Tolerance and autoimmunity Flashcards
(44 cards)
1
Q
What is autoimmunity?
A
Adaptive immune responses with specificity for ‘self antigens’ (autoantigens). Involves lymphocytes and antibodies
2
Q
…………
A
We have lymphocytes with receptors that are capable of recognising self tissue – normal autoimmunity
In most people, this doesn’t cause problems – they don’tT become activated and don’t lead to disease
There are various factors that lead to the development of autoimmmunity e.g. genetic and environmental factors
This leads to the break down of self tolerance, and manifestation of disease
3
Q
What are the genetic and environmental factors leading to autoimmunity?
A
- Genes: twin and family studies, GWAS (e.g. 40 key loci in SLE) – autoimmune diseases run in family
- Sex: women are more susceptible to autoimmune disease
- Infections: infections generate an inflammatory environment
- Diet: obesity, high fat, effects on gut microbiome: diet modification may relieve autoimmune symptoms
- Stress: physical and psychological, stress-related hormones play a role (e.g. cortisol)
- Microbiome: gut/oral microbiome helps shape immunity, perturbation may trigger autoimmune disease
4
Q
Mechanisms of autoimmunity
A
- All autoimmune diseases involve breaking of T-cell tolerance
- Disease mediated by antibodies is almost always IgG (so you need class switching – T cell involvement)
- Autoimmune diseases are chronic conditions
5
Q
What is the impact of autoimmune diseases?
A
Approx. 8% of individuals are affected by autoimmune disease
Approx. 80% of affected individuals are women
The incidence of autoimmune disease (and hypersensitivity) is increasing (hygiene hypothesis)
6
Q
Sex differences in autoimmune disease incidence
A
- In SLE, the ratio of affected males and females is 1:9
- However, in T1DM, males are affected MORE than females
- It depends on the specific condition in terms of which sex is more likely to be affected
- 80% of AI disease cases are female (don’t know why)
7
Q
Give examples of important autoimmune diseases
A
- Rheumatoid Arthritis
- Type I diabetes
- Multiple Sclerosis
- Systemic Lupus Erythematosus (SLE)
- Autoimmune thyroid disease: including Hashimoto’s and Graves’ disease
8
Q
How are autoimmune diseases classified and how do they vary?
A
- The organs affected
- The involvement of specific autoantigens
- The types of immune response
These can classify autoimmune diseases in humans - Some diseases are very organ-specific (e.g. thyroid diseases)
- Other diseases are more systemic (e.g. SLE)
9
Q
Autoimmune haemolytic anaemia
A
Autoantigens have been identified in various autoimmune diseases
- Early experiments showed that autoantibodies against RBCs were responsible for AIHA in humans
- Antibodies bind to the surface of red blood cells
- Result in the clearance or complement-mediated lysis of autologous erythrocytes
10
Q
Type 2,3 and 4 diseases - what does this mean
A
Immune reactions known to play a direct role in the pathology of human autoimmune disease:
Antibody response to cellular or extracellular matrix antigen (Type II hypersensitivity)
Immune complex formed by antibody against soluble antigen (Type III hypersensitivity)
T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV hypersensitivity)
11
Q
Give examples of type II diseases
A
Autoimmune haemolytic anaemia
Goodpasture’s syndrome
Grave’s disease
Myasthenia gravis
12
Q
What is Goodpasture’s syndrome?
A
- Antibodies against type IV collagen in the basement membrane
- Once antibodies are deposited: complement activation, inflammatory cell recruitment etc.
- This particularly affects the kidney glomerulus, and can result in glomerulonephritis
- Another consequence of Goodpasture’s syndrome is pulmonary haemorrhage
13
Q
What is Grave’s disease?
A
- Antibodies against the TSH receptor – they are agonistic so stimulate the receptor
- This causes excessive release of thyroid hormones – negative feedback is lost due to stimulation
- Grave’s disease leads to hyperthyroidism
14
Q
SLE (Type 3 immune complex disease)
A
- Immune complexes are formed and deposited around the body
- In SLE this happens particularly around the kidney, joints and skin
- This results in glomerulonephritis, vasculitis and arthritis
15
Q
What is the difference between type 2 and 3 diseases?
A
- In both cases, we see antibody binding to antigen. The effector mechanisms are the same (activation of complement and recruitment of inflammatory cells, particularly neutrophils).
- However, in type III, because soluble immune complexes form, they can circulate around the body and become deposited in various sites.
- Whereas, in type II, there is direct binding of the antibody in situ, either on cell surfaces or on ECM.
16
Q
What are type 4 reactions?
A
- In type IV reactions, T cells cause some of the symptoms directly. In T1DM, T cells destroy the beta cells.
- Autoantibodies are still involved
- Both cytotoxic (CD8+) and helper (CD4+) T cell responses can be involved.
17
Q
Give examples of type 2,3 and 4 reactions
A
2: Grave’s, myasthenia gravis
3: Lupus
4: mutliple sclerosis, rheumatoid arthritis, insulin dependent diabetes mellitus
18
Q
Autoantigens and pathologies of each type
A
Look at table in notes
19
Q
What is the normal T cell response to antigens?
A
- Antigen is presented to T-cells by MHC molecules, expressed on the surface of antigen-presenting cells
- Mature T cells are either CD8+ or CD4+. CD8+ T cells recognise MHC class I presenting peptide. CD4+ T cells recognise MHC class II presenting peptide on an APC
20
Q
Describe some evidence to support the concept of self tolerance
A
- These cattle have fused placentas and exchange cells and antigens in utero
- Non-identical twins have different sets of blood group antigens
- These twins are non-identical: as adult cattle they would be expected to react to each others tissues
- However, when adults, these cattle can tolerate blood transfusions from the non-identical twin
- They can also accept skin grafts from each other
- This suggests being exposed to these ‘foreign’ antigens in utero makes them tolerant to those antigens
21
Q
What is important about tolerance development?
A
- The timing of exposure is critical to the development of tolerance
- The tolerance is antigen specific
22
Q
Tolerance - what is it, when does it happen and what are some features of it?
A
- Tolerance is defined as the acquired inability to response to an antigenic stimulus
- It happens early in life, and the effects are maintained throughout life as an adult
- Acquired: involves cells of the acquired immune system and is ‘learned’
- Antigen specific
- Active process in neonates, the effects of which are maintained throughout life
23
Q
What are the 2 main types of tolerance?
A
Central tolerance: happens during lymphocyte development. This involves elimination of self-reactive lymphocytes during lymphocyte development
Peripheral tolerance: mechanisms to develop tolerance once we’ve generated mature lymphocytes
24
Q
What are the 3 types of peripheral tolerance?
A
- Anergy
- Immune privilege (ignorance of antigen)
- Regulation
25
Describe central tolerance for T cells
- T cell receptors are derived from the rearrangement of gene segments
- This is a random process – there is the potential for development of receptors reactive against self
- So lymphocytes need to be selected, on thymic epithelial cells in the thymus, and dendritic cells
- These cells express MHC molecules, which are loaded with self peptides
- Self peptides are presented to the developing T lymphocytes
There are three possible outcomes for the maturing T cells based on how strongly they bind to MHC:
- USELESS: the TCRs don’t recognise MHC at all –> death by apoptosis
- USEFUL: weakly associate with MHC – receive signal to survive – 'positive selection'
- DANGEROUS: associate with MHC too strongly – death by apoptosis – 'negative selection'
Only 5% of thymocytes survive
26
Describe central tolerance for B cells
- This selection takes place in the bone marrow
- They’re selected based on the interaction between B cell receptor and antigens present in bone marrow
- If there is no self reaction then the B cells go on to become mature B lymphocytes
- These mature B cells express their surface receptors (IgD and IgM)
- If they do recognise self antigens, they will usually die by apoptosis
- However, there is a second chance for B cells to amend themselves – this is called receptor editing
- If they recognise soluble autoantigens, they will still migrate to the periphery, but they are anergic
27
Definition of central tolerance
Mechanism of deletion of auto-reactive T and B lymphocytes in primary lymphoid organ
28
What are anergic B cells?
- Non-responsiveness, cannot be activated by T helper cells
- They express levels of surface IgM
- These anergic cells have a short half life, and tend to die out due to competition
- These cells that recognise self weakly have the potential to cause autoimmune disease
29
What is APECED?
Autoimmune PolyEndocrinopathy- Candidiasis- Ectodermal Dystropy:
- Results from a failure to delete T cells in the thymus
- It is caused by mutations in the transcription factor AIRE (autoimmune regulator) gene
- If AIRE doesn’t work properly, we don’t have expression of tissue specific proteins in the thymus
- Developing T cells aren’t exposed, so they can end up becoming self-reactive
30
What does AIRE do?
- AIRE is important for the expression of “tissue-specific” genes in the thymus
- Peptides derived from these gene products are being presented on cells in the thymu
- Developing T cells can be exposed to these peptides and selected for ones that don’t bind strongly
- It is involved in the negative selection of self reactive T-cells in the thymus
31
Which glands are affected in APECED?
| What are the symptoms of APECED?
- Thyroid
- Kidneys
- Chronic mucocutaneous candidiasis
- Gonadal failure
- Diabetes mellitus
- Pernicious anaemia
32
SLE and genetics
SLE: Genes affecting multiple biological pathways may lead to a failure of tolerance
- 40-50 genes have been implicated in genetic susceptibility to SLE
- Many of these genes are involved in the induction of tolerance, apoptosis and clearange of antigen
- Induction of tolerance (B lymphocyte activation: CD22, SHP-1): autoantibody production
- Apoptosis (Fas, Fas-ligand): failure in cell death
- Clearance of antigen (Complement proteins C1q, C1r and C1s): abundance/persistence of auto-antigen
33
Why is peripheral tolerance needed and how is it done?
- Some antigens may not be expressed in the thymus or bone marrow
- They may be expressed only after the immune system has matured
- Mechanisms are required to prevent mature lymphocytes becoming auto-reactive and causing disease: anergy, suppression by regulatory T cells and ignorance
34
What is anergy in T cells?
Absence of co-stimulation
- For naïve T-cells (ones that haven’t seen their antigen before), just recognising peptide MHC its own is not sufficient for activation
- Therehas to be co-stimulatory signals from the APC
- CD80, CD86 and CD40 are examples of costimulatory molecules expressed on APC
- These are absent on most cells of the body
- Without costimulation, then cell proliferation and/or factor production does not proceed
- The T cell becomes anergic – it is non functional and it is harder to activate this T cell
35
What is immunological ignorance?
- Occurs when antigen concentration is too low in the periphery for lymphocytes to recognise it
- It may also occur by physical segregation of antigen from lymphocyte (immunologically privileged sites)
- For example in the eye, central and peripheral nervous system and testes
- Occurs when relevant AP molecule is absent: most cells in the periphery are MHC class II negative
36
Give an example of ignorance failure in the eye
- In the eye, there is a condition that you can get called sympathetic ophthalmia
- If there is some sort of physical trauma to the eye, there is release of proteins (antigens) in the eye
- These proteins can enter nodes, and antigens can be presented to re-circulating T cells in the lymph nodes
- If T cells do become activated, adhesion molecules on the T cells change, and the T cells go back to the eye
- Both eyes can show symptoms of the disease despite damage in only on
37
What is IPEX?
Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome
- IPEX is a genetic condition
- There is onset of autoimmune symptoms and accumulation of auto-reactive T cells
- IPEX is a fatal recessive disorder presenting early in childhood
- It results from a mutation in the FOXP3 gene
38
What are the symptoms of IPEX?
- Early onset insulin dependent diabetes mellitus
- Severe enteropathy
- Eczema
- Variable autoimmune phenomena
- Severe infections
39
What doe FOXP3 do?
FOX P3 encodes a transcription factor critical for the development of regulatory T-cells
40
What are some infections associated with automimmune diseases?
- Multiple slcerosis: EBV, measles
- Type 1 DM: rubella, CMV, mumps, coxsackie
- RA: E.coli, EBV, hep c
- Lupus: EBV
- Myocarditis: coxsackie, CMV, chlamydia
- Rheumatic fever: streptococci
41
What do induction and maintenance of peripheral tolerance will depend on?
- Site of antigen expression (MHC expression, immune privilege)
- Timing of antigen expression
- Amount of antigen expression
- Costimulation
- T cell help for B cell responses
- Regulation
- Infections may help break tolerance by a variety of mechanisms
42
How can infections affect tolerance?
- Molecular mimicry of self molecules. This is where the microbe has a similar structure to self molecules. If there’s an immune response against the microbe, the response will attack the self molecule
- Infection can induce changes in the expression and recognition of self proteins
- Infection can cause induction of co-stimulatory molecules or inappropriate MHC class II expression. This results in a pro-inflammatory environment
- Failure in regulation: effects on regulatory T-cells
- Immune deviation: shift in type of immune response e.g. Th1-Th2
- Tissue damage at immunologically privileged sites
43
..........
In normal self-tolerance, T cells are not activated by MHC presenting self-peptides.
Microbes have PAMPs (pathogen associated molecular patterns) that help them to activate APCs. They upregulate co-stimulatory molecules and MHC molecules.
Activating APCs can be enough to activate a naïve, self-reactive T cell, causing autoimmunity.
44
MHC and autoimmunity
- Human MHC (HLA) class II is the dominant genetic factor affecting susceptibility to autoimmune disease
- Some of the most important genes that influence the susceptibility to autoimmune disease are MHC class II genes
- There are some DR molecules that are associated with increased risk of certain autoimmune conditions
