Flashcards in 2) Tolerance and Autoimmunity Deck (39):
What type of immune response is involved in autoimmunity?
Adaptive immune response
Which cell type is always involved in autoimmunity?
What proportion of people has lymphocytes with the capability of recognising self-antigens?
ALL of us – this is normal autoimmunity
What are the three main factors that affect the transition from normal autoimmunity to autoimmune disease?
Why are autoimmune conditions chronic?
Because self-tissue is always present
The effector mechanisms in autoimmunity resemble those of which type of immune reaction?
Hypersensitivity reactions (types 2, 3 and 4)
What proportion of people affected by autoimmune disease isfemale?
75% overall (this changes between diseases)
What is a possible reason for the increase in incidence of autoimmune disease?
Describe the pathophysiology of autoimmune haemolytic anaemia.
There are autoantibodies against red blood cells, which bind to red blood cells and activate complement
This results in clearance and complement-mediated lysis of the autologous erythrocytes
What is a type II hypersensitivity reaction?
Antibody response against cellular or ECM antigens (insoluble antigens)
What is a type III hypersensitivity reaction?
Immune complex formation by antibody against soluble antigen
What is a type IV hypersensitivity reaction?
T cell mediated disease – delayed type hypersensitivity
What is Goodpasture’s syndrome?
Type 2 hypersensitivity reaction in which there are IgG antibodies against a type IV collagen found on the basement membrane in the glomerulus
This results in deposition of autoantibodies in the renal corpuscle and activation of complement leading to infiltration of inflammatory cells and kidney damage
NOTE: the inflammatory cells (e.g. neutrophils) bind to the Fc portion of antibodies via their own Fc receptors
How do type II and type III immune reactions recruit inflammatory cells?
Inflammatory cells are recruited via the binding of inflammatory cells to the Fc portion of antibodies via their Fc receptors
What is the main difference between type II and type III hypersensitivity reactions?
Type II – insoluble antigens
Type III – soluble antigens
What is the autoantigen in multiple sclerosis?
Myelin basic protein
Other than antigen-TCR binding, what else is required for the activation of naïve T cells?
What is the dominant genetic factor affecting susceptibility to autoimmune disease?
HLA (class II in particular)
What did the freemartin cattle experiment show about tolerance?
It showed that early exposure to foreign antigens allows the development of tolerance to those antigens
Define immunological tolerance.
The acquired inability to respond to an antigenic stimulus
What are the main features of immunological tolerance?
It is acquired = involves cells of thee acquired immune system and is 'learned'
It is antigen specific
It is an active process in neonates
What are the two types of immunological tolerance?
Central Tolerance = happens during lymphocyte development
Peripheral Tolerance = once we’ve developed mature lymphocytes, there are mechanisms to develop tolerance
What are the three main mechanisms of peripheral tolerance?
Regulation - suppression by Treg
What are the three outcomes for T cells based on how strongly they bind to MHC in the thymus?
Useless –don’t recognise MHC at all – die by apoptosis
Useful – associate weakly with MHC - positive selection - receive signal to survive
Dangerous – associate too strongly with MHC – die by apoptosis
What percentage of thymocytes survives selection?
What class of immunoglobulin are the B cell surface receptors?
IgD and IgM
How does Anergy occur
Immature B cell responds to soluble autoantigens
The presentation of an antigen in the absence of costimulation makes the lymphocytes enter a refractory state
They will migrate to the periphery but they do not express normal levels of IgM and they are anergic (they are not very responsive)
What is the role of the AIRE transcription factor?
It is important for the low-level expression of a large variety of self-peptides in the thymus, against which the T cells are selected
What is APECED caused by?
Autoimmune polyendocrinolpathy candidiasis ectodermal dystrophy
Mutation in the AIRE transcription factor
So, T cells can’t be selected against a wide range of self-peptides
Failure to delete T-cells in the thymus
So, lots of self-reactive T cells get released into the circulation and can cause autoimmune disease
What is immunological ignorance caused by?
Occurs when the antigen concentration is too low
It can be due to the absence of antigen presenting molecules
It occurs at immunologically privileged sites where the immune cells don’t normally penetrate
This is ignorance – the T cells never see their antigen
Give an example of a failure of ignorance.
Damage to the eye can release eye antigens into the lymphatics and lymph nodes
These antigens are recognised by T cells, which become activated against the eye antigens
The T cells then go back to both eyes and cause damage
What are the main receptors expressed by Tregs?
CD25 –IL-2 receptor, which is an important growth factor for T cells
CTLA-4 – binds to B7 and sends a negative signal
FOXP3 – essential transcription factor for Treg development
What is IPEX caused by?
Mutation in FOXP3
FOXP3 encodes a transcription factor that is critical for the development of T regs
A mutation in FOXP3 leads to the accumulation of autoreactive T cells
What are the two types of Treg?
Natural Tregs (nTregs) – these are generated in the thymus
Inducible Tregs (iTregs) – these are produced as part of the normal T cell response as a mechanism of dampening down an immune response after it has happened
How can infections affect tolerant states?
Molecular mimicry of self-molecules
Induction of costimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment
Failure of regulation: effects on Tregs
Immune deviation: shift in type of immune response e.g. Th1 to Th2
Activation of APCs by pathogens leads to upregulation of costimulatory molecules
What is Autoimmunity
Adaptive immune responses with specificity for self "antigens" (autoantigens)
Where does B cell tolerance occur
Fatal Recessive disorder presenting early in childhood
variable autoimmune phenomena
early onset insulin dependent diabetes mellitus