Lecture 10: Autoimmune diseases and transplantation Flashcards
What is the purpose of immune system toelrance?
To prevent our immune system from attacking our own cells and tissues
What is central tolerance?
The elimination of strongly self-reactive T-cells or B-cells before they are allowed to mature
How is central tolerance acheived?
Negative selection:
T-cells in thymus - T-cells with TCRs that bind strongly to self antigens are eliminated by apoptosis
B-cells in bone marrow - clonal deletion of B-cells with a self-reactive BCR and by receptor editing
Why might some self-reactive B and T-cells not be eliminated by central tolerance?
Not all antigens are expressed in the thymus or bone marrow
Some B or T-cells that bind weakly to self-antigens are not negatively selected
How does central tolerance in thymus and bone marrow prevent autoimmunity?
In thymus: mTEC stromal cells have transcription factors (AIRE, FEZF2) that allow them to express a range of self-antigens in order to test the reactivity of the TCRs
In bone marrow: receptor editing results in deletion of B-cells with autoreactivity
What factors can promote the development of autoimmunity?
- predisposing genes (E.g. certain types of MHC genes)
- Sex (autoimmunity more common in females)
- Tissue damage
- Inflammation
- Infections
What is the role of peripheral tolerance?
To control the activity of escaped (from central tolerance) autoreactive T- and B-cells in the tissues this occurs by three main mechanisms:
- anergy and apoptosis
- ignorance
- Treg cells
Tolerance is favoured by antigens that what?
- are present at high doses (E.g. keratins)
- Show long-term persistence
- are introduced orally or intravenously
- are not accompanied by adjuvants (PAMPs) - no tissue damage or microbes present
- induce low levels of co-stimulation
- are presented by immature or unactivated APCs
What is one mechanism of peripheral tolerance?
Antigen sequestration
- retention of antigens in compartments without significant immune cell access that are immune privileged sites
- theses antigens cannot be accessed by B or T-cells leading to B and T-cell ignorance of these tissue-specific antigens
Give three examples of immune privileged sites
Eyes
Brain
Uterus
Testes
Explain how the peripheral tolerance mechanism of anergy and apoptosis prevent self-reactivity
When a T-cell recognises an antigen presented by an APC in the absence of co-stimulatory signals (CD80/86 - CD28, and CD40 - CD40L) this can lead to anergy or apoptosis of the T-cell
Explain how the peripheral tolerance mechanism of Treg cells prevent self-reactivity
- Secrete anti-inflammatory cytokines IL-10 and TGF-beta
- Inhibit the function of APCs when CTLA-4 on Treg binds CD80/86 on APC in place of the CD28 of T-cells sending an inhibitory signal into APC that inhibits release of proinflammatory cytokines and increases expression of IDO enzyme that promotes an immunosuppressive environment
What is bystander suppression in the context of APC inhibition by Tregs as part of peripheral tolerance?
Bystander suppression occurs when one APC engages several CD4+ T-cells of different specificities and the Treg cell bound to the same APC inhibits the activity of the other T-cells
What causes autoimmune diseases?
The failure of tolerance mechanisms which protect our tissues from destruction by our immune system
- can be caused by self-reactive autoantibodies or self-reactive T-cells (which can lead to cell lysis and organ damage)
- sometimes there are contributions also from innate immunity and complement
Give three examples of organ-specific autoimmune diseases? (give the name of disease, organ/cell/protein affected and the key immune mediators in the disease)
Disease: Type I diabetes mellitus
Affected: Beta cells
Immune mediator: Th1 cells and autoantibodies
Disease: Myasthenia gravis
Affected: acetylcholine receptors
Immune mediator: autoantibodies
Disease: Crohn’s disease
Affected: Gut mucosa
Immune mediator: innate immunity, Th17 cells
Give three examples of systemic autoimmune diseases? (give the name of disease, organ/cell/protein affected and the key immune mediators in the disease)
Disease: Multiple sclerosis
Affected: Brain, neurons
Immune mediator: Th1 cells, CTLs, autoantibodies
Disease: Rheumatoid arthritis
Affected: connective tissue, joint
Immune mediator: immune complexes, autoantibodies
Disease: Systemic Lupus Erythematosus (SLE)
Affected: RBCs, platelets, skin, kidneys
Immune mediator: interferons, autoantibodies, immune complexes
Which immune mediators contribute to the destruction of the beta cells in Type I DM?
Cytotoxic T-cells
Autoantibodies
Macrophages
What is myasthenia gravis?
an organ-specific autoimmune disease in which motor end plate cells of skeletal muscle are destroyed sue to autoantibodies against acetylcholine receptors that trigger complement-mediated lysis of these cells
(results in progressive loss of muscle function)
What are some potential treatments for myasthenia gravis?
Immunosuppressants (corticosteroids)
Cholinesterase inhibitors (prevent the breakdown of acetylcholine to increase chance of binding to receptor)
What is Systemic Lupus Erythematosus
(SLE)?
SLE is a systemic autoimmune disease in which individuals produce autoantibodies against a wide range of tissue antigens
- common targets are proteins associated with self DNA and RNA (thought that the detection of self-nucleic acids by PRRs plays a role in the disease)
What are some symptoms/characteristics of SLE?
Characteristic butterfly rash on face
other symptoms: fever, weakness, arthritis, kidney dysfunction
What is the main cause of kidney dysfunction in SLE?
Deposition of immune complexes containing antibodies and complement that damage the glomerulus
What causes the neurological symptoms seen in multiple sclerosis?
Due to the action of auto-reactive T-cells that attack the myelin sheath of nerve fibres and the spinal cord resulting in numbness, paralysis, loss of vision etc.
What factors may be associated with the cause of multiple sclerosis?
genetic risk factors
associated infections - compromises the BBB so autoreactive T-cells can enter the immune privileged site and react with CNS antigens
- destruction of cells, mast cell activation, complement activation, antibodies and cytokines released
–> results in demyelination of neurons
True or false: most autoimmune diseases are single gene disorders?
False: most are multifactorial diseases where many genes and environmental factors play a role
What is an example of an autoimmune disease caused by a single gene mutation?
IPEX (Immune dysregulation Polyendocrinopathy, Enteropathy and X-linked syndrome)
mutation in FoxP3 transcription factor
What genetic factors may increase susceptibility to autoimmune diseases?
- certain kinds of MHC variants
- genes for immune cell surface protein
- genes for innate immune signalling factors
What is the MHS variant that predisposes an individual to ankylosing spondylitis?
HLA-B27
Give examples of genes for immune cell surface proteins that increase susceptibility to T1DM and Crohn’s disease?
T1DM = IL-2 and CTLA-4
Crohn’s disease = IL-23
Give examples of genes for innate immune signalling factors that increase susceptibility to SLE?
TLRs and RNA receptors
Give 5 non-genetic factors that influence susceptibility to autoimmune diseases
- Hygiene hypothesis (early stimulation of the immune system prevents autoimmunity)
- Gut microbiome influences immune responses and tolerance
- Sex hormones (Oestrogen promotes inflammation)
- Injury - reveal antigens from immune privileged sites
- Molecular mimicry (infections containing antigens that are similar to self antigens)
Give an example of molecular mimicry between human host proteins and proteins of an infectious agent
There is sequence similarity between the IE2 protein of the human cytomegalovirus and the human host HLA-DR molecule
Hoe can microbiota dysbiosis promote autoimmunity?
change or absence of microbe produced factors can lead to a decrease in Treg cells and increase in Th17 and inflammation
What are the three main challenges to transplantation?
- Availability of organs
- Surgical techniques
- Graft rejection
What are the four types of graft used in transplantation?
- Autograft
- tissue transported from one site of body to another - Isograft
- graft of tissue from one genetically identical individual to another (monozygotic twins) - Allograft
- graft of tissue from a donor to recipient (not genetically identical but need good genetic match and immunosuppression) - Xenograft
- transplantation of organs from animals to humans (aortic valve with pigs as donors) - cells and soluble proteins are removed to reduce immunogenicity
What does autograft acceptance look like?
Revascularisation, healing and resolution (low neutrophil infiltration) within 14 days of graft
What does autograft rejection look like?
revascularisation, much higher immune response (high neutrophil and other immune cells infiltration), thrombosis and necrosis of graft
How does ‘first-set’ rejection differ from ‘second-set’ rejection of a autograft?
First set rejection takes place 12-14 days after graft
Since rejection displays specificity and memory, the ‘second set’ rejection takes places after a few days due to memory response
– this need to ensure second graft has different antigens to the original rejected graft
What are the effector mechanisms of the immune system that lead to graft destruction?
activated CD4+ T-helper cells:
- produce IL-17 that activate neutrophils and lead to inflammation
- secrete INF-gamma which activates macrophages that result in movement of lytic enzymes into graft site
- secrete Lymphotoxin-alpha which causes cytotoxicity at the graft site
CTLs (CD4+ and CD8+) bind to MHC II and MHC I, respectively, alloantigen causing membrane damage
Activated B-cells produce antibodies against graft antigens that recruit complement that results in lysis
–> also NK cells of macrophages can bind to antibodies via Fc receptor, triggering ADCC
Which type of graft is donor matching particular important for?
Allografts
- minimise the genetic differences between the donor and recipient
- match major antigens (ABO blood type and MHC molecules (HLAL))
Why is it important to match MHC molecules between donor and recipient of allograft?
MHC proteins are very polymorphic so they often vary between individuals and can be recognised as foreign in the graft
Who is commonly used as a good source of donor tissue in an allograft transplant?
family members
What are the two types of ‘recognition’ of a graft as foreign?
Direct allorecognition and indirect allorecognition
What is direct allorecognition?
When donor antigen presenting cells with intact donor MHC molecules presenting any peptide - the donor MHC molecules are recognised too strongly by the recipient T cells
What is indirect allorecognition?
Recipient APC with recipient MHC presenting peptide from donor MHC - the recipient T cells recognise the donor MHC peptide presented by self cells
Why are transplant recipients often more susceptible to infections and some cancers?
Transplant recipients often need to undergo immunosuppressive therapy for many years
- the treatments are not antigen-specific and cause general immunosuppression
