What is the difference between primary immunodeficiency & secondary immunodeficiency?
Primary Immune Deficiencies are caused by inherited genetic mutations, while Secondary Immune Deficiencies are caused by viral, toxin, stress, disease, age, malnutrition-induced genetic changes that develop later in life.
NB. If an animal continues to suffer repeated infections, relapsing even after therapy, then we should suspect underlying immunodeficiency. Additionally, if the animal is between 3-12 months of age, and there’s a known breed-susceptibility, then suspect inherited immunodeficiency (primary).
What is a secondary immunodeficiency that commonly affects cats?
Feline Leukaemia Virus (FeLV) - FeLV RNA virus takes over replication machinery (DNA) of B-cells & macrophages in lymph nodes (tonsils), causing viral replication by the immune system itself.
Feline Immunodeficiency Virus (FIV) - FIV caused by lentivirus, also an RNA virus, causes HIV-like syndrome.
CLAD, Equine SCID, Foal Immunodeficiency Syndrome (Fell Pony Syndrome), Canine X-linked SCID, Selective IgA Deficiency, Chronic Rhinitis (Bronchopneumonia Syndrome) & Pneumocystis Pneumonia are examples of:
a) Primary Immunodeficiency
b) Secondary Immunodeficiency
a. Primary Immunodeficiency (congenital)
What is the difference between Central T-cell Tolerance & Peripheral T-cell Tolerance mechanisms?
Central T-cell Tolerance:
Mechanism takes place in THYMUS. Involves Clonal deletion (negative selection) of self-reactive T-cells.
T-cell receptor must pass 2 tests before it can leave the thymus:
1) It must recognise major histocompatability complex MHC
2) It MUST NOT recognise a self peptide
If the T-cell fails one of these, then it’s killed.
Peripheral T-cell Tolerance:
Mechanism takes place in LYMPH NOTES. Involves clonal anergy: naive T-cell receptor recognises antigen presented by MHC Class II, but the absence of co-stimulatory molecules such as CD80 or CD86 from the APC -- ie., lack of “danger signals” -- renders the T-cell unresponsive, unactivated, so it can tolerate the harmless antigen.
Explain how antibodies cause tissue damage in Type I hypersensitivity.
Type I (Immediate-type) Hypersensitivity:
Allergen enters mucosal surface at least once before, causing sensitisation: With help of TH-2 cells in lymph nodes, class-switching occurs to cause B cells to abnormally produce IgE antibody against harmless environmental antigen (eg., pollen, peanut, seafood).
Mast cells in mucosal tissue become coated in IgE (the mast cells’ Fc receptors bind to the IgE) and become sensitised to the allergen -- ie., they become immunological mines floating around, waiting to be set off by the antigens.
When the IgE-coated/bound mast cells NEXT come into contact with the allergen, the IgE binds to the antigen, causing an immediate anti-parasite, inflammatory response, with the degranulation of the mast cells.
Degranulation is the secretion of antimicrobial cytotoxic molecules stored in mast-cell granules (vesicles). Inflammatory mediators including histamine & prostaglandins are released, causing IMMEDIATE vasodilation, oedema, smooth- muscle contraction and mucus secretion.
In a late-phase reaction, 4-6 hours later, cell-infiltration starts to happen with eosinophils and neutrophils invading the tissue as more mediators are released eg. leukotrienes and cytokines, which have chemotactic properties.
Type II Hypersensitivity
Explain how antibodies cause tissue damage in Type II hypersensitivity.
Type II Hypersensitivity:When IgM or IgG bind to antigens on the patient's own cell surfaces, mistaking them for foreign when they are actually "self".
Abnormal production of IgM or IgG causes neutralisation (blockage) of binding to FIXED target-cell surface receptors (as in the case of the acetylcholine receptor in Myasthenia gravis), or binding of the antibody to the target cell itself, inducing an auto-immune response. The antigens are typically fixed & endogenous cell-surface proteins or extracellular matrix proteins, such as collagen.
The binding of the antibody to a target cell, such as a red blood cell, can cause an immunological attack on that cell: Opsonisation (increased phagocytosis by macrophages) & Complement activation (destruction of cells by Membrane-Attack Complex, MAC)
- Haemolytic disease of the newborn foal (Neonatal isoerythrolysis - the foal ingests antibodies from mother’s MDA that attacks its RBCs because they’re a different blood type than the mare’s)
- Autoimmune haemolytic anaemia
- Feline infectious anaemia (Mycoplasma hemofelis infection) - immune system causes lysis of RBCs in circulation
Explain how antibodies cause tissue damage in Type III hypersensitivity.
Type III Hypersensitivity:
Abnormal production of IgG binding to soluble antigen floating around in the circulation results in deposition of the IgG-antigen complexes in blood vessels eg., vasculitis, affecting skin, joints (synovial fluid) or kidney (glomeruli).
￼The immune complex causes inflammatory reaction in tissues surrounding the vasculature -- the complex deposits between the endothelial cells, causing platelet aggregation and micro-thrombus (small-clot) formation. The complex initiates Complement Cascade via C5, causing neutrophils to move to thrombus via chemotaxis, phagocytose, and release pro-inflammatory mediators.
Explain how inappropriate T cell responses can cause Type IV hypersensitivity.
Type IV (Delayed-type) Hypersensitivity:
Abnormal activation of macrophages in healthy tissues causes an inflammatory response that can take a number of days to occur.
First, the body undergoes an initial sensitisation phase, when T-cells first encounter the antigen presented to them by dendritic cells in the lymph nodes.
The T-helper Type 1 cell becomes abnormally activated -- TH-1 cells aid in stimulating macrophage activity and exit into the circulation.
When the TH-1 cell binds again at another encounter with the antigen, it stimulates macrophages via interferon-ɣ (IFNɣ) to release prostaglandins, TNFa, NO & oxygen radicals to aid in phagocytosis / respiratory burst.
At the same time, the binding of the TH-1 cell to the antigen also causes the TH-1 cells to release their own inflammatory cytokines and chemokines, amplifying the inflammatory response. This takes at least 24 hours.
- Rheumatoid arthritis
- “Dry” or “non-effusive” for of Feline Infectious Peritonitis (FIP)
- Tuberculin test for TB in cattle - use calipers to measure skin thickness 72 hours after injecting the suspect cow with avian & bovine purified protein derivative (PPD)
What is Equine SCID?
It's an example of Primary Immunodeficiency (congenital).
Autosomal recessive mutation
Defect in the gene coding a DNA-repair enzyme required for V(D)J recombination, the process that assembles specific antigen receptors in the variable region of lymphocyte receptors.
No functional T- or B-cells produced
- Foals develop infections about 8-12 weeks of age & often die of bronchopneumonia as respiratory tract is one of key sites of infection in immunodeficiency
- Usually protected by maternally derived antibodies (MDA) so there are no signs before 8 weeks of age
Affects 2-3% of Arabians
What is Foal Immunodeficiency Syndrome, or Fell Pony Syndrome?
A primary immunodeficiency disease (congenital).
Autosomal recessive mutation
Mutation in the sodium/myo-inositol cotransporter gene that causes a substitution in the protein. The amino acid substitution alters the function of the co-transporter, leading to erythropoiesis failure and compromise of the immune system.
- Profound anaemia
- Mutation disrupts stem-cell development & differentiation into B cells, thus
there’s a lack of antibody development
- scouring, nasal discharge, breathing with abdominal effort, pale mucous membranes, failing to suckle, frequent chewing movements, dull coat, hunched stance and dull demeanor.
- appear normal at birth but at around two-four weeks of age, they show signs associated with immunodeficiency and progressive anaemia.
- eventually affected foals fail to thrive and succumb to persistent infections and die or are euthanized before they reach sixteen weeks.
What is Canine X-linked SCID?
Severe Combined Immune Deficiency - another Primary Immunodeficiency Disease.
Defect in gene coding for Interleukin-2 (IL-2) receptor, usually expressed on naive T cells, which drives cell division & proliferation
Abnormal protein synthesised from point mutation and premature STOP codon.
T cell doesn’t undergo clonal expansion upon first “seeing” antigen presented by dendritic cell
- Animal lacks T cells
- Bassett Hounds & Corgis vulnerable
What is CLAD?
CLAD is an example of Primary Immune Deficiency (congenital), involving defect in the INNATE immune system (eg., neutrophil adhesion).
CLAD stands for Canine Leukocyte Adhesion Deficiency
Missense mutation in amino-acid sequence of CD18 integrin molecule necessary for neutrophil migration & phagocytosis; neutrophils can't adhere to endothelial cells & exit blood vessel to target bacteria in tissue.
- Recurrent bacterial infections despite presence of a marked neutrophilia
- Huge #s of neutrophils appear in blood sample, but they can’t get out of blood vessels into the normal circulation.
- Integrin is needed to enable the neutrophils to migrate OUT of circulation into the site of infection.