What is an autoimmune disease?
A failure or breakdown of immune system that maintains tolerance to self tissues
What is loss of tolerence most likely due to?
Abnormal selection of self-reactive B and T cells
What may autoimmune disease may arise due to?
What does the treatment of autoimmune diseases deal with?
Symptoms rather than curing the disease
How many people suffer from an autoimmune disease?
1 in 20 worldwide
What is a hypersensitive response?
Hyper response from the immune system, harmful that may produce tissue damage and cause serious disease
What are the 4 categories of hypersensitive responses?
Type II (also type V)
Which of the hypersensitive responses are antibody mediated?
Type I, II and III
Which hypersensitive response is T cell mediated?
What are the exposures during a hypersensitive response?
First exposure (sensitisation)
What is the produce of type I hypersensitivity?
1) First exposure to antigen
2) Activation of TFH cells and stimulation of IgE class switching in B cells
3) Production of IgE
4) Binding of IgE to mast cells
5) Repeated exposure to antigen
6) Mast cells form cross links with allergen and are activated
7) Release mediators such as cytokines, amines and lipid mediators
a) Histamine/lipid mediators cause immediate reaction which is vascular and smooth muscle
b) Cytokines cause late phase reaction which is inflammatory
8) During the late phase, cytokines activates eosinophils, neutrophils and T cell infiltrates which travel to the site
What do amines cause during a type I hypersensitive response?
Vasodilation and increased permeability
What do lipid mediators cause in a type I hypersensitive response?
Broncho-constriction and intestinal hypermotility
What do cytokines cause during a type I hypersensitive response?
What do enzymes (proteases) cause during a type I hypersensitive response?
How do mast cells bind to allergens?
Fc receptors on mast cells bind to antibodies unique to the allergen, which must bind to two of these to create a cross bridge and release its mediators
What is atopy?
Genetic tendency to develop allergic diseases
What are levels of immunoglobulin E like in atopic patients?
What is the process of type II hypersensitivity?
1) Self reactive T cells pass through central tolerance and escape
2) Escaped B cells produce IgM and IgG antibodies which attach to antigens on host cells, creating an antigen-antibody complex
3) There are then 4 process of killing the cell:
a) Compliment cascade (MAC, membrane attack complex) bind to this and kill the cell by creating a pore, causing the cell to swell and burst
b) Compliment proteins from this system attract neutrophils which degranulate and kill the cell
c) C3b compliment protein binds to antibody-antigen complex which optimises the cell which encounters phagocytes which bind and engulf the cell by phagocytosis
d) Antibody dependent cell mediated cytotoxicity (ADCC) where natural killer cells bind and release toxic granules which form pores in the cell, enzymes enter and destroy the cell by apoptosis
What are the ways cells are killed in type II and III hypersensitive responses?
Compliment cascade (MAC, membrane attack complex) bind to this and kill the cell by creating a pore, causing the cell to swell and burst
Compliment proteins from this system attract neutrophils which degranulate and kill the cell
C3b compliment protein binds to antibody-antigen complex which optimises the cell which encounters phagocytes which bind and engulf the cell by phagocytosis
Antibody dependent cell mediated cytotoxicity (ADCC) where natural killer cells bind and release toxic granules which form pores in the cell, enzymes enter and destroy the cell by apoptosis
What is type V hypersensitive response?
The same as type II, except, instead of destroying the cell the function is just lost which is known as antibody mediated dysfunction
What is the process during type V that differs from type II?
1) Antibodies bind to antigen on the cell
2) Blocks binding of other things and effects the function of the cell, or may activate the receptors
What are the two types of antigens involved in hypersensitive responses?
Intrinsic (normally made by the host)
Extrinsic (antigen from infection)
What are key differences between type II and III?
During type III antigens bind to soluble antigens and not cells
During type III compliment system is used in large amounts not small
In type III clinical systems correspond to where the immune system complexes are deposited and not where they are made
What is the process of a type III hypersensitive response?
1) Self reactive cells escape
2) B cells switch from making IgM to IgG antibodies
3) Antibodies bind to soluble antigens (different from type II not cell surfaces)
4) Creates a small complex which is less immunogenetic (macrophages are not as attracted and not removed from the blood as quickly)
5) Complex flows around in blood and makes their way into basement membranes of blood vessels, becoming ionically attracted due to being positively charged while the basement membranes are negatively charged
6) Compliment system is activated (different from type II as used in large amounts instead of small)
7) Causes the same effects as type II such as neutrophils being recruited
8) Degranulation causes inflammation and tissue necrosis
What is the process of type IV hypersensitivity?
1) Dendritic cell presents antigen at lymph node using MHC II receptor
2) T helper cell binds using MHC II receptor
3) Dendritic cell releases cytokines, causing the helper T cell to mature into a TH1 cell
4) TH1 cell releases IL-2 (causes differentiation of more T cells) and IFNgamma (activates phagocytes like macrophages and creates more TH1 cells
5) Activated macrophages produce proinflammatory cytokines causing leaky epithelial barriers allowing more immune cells into the area
6) Leading to local swelling, redness and systematic symptoms like fever
7) Macrophages release enzymes which damages tissue
8) Original naive T cell could have also differentiated into TH17 cells due to different cytokines from the dendritic cells which secreates cytokines (IL-17) which recruits lots of neutrophils
What is another way that cells are killed during type IV hypersensitivity (T cells)?
1) MHC I receptors are present on all nucleated cells which presents antigens from inside the cell
2) T cell receptor (TCR) binds to MHC I receptor on the cell
3) Releases granzymes which form pores that allow the granzymes to enter the cell, inducing apoptosis
Which of the hypersensitive responses is a delayed type of reaction?
What are common type IV immunological diseases?
Type 1 diabetes
What do autoimmune diseases seem to be due to a combination of?
Genetic background and the environment