How do Hypersensitivity Reaction Type I & Hypersensitivity Reaction Type 4 differ in terms of time of onset / speed of reaction?
Immediate, with late-phase reaction 4-6 hours later
Delayed, at least 24 hours after exposure to antigen
How do the mechanisms differ between Types 1 & 4 Hypersensitive Reactions?
Hypersensitivity Type 1:
INNATE: Mainly involves change in antibody response, brought on by CD4+ T Helper cell Type 2 (Th2): Previously encountered allergen prompts TH-2 in lymph nodes to induce class- switching in B-cells to abnormal production of IgE (or IgG), which coats mast cells. On next exposure, coated mast cell degranulates, releasing cytotoxic mediators eg. prostaglandins & histamines. In late phase a few hours later, LT release (chemotactic), recruits more mast cells to site.
Hypersensitivity Type 4:
ADAPTIVE (cell-mediated): Mainly involves abnormal activation of CD8+ Killer T cells: Previously encountered allergen prompts abnormal activation of TH-1 cells, which upon next encounter with allergen stimulate, via interferon-ɣ (IFN-ɣ), macrophages to release prostaglandins & step up phagocytosis & respiratory burst. TH-1 cells also release their own inflammatory meditators.
What are some of the clinical manifestations of Type I & Type 2 Hypersensitivity Reactions?
- mild skin reaction
- more serious, soft-tissue swelling (eyelids, lips)
Anaphylaxis / Anaphylactic shock
- most serious, systemic mast-cell degranulation & histamine release (often preceded by V&D in dogs or dyspnoea in cats
What are some veterinary examples of Type I Hypersensitivity Allergic Reactions?
Flea allergic dermatitis
Canine Atopic dermatitis (West Highland White Terriers)
Feline eosinophilic granuloma complex
Sweet itch in horses (caused by Culicoides midges)
What is the difference between Allergy & Autoimmune disease?
What types of Hypersensitivity Reactions do each of them trigger?
Allergy is an abnormal immune response to a harmless, foreign antigen. Allergy can trigger Types 1 & 4 Hypersensitivity Reactions.
Autoimmunity is abnormal immune response to "self" antigens. Autoimmunity can trigger Types 2, 3 & 4 Hypersensitivity Reactions.
What are some examples of Type 4 Hypersensitivity Allergic Reaction?
Allergic contact dermatitis (from lying on mouldy bedding, for example)
Inflammatory Bowel Disease
What are the differences between systemic allergic reaction & local allergic reaction?
Systemic Allergic Disease:
Allergens enter bloodstream directly via bite or sting or
indirectly via absorption in GIT, and cause serious multisystemic reactions such as anaphylaxis or anaphylactic shock
Tend to be Type I Hypersensitivity Reactions (immediate)
Local Allergic Disease:
Allergens enter blood stream through bite, oronasal mucosa (inhaled) or eaten, and cause reaction at site or system of entry or of highest concentration, or where mast cells are concentrated (eg., GIT in dogs).
Skin allergies tend to be Type I Hypersensitivity Reactions
What are some examples of Localised Allergic SKIN Disease?
These tend to be Type I Hypersensitivity allergies:
CD4+ T-helper Th-2 cells that have enountered allergen before upon next encounter activate B-cells to turn into plasma cells, & cause class-switching of antibody production to IgE.
IgE coats mast cells, which degranulate when they bind the antigen, releasing inflammatory & cytotoxic mediators such as histamines & prostaglandins . This is followed by leukotriene release, which are chemotactic for more mast cells to the site of bite, sting, scratch, etc.
Flea Allergic Dermatitis - allergy to antigenic components of flea saliva
Canine Atopic Dermatitis - allergy to environmental allergens eg. pollens, dust mites
Sweet Itch in Horses - allergy to midge (culicoides) bites; similar to flea-allergic dermatitis in dogs
What causes Localised Allergic Respiratory Disease & what are some examples?
Type I Hypersensitivity Reaction (like skin allergies)
Inhaled allergens set off mast-cell degranulation beneath bronchial mucosa, causing smooth-muscle contraction & mucus secretion
Feline asthma - dyspnoea
Allergic bronchitis in dogs - dyspnoea, bronchospasm
Chronic Obstructive Pulmonary Disease (COPD) aka Inflammatory Airway Disease in horses - allergy to mould spores in hay causes coughing, wheezing, exercise intolerance & excess mucus production in airways
What type of hypersensitivity reaction is caused by Localised Immune-mediated GIT diseases?
Type 4 Hypersensitivity Reaction, which is delayed, T-cell mediated (CD4+ and CD8+ can be involved)
as well as
Gluten-sensitive enteropathy in Irish Setters - allergy to gluten in diet that can cause chronic diarrhoea & weight loss; Type 4 hypersensitivity reaction
Inflammatory Bowel Disease - Inappropriate IgE response (innate) to dietary or enteric microbial antigens (eg. food or commensal flora); IgA deficiency; poor T-regulatory cell responses (failure of tolerance; adaptive) - results in increased intestinal permeability, potential for secondary infection; Type I & Type 4 response
What role do antibodies play in autoimmune disease and the different types of Hypersensitivity?
Autoimmune disease can be caused by abnormal production of IgM & IgG autoantibodies in Type II & Type III Hypersensitivity.
What is an example of autoimmune disease that is a Type 2 Hypersensitivity reaction involving auto-antibody attack on extracellular-matrix proteins?
Type 2 Hypersensitivity is characterised by abnormal production of IgM & IgG antibodies to harmless cells or extracellular-matrix proteins of basement membrane, or antibody disruption of protein function.
NB: IgM is most effective at triggering complement -> MAC (lysis of cells) & IgG neutralises, opsonises & triggers complement.
- attack of “glue” that holds skin together, the keratinocyte cell-adhesion molecules; desmosomes
- results in vesicles, ulceration & crusting lesions of skin & mucocutaneous junctions such as nasal region & nail beds
What is an example of autoimmune disease that is a Type 2 Hypersensitivity reaction involving auto-antibody attack on target cells?
Immune-mediated haemolytic anaemia - RBCs attacked, lysed by macrophages
Immune-mediated thrombocytopenia - platelets attacked, lysed by macrophages, results in lots of bleeding, melaena, haematuria, epistaxis
What is an example of autoimmune disease that is a Type 2 Hypersensitivity reaction involving auto-antibody disruption of protein function?
Weakness is caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of Ach on nicotinic receptors throughout neuromuscular junctions.
Autoantibodies form against desmoglein, a protein that forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes. The cells become separated from each other and the epidermis becomes "unglued", a phenomenon called acantholysis. This causes blisters that slough off and turn into sores.
(pemphigus is also an example of a Type 2 Hypersensitivity involving autobody attack on extracellular-matrix proteins)
What's an example of Type III hypersensitivity?
Another autoimmune reaction, caused by abnormal IgG binding to soluble antigens, such as histones in DNA. Immune-complex disease results due to deposition of IgG-antigen complexes in blood vessels.
SLE (systemic lupus erythematosus)
- Anti-DNA/Histone antibodies
Destruction of cells in tissue & circulation expose nuclear proteins, specifically histones, leads to antibody binding to these proteins to form large IgG/histone complexes that get deposited in blood vessels in joints, skin & kidney.
- Possible to have several anti-histone diseases simultaneously, resulting in swollen joints & skin lesions Ie., Multi-systemic Immune-Mediated Disease along with:
- IMHA / IMTP Immune-mediated Haemolytic Anaemia/Thrombopaenia
- Skin lesions
What are the two types of Type IV Hypersensitivity autoimmune diseases? (Hint: involve both types of T cells)
CD4 T-cell mediated (TH-1: IFN-ɣ → macrophages)
- abnormal activation of macrophages
- macrophage production of inflammatory mediators PG, LT, etc. & MMP (matrix metalloproteinase) enzymes causes tissue damage
CD8 Killer T-cell mediated (CTL)
- CTLs kill healthy cells mistakenly as if they were infected by virus
Name some examples of Type 4 Hypersensitivity Autoimmune reactions involving abnormal CD4+ Helper T-cell & CD8+ Killer-T-cell production.
Rheumatoid arthritis - T-cells react to synovial proteins presenting cartilage, resulting in collagenase production. Can lead to erosive arthritis
Hypothyroidism (most common autoimmune disease in dogs)
- Lymphocytic thyroiditis
- almost complete destruction of thyroid architecture,
probably by MMP (metalloproteinase) enzymes
- thyroglobulin autoantibodies (TgAA) are probably a
consequence rather than the cause of the disease
(it is just easier to measure them than T cells) - Hair loss, weight gain, lethargy
Keratoconjunctivitis Sicca aka “dry eye”
- lymphocytic, T-cell infiltration disease
- immune-mediated destruction of lacrimal glands
What are some treatments for autoimmune disease?
Immunosuppressive drugs, such as Glucocorticoids, are often used.
Eg., Prednisolone & Ciclosporin (this one is used for Dry Eye; blocks activation of T-cells via C3-coreceptor blockage down-regulation)