Hypersensitivity Flashcards
What classification system categorises hypersensitivity reactions?
Gell and Combs
4 main types
type 5 recently added
What is a type 1 hypersensitivity reaction?
anaphylaxis
caused by Ag reacting with IgE bound mast cells
other e.g. include atopy (asthma, hay fever, allergy)
What is a type 2 hypersensitivity reaction?
cell bound caused by IgG or IgM binds to antigen on cell surface e.g. Autoimmune haemolytic anaemia • Idiopathic Thrombocytopenic Purpura • Goodpasture's syndrome • Pernicious anaemia
What is a type 3 hypersensitivity reaction?
immune complex caused by free antigen and antibody (IgG, IgA) combining e.g. Serum sickness • Systemic lupus erythematosus • Post-streptococcal glomerulonephritis
What is a type 4 hypersensitivity reaction?
delayed hypersensitivity T cell mediated e.g. • Tuberculosis • Graft versus host disease • Allergic contact dermatitis • Scabies
What is a type 5 hypersensitivity reaction?
Autoantibodies
Antibodies that recognise and bind to the cell surface receptors.
This either stimulating them or blocking ligand binding
e.g. Graves disease, myasthenia graves
What is hypersensitivity?
diseases caused by abnormal immune responses, which then cause tissue damage
What are the characteristics of hypersensitivity reactions?
- triggered by environmental or endogenous Ag
- imbalance of effector mechanisms and regulatory/control mechanisms
- genetic predisposition
- tissue injury mediated through same immune cascades used to treat infection
What are the mechanisms underlying ‘Ab binding?’
- complement activation => inflammation
- FcR activation => inflammation
- stimulating/blocking Ab
What is the main T cell mediated mechanism for hypersensitivity?
delayed type hypersensitivity, cell lysis
What is the nature of a type 1 hypersensitivity reaction?
fast immune reaction to sensitised subject
triggered by expo to allergens
allergen binds to IgE on mast cell surface
What is atopy?
increased propensity to develop allergies
What are the risk loci implicated in type 1 hypersensitivity responses?
Chr 5q31
locus which encodes genes for IL-4, IL-5, IL-13: Th2 responses
What environmental factors may increase risk for development of Type 1 hypersensitivity reactions?
- pollutants
- respiratory infections
- bacterial skin infections
What is the hygiene hypothesis?
increased allergy incidence in developed countries
related to reduced infections in early life
childhood infections educate immune system so it is less likely to react to innocuous allergens
What is the mechanism underling type 1 hypersensitivity?
- DC present Ag to CD4+ T cells
- Th2 cell response
- B cell activation and IgE switch
- IgE production
- IgE bind Fc receptors on mast cells (sensitisation)
Where are mast cells located?
- located to small vessels e.g. capillaries
in tissue depots
mature upon tissue entry
What are the main stages in the allergen exposure in type 1 hypersensitivity?
- allergen crosslinks IgE-FcR on mast cells
- mast cell activation
- inflammatory mediator release
- vascular/smooth muscle reactions [mins]
- LATE phase reaction [2-24hr]
Which cells carry the IgE-FcR?
FcR = epsilon receptor for IgE
- mast cells
- eosinophils
What Rx suppresses the expression of pro-inflammatory cytokines?
corticosteroids
promoter function is repressed
What is the relationship between mast cell degranulation and allergic response?
the more mast cells that degranulate over a wide body system/SA, the more widespread/systemic the reaction is
local response vs anaphylaxis
What happens when mast cells are activated?
- release of preformed mediators
- secretion of lipid mediators
- release of cytokines
Which preformed mediators are released by activated mast cells?
- histamine
- enzymes
Which lipid mediators are released from activated mast cells?
- PGs
- leukotrianes
- platelet activating factor
Which cytokines are related from activated mast cells?
- IL-3
- IL-4
- IL-13
- TNFa
causes inflammation and an IgE switch
How are mast cells involved in non-atopic allergy?
triggered by extreme temp and exercise
IgE and Th2 not involved
mast cells are hypersensitive to activation
20-30%: immediate hypersensitivity
What is the late reaction in type 1 hypersensitivity?
occurs 2-24hr post initial reaction
appears without further allergen exposure
may last several days
common in allergic rhinitis, bronchial asthma
What is the mechanism for the late reaction in type 1 hypersensitivity?
influx of:
- eosinophils
- neutrophils
- basophils
- Th2 cells
mediated by mast cell chemokines and cytokines
inflammation and damage to mucosal epithelia
Rx: corticosteroids
What stain can be used to differentiate basophils and eosinophils?
= Wright-Giemsa staining
Basophil: purple granules
Eosinophil: red/brown granules
How do eosinophils contribute to a type 1 hypersensitivity reaction?
Release of pre-formed mediators:
MBP
ECP
enzymes
Lipid mediators: leukotrienes
Cytokines:
IL-3, IL-5,
chemokines (IL-8, RANTES)
What is anaphylaxis?
systemic type 1 hypersensitivity reaction
Activation of mast cells in many tissues
Sx: vascular shock, hypotension, airway and systemic oedema, vomiting, abdo cramps, diarrhoea
How do type 2 and type 5 hypersensitivity responses differ?
type s: autoantibodies directed against self Ag on host surface
type 5: autoantibodies are directed against host PM receptors e.g. Graves, myasthenia gravis
What are the mechanisms underlying type 2 hypersensitivity?
- opsonisation and phagocytosis
- complement activation and Fc receptor-mediated inflammation
- Ab-mediated cellular dysfunction (no inflammation, no tissue damage)
What are examples of conditions caused by type 2 hypersensitivity reactions?
autoimmune haemolytic anaemia
agranulocytosis
transfusion reactions
haemolytic disease of newborn
What occurs in the complement-mediated reaction in type 2 hypersensitivity?
- Ab deposit in tissues
- complement activation -> inflammation
- neutrophil recruitment, monocytes
- leukocyte activation (Fc and complement receptors)
- tissue damage
e.g. Ab-mediated glomerulonephritis, vascular rejection
What causes Goodpasture’s syndrome?
type 2 hypersensitivity reaction
Ab directed against glomerular basement membrane
causes smooth, linear deposit
What is the mechanism underlying antibody-mediated cellular dysfunction?
Ab bind to cellular receptors/proteins
this MODIFIES FUNCTION
e.g. myasthenia gravis: blocking Ab
Graves disease: stimulating Ab
NO INFLAMMATION, NO TISSUE DAMAGE
What is the pathophysiology in myasthenia gravis?
Ab bind and block the Ach receptors on the post-synaptic membrane
preventing Ach to bind at activate them
this causes severe muscle weakness
What are the mechanisms underlying a type 3 hypersensitivity reaction?
self/foreign antigen or soluble antigen
Ab combine with Ag in circulation (IMMUNE COMPLEX)
deposition of immune complex in vessel walls
Causes systemic effects: glomerulonephritis, arthritis, vasculitis
What is serum sickness?
type 3 hypersensitivity
caused by diphtheria immunisation, horse serum
Immune complexes formed in circulation deposit in small arteries, glomeruli and synovia
inflammation caused by complement activation
injury caused by neutrophil influx
What is SLE?
= systemic lupus erythematosus
type 3 hypersensitivity reaction
autoantibodies (often targeting nuclear Ag)
immune complexes deposit in tissues causing vasculitis
How do the deposits in type 3 hypersensitivity reactions differ from that of type 2 hypersensitivity reactions?
Type 2: SMOOTH LINEAR deposit e.g. Goodpasture’s syndrome
Type 3: COARSE GRANULAR deposit
e.g. SLE
What are the mechanisms underlying type 4 hypersensitivity reactions?
mediated by either CD4+ or CD8+ T cells
CD4+: delayed hypersensitivity (e.g. TB), Th1 and Th17-mediated autoimmune disease
CD8+:
type 1 DM, viral hepatitis-mediated cirrhosis, organ transplant rejection
What is the mechanism underlying DTH in type 4 hypersensitivity?
CD4+ Th1 cytokines (IFNg) cause inflammation
chronic macrophage activation lead to tissue injury
- lysosomal enzymes
- ROS, NO
- inflammatory cytokine
In Th1 response, what signals are required for macrophage activation?
- TCR: MHCII-peptide complex
- CD40L (Th1): CD40 (mQ)
- IFNg secreted by Th1 cell
What is the tuberculin reaction?
= DTH type 4 hypersensitivity
in previously ‘sensitised’ individual (TB, BCG vaccination)
Ag administered intradermally
Checked at 72hr
Ag is purified protein derivative (PPD)
24-72hr later: erythema, oedema (8-12h) - accumulation of monocytes, CD4+ T cells - ROS, NO - inflammatory cytokines
What is the underlying cause of the tuberculin reaction seen in the Mantoux test?
= Perivascular accumulation of monocytes and CD4+ T cells
[DTH Type 4 reaction]hypersensitivity]
What causes granulomatous inflammation in type 4 hypersensitivity reaction?
- strong Th1 and macrophage activation -> tissue destruction
- inflammatory cytokines (e.g. TNFa, IFNg)
e.g. in TB (persistent microbial inflammation)
What is the cause of contact dermatitis?
= DTH type 4
local expo to chemicals/allergens
e.g. nickel, poison ivy
protein conjugates are taken up by DC cells -> Th1 cells
T cell and mQ infiltration
shows as VESICULAR dermatitis
What are the causes of organ-specific and systemic autoimmune diseases?
= DTH type 4
Th1 cells: mQ infiltration
Th17 cells: neutrophil infiltration
- RA
- MS
- IBD
- Psoriasis
What is cytotoxic T cell type 4 hypersensitivity?
= tissue destruction mediated by CTLs
e.g. T1DM, Hep B, transplant rejection
What are the principles of Rx in hypersensitivity disorder?
- avoid allergen or desensitisation
- reduce tissue injury
What are e.g. of Rx that are used in hypersensitivity reactions?
[reduces tissue injury]
Plasmapharesis: remove circulating Ab or immune complexes that can cause hypersensitivity reactions
OMALIZUMAB: block IgE effects
SODIUM CROMOGLYCATE: block mast cell degranulation
HISTAMINE H1R ANTAGONISTS
CORTICOSTEROIDS
mAb INFLAMMATORY CYTOKINES (anti-TNF, IL-1 antagonist)
ANTI-INTEGRIN Ab: block T cell entry into tissues
Which immunosuppressive drugs may be used in hypersensitivity reactions?
- cyclosporine (blocks T cell activation)
- rapamycin
- methotrexate (blocks lymphocyte proliferation)
