Tolerance and autoimmunity Flashcards
What is autoimmunity?
It is an adaptive immune response with specificity for self antigens
As it is an adaptive immune response, what does it always involve?
Lymphocytes
How are receptors on lymphocytes generated?
Via random recombination of gene segments- allows generation of receptors against self antigens
What is normal autoimmunity?
Lymphocytes that are capable of recognising self antigens but don’t cause any damage
What three main factors affect the transition from normal autoimmunity to autoimmune disease?
Genetic susceptibility
Infections Environmental factors
- These can all lead to the breakdown of self tolerance and progression to autoimmune disease
What mechanism do adaptive immune reactions against self use?
The same mechanisms as immune reactions against pathogens (and environmental antigens)
What does autoimmune disease involve breaking?
T cell tolerance
What sort of conditions are autoimmune diseases?
Chronic conditions because self tissue is always present
What do the effector mechanisms of autoimmune disease resemble?
Those of hypersensitivity reactions (types 2, 3 and 4)
How does autoimmune prevalence differ between gender?
75% of affected individuals are female
How is the incidence of autoimmune disease changing?
It is increasing- hygiene hypothesis
Name the major autoimmune diseases?
Rheumatoid arthritis Type I diabetes Multiple sclerosis Systemic lupus erythematosus (SLE) Autoimmune thyroid disease
What is a common hypothesis for high incidence in females?
Oestrogen
What are autoimmune diseases categorised based on?
Organs affected
Involvement of specific auto-antigens
Types of immune responses
What was found to be responsible for autoimmune haemolytic anaemia and how is it?
Autoantibodies against red blood cells- They bind to red blood cells and activate complement. This results in clearance and complement mediated lysis of the autologous erythrocytes. There is a direct link between autoantibodies and disease
Which immune reactions are known to play a direct role in the pathology of human autoimmune disease?
Type II- Antibody response to cellular or extracellular matrix antigens
Type III- immune complex formed by antibody against soluble antigen
Type IV- T cell mediated disease- delayed type hypersensitivity
What happens in good pasture’s syndrome?
IgG antibodies form against type IV collagen found on the basement membrane which leads to deposition of autoantibodies in the renal corpuscle so this particularly affects the kidneys- it will activate the complement and attract inflammatory cells like neutrophils. The influx of inflammatory cells can cause damage
What happens in Graves’ disease?
There is an autoantibody that can bind to the TSH receptor and mimic the action of TSH- it stimulates the production of thyroid hormone.
The autoantibody isn’t under negative feedback control so results in constant stimulation of thyroid hormone production -> hyperthyroidism
What do type III reactions involve?
Antibodies binding to soluble antigens and forming immune complexes
In type III reactions, how do immune complexes cause problems?
These immune complexes circulate to different places i the body via the blood and get deposited in various tissues. This can cause problems particularly in kidneys, it can also affect joints and joint pain.
What is the difference between the effector mechanism for type II and type III hypersensitivity?
The effector mechanism is the same, the only difference is the nature of the antigen- insoluble in II but soluble in III. Both types can recruit inflammatory cells which bind via their Fc receptors to the Fc portion of the antibodies
Give a summary of the differences between type II and type III?
Type II: Insoluble antigens Activation of complement Binding of inflammatory cells to Fc portion of the antibodies via their Fc receptors Causes more localised tissue injury Type III: Soluble antigens Immune complexes form that can deposit in various sites Effector mechanisms are the same
Give some examples of autoimmunity T cell mediated disease?
Type 1 diabetes mellitus (pancreatic beta cell antigen) Rheumatoid arthritis (Unknown synovial joint antigen) Multiple sclerosis (myelin basic protein)
What presents antigens to T cells?
MHC expressed on the surface of antigen presenting cells
What MHC class is there for CD4+ (helper) and CD8+ (cytotoxic) T cells?
CD4+- MHC class II CD8+- MHC class I
What does a naive T cell require to become activated?
The antigen specific reaction isn’t sufficient, it requires costimulation from APC. Once fully active, it will go on to proliferate
What is the strongest genetic link to autoimmune disease?§
Human MHC (HLA) is a dominant genetic factor affecting susceptibility to autoimmune disease. They are mostly class II genes
What effect does being exposed to foreign antigens in utero have?
In freemartin cattle experiment it showed that you develop tolerance to these antigens so wont respond to them when an adult
What is critical to development of tolerance?
Timing of exposure
If you take spleen and bone marrow cells from a black strain mouse and inject them into a newborn white mouse, when the white mouse is an adult how will it respond to skin grafts from black strain mouse?
It can accept them, if you did the same experiment but injected them into an adult instead of a newborn, they would not be able to accept skin grafts from black mouse
If you take spleen and bone marrow cells from a black mouse and inject it into a newborn white mouse, then give a skin graft from blue mouse what will happen and why?
Graft will not be accepted as tolerance is antigen specific
What is immunological tolerance?
Acquired inability to an antigenic stimulus
What are the 3 As that describe the features of immunological tolerance?
Acquired- involves cells of the acquired immune system and is learned
Antigen specific
Active processes in neonates
What are the two main types of tolerance?
Central- Happens during lymphocyte development
Peripheral- Once we’ve generated mature lymphocytes there are mechanisms to develop tolerance
What are the three main mechanisms of peripheral tolerance?
Anergy
Immune privilege (ignorance of antigen)
Regulation
Where do all lymphocytes come from?
Stem cells in bone marrow
Where do precursors of T cells migrate to and mature?
Thymus- undergo a rigorous selection process here
Where does the selection of B cells occur?
In the bone marrow
What does selection of T cells in the thymus involve?
Extent of binding of the TCR to the MHC molecules- end up with two cell population (CD4+ and CD8+) depending on which MHC class molecule they bind to best.
What are the three possible outcomes for maturing T cells based on how strongly they bind to MHC?
Useless- 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- receive signal to die by apoptosis ‘negative sleection’
What percentage of thymocytes survive selection in the thymus?
5%
What are B cells in the bone marrow selected based on?
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 which express their surface receptors (IgD and IgM)
If they recognise self antigens, they will usually die by apoptosis
What is the second chance for B cells to amend themselves?
Receptor editing
What happens if a B cell recognises soluble autoantigens?
They will still migrate to the periphery but don’t express normal levels of IgM and are anergic (not responsive to B cells)
What happens if a B cell has a weak interaction with soluble antigens?
The B cells will develop fine and there will be normal levels of cell surface receptors
Define central tolerance
Mechanism of deletion of auto reactive T and B lymphocytes in primary lymphoid organs
What does APECED stand for?
Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy also called APD
What is APECED?
Rare autoimmune condition that affects the endocrine glands- thyroid and kidneys, causes chronic mucocutaneous candidiasis, gonadal failure, diabetes mellitus, pernicious anaemia
What causes APECED?
It involves a mutation in transcription factor AIRE (autoimmune regulator) gene.
What is AIRE important for?
Expression of tissue specific genes in thymus- allows low level expression of large variety of self peptides in thymus against which T cells are selected. It is crucial in negative selection of self reactive T cells in thymus
What does AIRE gene mutation lead to?
People with dysfunction AIRE gene won’t express self peptides properly in the thymus so T lymphocytes can’t be selected based on their reactivity. They will produce lots of self reactive T lymphocytes that get released into circulation and cause autoimmune disease
What are the main processes affected in autoimmune disease?
Induction of tolerance
Apoptosis
Clearance of antigen.
(most autoimmune diseases are associated with multiple defects and genetic traits)
What mechanisms are required to prevent mature lymphocytes becoming auto-reactive and causing disease by expressing antigens only after thymus or bone marrow and immune system has matured?
Anergy
Ignorance of antigen
Suppressions by Tregs
What is anergy?
Absence of costimulation
Why is absence of costimulation a problem?
Naive T cells require costimulation for full activation- without it, cell proliferation and/or factor production doesn’t proceed
Give some examples of costimulatory molecules expressed on APC
CD80, CD86 and CD40
What does subsequent stimulation by the same antigen lead to?
A refractory state called anergy
When do APCs express high levels of costimulatory molecules?
When activated
How do APCs recognise pathogens?
They have pattern recognition receptors (PRRs)- pathogens and inflammation can upregulate costimulatory molecules on APCs.
What normally occurs upon presentation of an antigen by an APC in presence of pathogens and inflammation?
The APC will have sufficient costimulatory molecules to activate the T cell and stimulate a response
What is immunological ignorance?
It occurs when the antigen concentration is too low in the periphery, when relevant antigen present molecule are absent and occurs at immunologically privileged sires where immune cells can’t normally penetrate e.g. eye, CNS, PNS and testes. T cells can never see the antigen
Give an example of the failure of ignorance?
Sympathetic ophthalmia- if there is tissue damage, ignorance can fail. Damage to the eye can release eye antigens that drain via the lymphatics into lymph nodes. These antigens will then be presented to T cells in the lymph nodes and T cells will become activated against eye antigens. T cells will go back to both eyes and cause damage
What is suppression/regulation?
Auto reactive T cells may be present that don’t respond to auto antigens. Controlled b other cell types (regulatory T cells)
What are Tregs?
Specialised cells that can emulate activity of other T cells
What receptors do Tregs express?
CD4
CD25 (IL-2 receptor- growth factor for T lymphocytes)
CTLA-4
FOXP3
What is IPEX?
Immune dysregulation, polyendocrinopathy, enteropathy and x-linked inheritance syndrome
It is a fatal recessive disorder presenting early in childhood which leads to failure in regulation of peripheral tolerance
What causes IPEX?
Mutation in the FOXP3 gene which encodes a transcription factor that is critical for development of Tregs which causes accumulation of autoreactive T cells
What are the symptoms of IPEX?
Early onset insulin dependent diabetes mellitus Severe enteropathy Eczema Variable autoimmune phenomena Severe infections
What are the two types of T regs?
Natural T regs (nTreg)- these are generated in the thymus
Inducible T regs (iTreg)- these are produced as part of the normal T cell response as mechanism for dampening down an immune response after it has happened
How can infections affect tolerant state?
Molecular mimicry of self molecule- if a pathogen expresses a molecule that is very similar to a self molecule, the immune response against the pathogenic antigen could lead to immune response against self antigen
Induce changes in expression and recognition of self proteins
Induction of co-stimulatory molecules or inappropriate MHC class II expressions: pro-inflammatory environment
Failure of regulation: Effect on Tregs
Immune deviation- shift in type of immune response
Tissue damage in immunologically privileged sites
