allergic disease
- Self- antigens (Ubiquitous protein, tissue-specific protein): Autoimmune disease
T cell tolerance
Central Tolerance:
– Clonal deletion of most autoreactive T cells in the thymus
– Some self- reactive T cells are rescued & forced to regulatory T cells
Peripheral Tolerance
– Immunological ignorance (never meets its antigen therefore never reacts)
– Clonal anergy to harmless antigens in the absence of “danger” signals
– Active suppression by induced Tregs (produce immunosuppressive cytokines)
Hypersensitivity
- an inappropriate, hyperactive immune response to an antigen
Type I hypersensitivity- Immediate-type hypersensitivity
MOST COMMON
- Harmless environmental antigen (allergen)–> body (usually by mucosal route) & triggers B cells, no anergy/ Tregs produced so tolerance fails–> many TH-2 cells which cause class switch of antibody to IgE
- This abnormal production of IgE–> sensitises mast cells, so if exposed to allergen again–> rapid Immunological “anti-parasite” response–> massive inflammatory reaction at site of exposure
- Can’t have an allergic reaction the first time you’re exposed to something
Type II Hypersensitivity
- Production of IgM or IgG against cell surface antigens or extracellular matrix proteins
- “Neutralisation” blockade of receptors –in myasthenia gravis, auto-antibodies are produced against the ACh receptor- so NMJ doesn’t work weak & lethargic animals
- Immunological attack on target cell – become sensitised to antigens on RBCs
- Haemolytic disease of the newborn (neonatal isoerythrolysis)
- Autoimmune haemolytic anaemia
- Feline infectious anaemia (Mycoplasma hemofelis)
Type III Hypersensitivity
- Antibody (IgG) binding to a soluble antigen (usually in the circulation)–> immune complex formation, which get trapped –>inflammatory reaction in the capillary bed (vasculitis)
- Vasculitis– Drug reactions- e.g. sulphonamide antibiotics can–> cutaneous vasculitis
– Wet (effusive) FIP
– Anti-DNA/ histone antibodies in lupus (SLE) can cause glomerulonephritis, skin lesions, IMHA/IMTP & polyarthritis depending where the immune complexes are deposited
Type IV hypersensitivity- Delayed-type Hypersensitivity (DTH)
THE ONLY T-CELL MEDIATED ONE
CD4 T cell-mediated
- When allergen presented to T-cell, tolerance mechanism fails–> TH-1 instead of Tregs
- If subsequently exposed to same allergen, TH-1 cells recognize it–> IFNγ –>super activates macrophages (hulks)–> inflammatory mediators & MMP enzymes–> tissue damage e.g rheumatoid arthritis
CD8 T cell-mediated
- Killer T cells destroy healthy cells mistakenly (think they’re infected)
Example of type IV hypersensitivity:
- Tuberculin test (cattle)- measure skin thickness, inject antigen into skin (PPD-avian & bovine) & measure skin thickness 72 hrs later (Heaf test is the human equivalent)
