Tolerance and Autoimmunity Flashcards
What type of immune response is involved in autoimmunity?
Adaptive immune response
Which cell type is always involved in autoimmunity?
Lymphocytes
What proportion of people has lymphocytes with the capability of recognising self-antigens?
ALL of us – this is normal autoimmunity
What are the 2 main factors that affect the transition from normal autoimmunity to autoimmune disease?
Genetic susceptibility
followed by
Environmental factors that trigger it (infection, diet)
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 is female?
75% overall (this changes between diseases)
What is a possible reason for the increase in incidence of autoimmune disease?
Hygiene hypothesis
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 hypersensitivity – 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?
2 ways:
- Complement activation by immune complexes. Complement then recruit phagocytes (the other function of complement is to form the membrane attacking complex)
- Inflammatory cells are directly activated by their Fc receptors binding to the Fc portion of the antibodies within the immune complexes
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?
Costimulation
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
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 , deletion of autoreactive cells in primary lymphoid organs
Peripheral Tolerance = once we’ve developed mature lymphocytes, there are mechanisms to develop tolerance
Nb both B and T cells have mechanisms of central and peripheral tolerance
What are the three main mechanisms of peripheral tolerance?
Anergy
Ignorance (immune privilege)
Regulation (Treg)
What are the three outcomes for T cells based on how stronglythey bind to MHC in the thymus?
Useless –don’t recognise MHC at all – die by apoptosis
Useful – associate weakly with MHC
Dangerous – associate too strongly with MHC – die by apoptosis
What percentage of thymocytes survives selection?
5%
What class of immunoglobulin are the B cell surface receptors?
IgD and IgM
What happens to B cells that recognise soluble autoantigens?
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
This mutation means that the T cells can’t be selected against a wide range of self-peptides so lots of self-reactive T cells get released into the circulation and can cause autoimmune disease
What is anergy caused by?
The presentation of an antigen in the absence of costimulation – this makes the lymphocytes enter a refractory state
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 or the lack of accessibility to the antigens
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.
Sympathetic ophthalmia
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?
( NO NEED TO KNOW THIS)
CD4
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: pathogen very similar to antigen on self tissue. Immune response made towards pathogen, then immune response is also made on self tissue.
- Induction of costimulatory molecules or inappropriate MHC class II expression leading to pro-inflammatory environment
- Failure of regulation: effects on Tregs
- Immune deviation: shift in type of immune response (dont understand, just memorise)
- infections can cause damage at privileged sites which lead to leak of self antigens which are previously not seen by the immune system
What happens when an immature b cells bind to a multivalent self molecule during its development in the bone marrow
apoptosis or receptor editing, making it non-autoreactive
What type of B cells are likely going to escape from the central tolerance system within the bone marrow?
B cells that bind to some non crosslinking self antigens with low affinity
explanation:
There may be some self antigens in the bone marrow where the B cells can bind to weakly. However, there are not enough of these self antigens in the bone marrow for the B cells to trigger a response, so they are not deleted. They escape to periphery and these B cells mature and could cause an autoimmune response because the levels of the weak antigens will be higher than the bone marrow
what factors can influence the development of autoimmunity
genes sex infections diet stress microbiome
L.O. Clinical disease: list examples of important autoimmune diseases
Rheumatoid arthritis T1DM Multiple sclerosis SLE Autoimmune thyroid disease, including Hashimoto’s and Graves
What did the evidence using skin grafts on mice show?
Showed 2 things:
1. Timing is critical = tolerance is more easily developed during neonatal period compared to adult
2. Tolerance is antigen specific, being tolerant to one antigen does not mean tolerance to another
(slides 28/9)
Outline the cell types that present antigens to T cells within the THYMUS during their development (part of central tolerance)
Thymic epithelial cell
dendritic cells
Outline the systems affected by APECED disease
Thyroid Kidneys Chronic mucocutaneous candidiasis Gonadal failure Diabetes mellitus Pernicious anaemia
these are all caused by mutations of AIRE gene leading to multi system effects
What is AIRE gene important for
AIRE gene allows medullary thymic epithelial cells (mTEC) to present low levels of antigens from around the body to the T cell to test for autoreactivity
