Immunopathology Flashcards
What are the different types of hypersensitivity?
Type 1 - anaphylactic Type 2 - cytotoxic Type 3 - immune complexes Type 4 - delayed-type hypersensitivity (DTH) Type 5 - stimulatory hypersensitivity
What is immunopathology?
The concept that immune responses can cause harm to the host and are central to many clinically important diseases
Summarise immune reactants part of each type of hypersensitivity
Type 1 → IgE
Type 2 → IgG
Type 3 → IgG
Type 4 → Th1, Th2 or CTL
What type of hypersensitivity involves only T cells?
4
What is the effector mechanism in type 1?
Mast cell degranulation and release of granular mediators, such as histamine, as well as second phase lipids (PG and TX)
What diseases is type I hypersensitivity associated with?
- hayfever
- eczema
- asthma
- gastroenteritis
- anaphylaxis
Describe primary exposure to an allergen in T1?
- first exposure = activation of T cell response
- T cell response, through IL-4, drives IgE production in B cells
- IgE binds mast cells and is pollen specific
- causes release of mast cell contents
What do the two phases of mast cells response depend on?
Whether the mediators are in pre-formed granules or are synthesized de novo
Describe mast cell response w pre-formed granules
Histamine, Heparin –> toxic to parasites, increase vascular permeability and cause Smooth Muscle Contraction
Enzymes which remodel the connective tissue matrix
Describe mast cell response when mediators are formed de novo
Cytokines (IL-4; stimulates Th2 cell response which skews an anti-parasitic response) (IL-3, IL-5 and GM-CSF; promotes eosinophil production and activation) (TNFa; promotes inflammation and activates endothelium)
Eosinophils secrete granule proteins (toxins and enzymes) as well as cytokines and leukotrienes to potentiate the response
CCL3 chemokine for monocyte, macrophage and neutrophil attraction
PGD2, PGE2 and LTB4, LTC4 - Lipids which increase vascular permeability, cause SM contraction and stimulates mucus secretion
PAF - lipid which attracts leukocytes, amplifies production of lipid mediators, and activates neutrophils, eosinophils and platelets
What do IgE antibodies bind to on mast cells?
FcεRI
Mnemonic for types of hypersensitivity
The hypersensitivity reactions can be memorized with the mnemonic ACID: A – Allergic/Anaphylactic/Atopic (Type I); C – Cytotoxic (Type II); I – Immune complex deposition (Type III); D – Delayed (Type IV)
Clinical findings of T1
Immediate reaction: allergic reaction within minutes of contact with the antigen - (signifies the preformed antibody presence) - vasodilation and increased vascular permeability, with smooth muscle contraction (eg. Bronchi - respiratory distress)
Late-phase reaction: occurs hours after immediate reaction for a duration of 24–72 hours - where the endothelium expresses adhesion molecules and chemokines cause recruitment of cells - not blocked by anti-histamines.
Treatment of T1
Prevention of Histamine effects - anti-H1
Targeting SM (e.g in anaphylaxis we give EPIPEN - adrenaline, to cause vasoconstriction and increase BP)
Suppress inflammation - corticosteroids reduce lipid mediator formation
Cromoglycate - mast cell stabiliser
Leukotriene receptor antagonists
Induce tolerance - Treg; desensitize individuals by injecting incremental doses of the allergen. It has been noted that nasal or oral application of allergen can induce tolerance through the mucosal immune network (either through inducing anergy in the antigen specific effector cells, or through upregulation of Treg cells specific to that antigen).
Describe pathophysiology of T2 reactions
IgG (and IgM) bind to antigens on body cells and complement - leading to:
1 - opsonisation & phagocytosis
2 - complement activation
3 - antibody-dependent cell cytotoxicity (ADCC)
What conditions can result from T2 hypersensitivity?
1 - transfusion reactions - ABO and Rhesus blood groups
2 - Haemolytic disease of the new-born
3 - hyper-acute allograft rejection (initiated by pre-existing humoral immunity)
Describe haemolytic disease of newborn
here Rh -ve mother is sensitized by Rh+ baby at the time of birth when there is slight mixing of blood. If the mother becomes pregnant with a Rh+ fetus, IgG antibodies cross the placenta and damage fetal RBC. We can treat this anti-Rh antibodies to prevent sensitization against Rh+ pregnancies.
Describe pathophysiology of T3
Antigen (e.g., the molecules of a drug in circulation) binds to IgG to form an immune complex = antigen-antibody complex
Harmless in circulation
Immune complexes are deposited in tissue, especially blood vessels → initiation of complement cascade → release of lysosomal enzymes from neutrophils → cell death → inflammation → vasculitis
Example of local T3 reaction
Farmers Lung, where antigen is inhaled and the deposits are in the lung - antigens include spores and other biological antigens such as hay dust. This leads to a hypersensitivity pneumitis
Example of diffuse (circulating) T3 reaction
Systemic lupus erythematosus - antibodies form against nuclear proteins such as laminin, histones and DNA, and lead to a number of consequences specific to sites of deposition; renal –> glomerulonephritis, vascular –> vasculitis, joints –> arthritis. Characteristic butterfly rash
What is T4 hypersensitivity?
DELAYED TYPE HYPERSENSITIVITY ‘DTH’ (TYPE 4)
Summarise T4 hypersensiivity
- Contact of antigen with presensitized T lymphocytes
- Presensitized CD4+ T cells recognize antigens on antigen-presenting cells → release of inflammatory cytokines
- Presensitized CD8+ T cells recognize antigens on somatic cells → cell-mediated cytotoxicity
OR
Sensitization: antigen penetrates the skin → uptake by Langerhans cell → migration to lymph nodes and formation of sensitized T lymphocytes
Eruption: repeated contact with antigen → secretion of lymphokines and cytokines (e.g., IFNγ, TNF α) by presensitized T lymphocytes → macrophage activation and inflammatory reaction in the tissue
What is allergic contact dermatitis?
T4 reaction - skin rash + blisters from environmental chemicals from poison ivy/oak, nickel or topical medication
An infection by what microorganism can lead to T4 reaction?
TB Ag
What is the Mantoux test?
a small amount of tuberculin is injected into the skin of a person previously exposed to Mycobacterium tuberculosis, mononuclear cells accumulate in the subcutaneous tissue along with abundance of CD4 Th1 cells leading to induration and redness developing at its peak in 24–72 hours.
Describe type 5 hypersensitivity
Mediated by autoantibody acting as agonists on cell surface receptors
e.g. Graves’s Disease (hyperthyroidism).
