2. Tolerance and autoimmunity Flashcards
What are the genetic and environmental risk factors of autoimmune diseases?
- Genes - runs in family
- Sex - women more susceptible
- Infections
- Diet
- Stress
- Microbiome
What happens to T cell tolerance in autoimmune disease?
T cell tolerance is broken
Which antibodies almost always mediate autoimmune diseases?
IgG (need class switching - T cell involvement)
Are autoimmune diseases acute, chronic or can they be both?
Chronic
Which hypersensitivity reactions do autoimmune diseases resemble?
Types II, III and IV
How are mechanisms different in adaptive immune reactions against self?
The same
Which hypothesis potentially explains the rising incidence of autoimmune disease?
Hygiene hypothesis
How is a baby affected in a pregnant woman with Grave’s disease?
- IgG involved can cross the placenta
- Developing foetus can acquires the antibodies
- Is born with neonatal Grave’s disease
- Symptoms stop as the maternal antibodies are removed
What is Goodpasture’s syndrome?
- Type II hypersensitivity
- Antibodies against type IV collagen
- Complement activation, inflammatory cell recruitment etc.
- Particularly affects kidney => glomerulonephritis
- Pulmonary haemorrhage is another consequence
What causes Grave’s disease?
- Type II hypersensitivity
- Antibodies stimulate the TSH receptor (agonistic)
- Excessive release of thyroid hormones
- Negative feedback lost due to stimulation
- Hyperthyroidism
What causes SLE?
- Type III hypersensitivity
- Immune complexes formed and deposited around the body
- Affect DNA, histones, ribosomes, snRNP, scRNP
- Particularly affects the kidney, joints and skin
- Results in glomerulonephritis, vasculitis and arthritis
How are the effector mechanisms different in type II and III hypersensitivities?
They are the same i.e. complement activation, inflammatory cell recruitment etc.
What directly destroys beta cells in T1DM?
T cells - CD4+ and CD8+ (type IV)
What presents antigens to T cells in type IV hypersensitivity?
MHC on APC
Which MHC molecules do CD4+ and CD8+ recognise?
- CD4+ = MHC class II
* CD8+ = MHC class I
Which MHC is the dominant genetic factor affecting susceptibility to autoimmune disease?
Human MHC (HLA) class II
What are the most polymorphic genes in the body?
HLA genes
Can B cells be involved in autoimmunity?
Yes
How does the Freemartin Cattle experiment provide evidence for the concept of self tolerance?
- Cattle have fused placentas and exchange cells and antigens when in utero
- They are non-identical - have different sets of blood group antigens
- When adults, they can tolerate blood transfusions and skin grafts from each other
- This suggests that exposure to foreign antigens in utero makes them tolerant to them
If you inject some spleen and bone marrow cells from an adult to a newborn mouse of different strains, will the newborn be able to accept skin grafts from the other strain when older?
Yes, as long as the skin graft is from the same strain as the bone marrow cells (but this doesn’t work if you inject the cells into an adult mouse)
What is tolerance?
Acquired inability to respond to an antigenic stimulus
When does tolerance occur in life?
Early in life, and maintained throughout life (active process in neonates)
What are the 2 types of tolerance?
- Central
* Peripheral
When does central tolerance occur and what does it involve?
- During lymphocyte development
* Mechanism of deletion of autoreactive T and B lymphocyte in primary lymphoid organs
What does peripheral tolerance involve and what are the 3 types?
Mechanisms to develop tolerance once we’ve generated mature lymphocytes
• Anergy
• Immune privilege
• Regulation
Where do all lymphocyte originate?
Stem cells in the bone marrow
Where do precursors of lymphocytes migrate to?
Thymus
Where do B cells develop to become a antibody-secreting plasma cells when activated?
Bone marrow
Why do lymphocytes need to be carefully selected?
- T cell receptors are derived from the random rearrangement of gene segments
- Potential for development of receptors reactive against self
Where exactly are lymphocytes selected?
On thymic epithelial cells and dendritic cells in the thymus
What do the thymus cells, involved in selection, express?
MHC molecules with self peptides, which are presented to the developing T lymphocytes
What are the 3 possible outcomes for maturing T cells?
Based on how strongly they bind to self MHC
• Don’t recognise MHC, useless => apoptosis
• Weakly associate with MHC, useful => signal to survive (positive selection)
• Associate with MHC too strongly => apoptosis (negative selection)
What is B cell selection based on?
- Interaction between BCR and antigens in bone marrow
- No self reaction => become mature B lymphocytes
- Reaction => apoptosis
What antibodies do mature b cells express?
IgD and IgM
What happens if mature B cells recognise soluble autoantigens?
Receptor editing
• Still migrate to the periphery
• However, they express low levels of IgM => anergic (not very response)
• Prevents autoimmunity
When can receptor editing sometimes not work?
- If the B cell has a weak interaction with the soluble autoantigen
- It can then develop fine and have the potential to cause autoimmune disease
What is APECED and the cause?
• Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy
• Failure to delete T cells in the thymus
• Caused by mutations in the transcription factor AIRE
- important for expression of tissue-specific genes in the thymus
• Developing T cells aren’t exposed, so can become self-reactive
What do the gene products of AIRE do?
- Peptides derived from the genes are presented on cells in the thymus
- Developing T cells are exposed to the peptides and selected for
What is APECED also known as, and what tissues does it affect/conditions does it cause?
• Autoimmune poly-glandular disease (APD)
- Thyroid
- Kidneys
- Chronic mucocutaneous candidiasis
- Gonadal failure
- Diabetes mellitus
- Pernicious anaemia
What happens to mature the T cell apart from the MHC-TCR reaction, for full activation?
- Co-stimulation e.g. by CD80, 86 expressed on APCs (only when activated)
- These interact with e.g. CD28 on the T cell
- CD4 on T cell interacts with MHC II on APC
- Cell proliferation doesn’t proceed with co-stimulation
- T cell becomes anergic - harder to activate
- Only specialised APCs can express and activate it, most cells can’t do this
What does immunological ignorance refer to?
- Antigen concentration is too low in the periphery for lymphocytes to recognise it
- May also occur by physical barrier e.g. in immunological privileged sites, where immune cells normally cannot penetrate e.g. eye, CNS, PNS and testes
- Cells don’t become tolerised against autoantigens
What is sympathetic opthalmia?
- Damage to immune privileged site in the eye
- Physical trauma can release proteins (antigens) which can enter lymph nodes
- These antigens can be presented to re-circulating T cells
- T cells can become activated and go to the eyes
- Both eyes can show symptoms, even if one eye is affected
- Can lead to blindness
Auto-reactive T cells may still be present but don’t respond to autoantigens, so how are they controlled?
Regulatory T cells with:
• CD4
• CD25 - high affinity IL-2 receptor
• CTLA-4 - binds to B7 and sends a negative signal
• FOX P3 - transcription factor required for Treg development
What is IPEX, it’s cause and symptoms?
- Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome
- Genetic condition - recessive
- Mutation in FOXP3 gene
- Treg cells don’t develop + work properly
- Onset of autoimmune symptoms and accumulation of auto-reactive T cells
- Early onset insulin dependent diabetes mellitus
- Severe enteropathy
- Eczema
- Variable autoimmune phenomena
- Severe infections
Which viruses are linked to T1DM?
Coxsackie virus B4, rubella, CMV, mumps
Which viruses are linked to Lupus Erythematosus?
EBV
Why can streptococci cause myocarditis?
Antibodies against streptococci can also target the heart muscle
What is molecular mimicry?
• Microbe has similar structure to self molecules
• Cross-activation of autoreactive lymphocytes:
- infection can induce co-stimulatory molecules or inappropriate MHC class II expression
- pro-inflammatory environment
• Immune response against microbe will cause response against self molecules
• Immune deviation e.g. Th1 => Th2
Which structure on microbes help the activation of APCs?
PAMPs (pathogen associated molecular patterns)
Can activating an APC be enough to activate a naïve, self-reactive T cell?
Yes
