Hypersensitivity Flashcards
Some features of antibodies (GAMED)
IgG3 potently activates complement and Fc receptor mediated phagocytosis
IgA can cross mucosal epithelium
IgE can induce mast cell degranulation.
Main differences between CD4+and CD8+ T cells
CD4+ activated macrophages , B cells and other cells while CD8+ cells kill infected ‘target cell’s’and act in macrophage activation
What is Type 1 Hypersensitivity
Immediate/anaphylactic hypersensitivity. Allergic reactions that is provoked by interaction with allergen , examples include asthma, allergic rhinitis and atopic dermatitis.
Antibodies included in Type 1 hypersensitivity
Antigen specific IgE antibodies ( non allergic, e.g. in response to parasitic infections or very potent venoms).
With allergens : antibodies against common multivalent environmen
Common allergens
Foods ( peanuts), plants( Timothy grass and birch trees) , animal dander( cats and dogs), drugs ( penicillin and sulphonamides) and insect products ( bee venom, house dust, mites)
How does the initial sensitisation of the immune response to allergens occur
- Generation of type 2 helper (Th2) CD4 T cells and B cell helper follicular CD4 T cells
- Produce type 2 cytokines IL-4 and IL-13
- Act on B cells => promote B cell to switch from IgM to producing antigen specific IgE ( IgE is rarely found in circulation)
What happens when the IgE ( after it has been sensitised by one allergen) comes into contact with allergen ( again)
- IgE rapidly bound to the surface of innate immune cells, esp mast cells and basophils. These granulocytic cells express a high affinity IgE receptor, Fc epsilon receptor I (FcεRI).
If an allergen is encountered by cell bound IgE
1.Rapid crosslinking and degranulation of the mast cell or basophil.
The end product of these reactions is the release of histamine, a host of cytokines that can recruit other cells and promote further Th2 differentiation, and highly active smooth muscle contracting molecules such as leukotrienes and prostaglandins.
Early phase response on Type 1
Theearly phase, a result of bioactive small molecules produced directly by mast cells, occurs within minutes of allergen exposure.
Later response of Type 1 hypersensitivity
• Alater response, often seen within a few hours is the result of the recruitment of early inflammatory cells such as neutrophils.
Third phase of Type 1 hypersensitivity
• A third phase, orlate response, is often peaks 3-4 days after exposure where high frequencies of eosinophils are recruited and Th2 cells are present
What is type 2 hypersensitivity
known as antibody-mediated cytotoxic hypersensitivity, involves the destruction of cells by IgG or IgM antibody bound to antigens present on the surface of the cells.
Examples of type 2 hypersensitivity
Mismatched blood transfusion which results in the destruction of rbc, inflammation and tissue damage
- haemolytic disease of newborns ( mismatch of RhD alleles)
- immune thrombocytopenia ( antibodies develop against platelet surface proteins )
- Graves’ disease (patients develop thyroid stimulating antibodies that bind the thyrotropin receptor resulting in secretion of thyroid hormones. )
Type 2 sensitisation can involve either
- Exposure to a foreign antigen (for example some drugs can bind to the surface of cells in the blood), or non-self antigens (blood transfusions or organ transplants)
- Aberrant response to a self-antigen resulting in IgGs or IgMs that recognise cell surface structures.
How can the antibodies involved in Type 2 sensitisation result in diseases
- Anti-receptor activity – blocking or activating its function
- Antibody dependent cell-mediated cytotoxicity (abbreviated to ADCC)
- Classical activation of the complement cascade
How does the complement cascade work
a complex process by which antibody on the surface of cells is recognised by the complement components, ultimately leading to the formation of the membrane attack complex (MAC) in the surface of the cell, and cell death due to loss of osmotic integrity.
Activation of the classical complement pathway also however results in inflammation, opsonisation and recruitment and activation of immune cells.
What is the classical pathway
Antigen-antibody immune complexes
What is the lectin pathway
PAMP recognition by lectins
What is the alternative pathway
Spontaneous hydrolysis of pathogenic surfaces
Antibody dependent cell-mediated cytotoxicity ( ADCC)
InADCCantibody-antigen complexes on the surface of cells are bound by Fc receptors (which bind the constant (Fc), not antigen specific, tail regions of IgM and IgG antibodies) expressed by cells such as granulocytes and NK cells lead to directed lysis of the target cell, but also the release of inflammatory mediators, chemokines and cytokines.
How does type 2 hypersensitivity result in multiple mechanisms of tissue injury .
local or systemic inflammation, cell depletion leading to a loss of function or imbalance in organ function.
How does type 3 hypersensitivity work
known as immune complex driven disease.Immune complexesare non-cell bound antigen-antibody complexes which are normally cleared through the activity of the immune system.
If immune complexes cannot be efficiently cleared they end up being deposited in the blood vessel walls and tissues, promoting inflammation and tissue damage.
Symptoms of type 3 hypersensitivity
- Fever, rashes, joint pain
- Protein in the urine
- Vasculitis if deposited in blood vessels
- Glomerulonephritis if in the kidneys
- Arthritis if in the joints.
This can happen if the complexes are the result of antibodies reacting against self-antigens such as nuclear DNA.
Examples of auto immune diseases involving type 3 hypersensitivity
- Rheumatoid arthritis
- Multiple sclerosis (MS)
- Systemic lupus erythematosus (SLE)- in SLE patients develop IgGs against DNA or nucleoproteins (proteins present in the nucleus of cells) which form persistent immune-complex deposits and a variety of pathologies.
Examples of type 3 hypersensitivity that involves foreign antigens ( instead of autoimmune disorders)
- Persistent infections such as hepatitis virus infections can result in immune complex deposition
- Exposure to freely circulating foreign antigens such as drugs.
○ Serum sickness:
§ Person is bitten by a snake => given anti-serum (antibodies specific to the snake venom proteins) to neutralise the snake venom.
§ These are foreign proteins, and while they neutralize the venom our bodies will react against them to produce antibodies that recognise the anti-venom antibodies.
§ First exposure => process may take several weeks so not a problem as anti-sera and the snake venom will be long cleared.
§ If however the person gets bitten by a snake again, these antibodies will rapidly recognise the anti-serum and drive rapid inflammation; another good reason to avoid venomous snakes.
- Exposure to freely circulating foreign antigens such as drugs.
Type 4 hypersensitivity
other known as delayed-type or T cell mediated hypersensitivity, is primarily initiated by T cells.
Sensitisation of type 4 hypersensitivity
antigen is presented to naïve T cells by antigen presenting dendritic cells => leads to generation of antigen specific memory T cells; like other forms of sensitization it takes several weeks.
What happens during the subsequent exposure in Type 4 hypersensitivity
On a subsequent exposure these memory T respond promoting inflammation at the site of exposure. However because the memory T cell response is slightly slower than antibody mediated memory there is often a delay between exposure and response, with peak responses often seen 2-3 days after inflammation (T cell response requires recruitment and expansion)
Example of Type 4 hypersensitivity
The most common example is contact dermatitis caused by exposure to poison ivy, where a small molecule called urushiol, drives a T helper 1 response (but due to its small nature rarely results in antibody production).
On re-exposure these memory cells produce cytokines such as IFN-gamma which promote the pro-inflammatory activation of macrophages resulting in swelling and oedema, and the formation of blister like lesions.
Other examples include nickel salts or hair dyes which can drive Th1 based inflammation or other intracellular pathogens like measles and tuberculosis
How does tuberculin skin test work
measures previous exposure to tuberculosis bacteria by injection of small amounts of M. tb protein into the skin, is a type IV hypersensitivity reaction.
Asthma and type 4 hypersensitivity
allergens can cause overreaction of T helper 2 cells => produce soluble mediators => promote bronchoconstriction. In many diseases more than one hypersensitivity reaction can take place.
Transplant cells and hypersensitivity
While CD8 T cells can lead to inflammation and rejection of a tissue graft by directly killing transplanted cells.
