2 - Tolerance and Autoimmunity Flashcards
What is autoimmunity?
AUTOIMMUNITY = adaptive immune responses with specificity for self “antigens” (autoantigens)
- B Cells
- T Cells
Everyone has receptors for self-antigens, but they do not cause disease in most people. In normal people, they are formed in recombination.
What are the criteria for disease to be ‘autoimmune’?
Evidence of disease-specific adaptive immune response in the affected target tissue, organ or blood
Passive transfer of autoreactive cells or antibodies replicates the disease
- can occur sometimes naturally
- antibody-mediated disease is often IgG
- IgG can cross from mother to fetus via umbilical cord
- therefore, if mother has Grave’s Disease, fetus may have symtpoms of the disease initially when born
Elimination of the autoimmune response modifies disease
History of autoimmune disease (personal or family), and/or MHC associations
- doesn’t have to be the same autoimmune disease
What genetic and environmental factors can predispose to autoimmunity?
Genes:
- twin and family studies
- GWAS (e.g. 40 key loci in SLE)
Sex:
- women more susceptible (e.g. 9:1 in SLE)
- women have stronger immune responses
Infections:
- inflammatory environment
- more activation of immune cells
Diet:
- obesity
- high fat
- effects on gut microbiome
- diet modification may relieve autoimmune symptoms
Stress:
- physical and psychological
- stress-related hormones
Microbiome:
- gut/oral microbiome helps shape immunity
- perturbation (dysbiosis) may help trigger autoimmune disease
- potential sex differences in microbiome between men and women
Outline the importance of the human microbiome
Gut microbiome helps regulate our immune responses (homeostasis)
What are the mechanisms of autoimmunity?
Adaptive immune reactions against self use the same mechanisms as immune reactions against pathogens (and environmental antigens)
Autoimmune diseases involve breaking T-cell tolerance
- T cells help B cells with class switching, despite the disease being mediated by antibodies
Because self tissue is always present, autoimmune diseases are chronic conditions (often relapsing)
- autoimmunity can be treated but will still require life-long management
- symptoms can be well controlled but relapse is common
- very difficult to cure
Effector mechanisms resemble those of hypersensitivity reactions, types II, III, and IV
Describe the impact of autoimmune diseases
Approx:
- 100 chronic disorders have been identified which relate to aberrant immune responses causing the body to attack it’s own tissues
- 8% of individuals are affected by autoimmune disease
- 80% of affected individuals are women
The incidence of autoimmune disease (and hypersensitivity) is increasing (hygiene hypothesis)
Describe the sex differences in autoimmune disease incidence
Different autoimmune diseases have different levels of prevalence in males and females
e. g.
* SLE: Much more prevalent in females
However, some diseases have less of a difference between the sexes than others
List examples of important autoimmune diseases
Rheumatoid Arthritis
- 1 in 100
- 2.1 million cases
- 30-50,000 children (not just older people susceptible)
Type I diabetes
- 1 in 800
- 300-500,000 cases
- 123,000< 20yrs old
Multiple Sclerosis (MS)
- 1 in 700
- 250-300,000 cases
- 25,000 hospitalisations per year
Systemic Lupus Erythematosus (SLE)
- 240,000 cases
Autoimmune Thyroid Disease (ATD)
- including Hashimoto’s and Graves’ disease
- 5 cases/ 1000 women
- 0.8 cases per 1000 men
How do you describe autoimmune reactions in humans?
Used to be described based on organs affected
Now:
- Involvement of specific autoantigens
- Types of immune responses
List organ-specific autoimmune diseases and multi-systemic autoimmune disease, as well as their targets
What type of antigens have been identified as playing a direct role in immune diseases?
Autoantigens have been identified in various autoimmune diseases which play a direct role in the immunopathogenesis
Early experiments showed that autoantibodies against red blood cells were responsible for autoimmune haemolytic anaemia in humans
Result in the clearance or complement-mediated lysis of autologous erythrocytes
- Direct link between autoantibodies and disease (also antibody transfer experiments)
What immune reactions are known to play a direct role in the pathology of human autoimmune disease?
Antibody response to cellular or extracellular matrix antigen (Type II)
Immune complex formed by antibody against soluble antigen (Type III)
T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV)
In most conditions, it is not one type of reaction but a mixture of the different types
Name autoimmune diseases that are type II reactions
What is Goodpasture’s syndrome?
It is also known as anti-glomerular basement membrane disease
It is a rare autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys, leading to bleeding from the lungs and kidney failure.
What is Graves’ Disease and outline its autoimmune nature?
Antibody stimulates TSH receptor
Normal negative feedback doesn’t work because antibody continues binding to receptor
Hyperthryoidism
Name an autoimmune disease that involves Type III reactions
Systemic Lupus Erythematosus (SLE)
- antibodies against nuclear components (histones, double-stranded DNA)
- antibodies bind to antigens
- circulate as immune complexes
- deposited in organs and joints
- causes problems particularly in the kidneys
- leading to glomeruler nephritis
Why do some autoimmune diseases get better during pregnancy?
During pregnancy, there is a shift in immune responses away from inflammatory responses in order to protect the foetus
- e.g. rheumatoid arthritis symptoms may get better during pregnancy
However, for an antibody-mediated autoimmune disease, symptoms often get worse
- e.g. SLE
What occurs in Type II and Type III hypersensitivity reactions?
TYPE II
- Insoluble antigen
- Antibody binds
- Localised tissue injury and recruitment
- Activation of complement
- Recruitment of inflammatory cells
TYPE III
- Same mechanism as Type II, just the location differs
- Soluble immune complexes in the circulation
- These complexes get deposited once they bind to a surface
- Then they can activate complement and inflammatory cells
- Inflammation at the site of deposition of the immune complexes
Give some examples of Type IV (T-Cell mediated diseases) hypersensitivity
These reactions involve predominantly T-cells instead of antibodies
Outline the normal T-cell response to antigens
Antigen is presented to T-cells by MHC molecules expressed on the surface of antigen-presenting cells
- CD4 T-cells restricted by class 2 molecules
- CD8 T-cells restricted by class 1 molecules
What MHC class is the dominant genetic factor affecting susceptibility to autoimmune disease?
Human MHC (HLA) class II is the dominant genetic factor affecting susceptibility to autoimmune disease
- strongest association with autoimmune disease
- relative risk goes up if you have HLA-DR molecules
What does early exposure to foreign antigens in neonatal mice allow for in adult mice?
If an adult mouse is given a skin graft from another mouse, the graft will be rejected.
However, if you give a neonatal mice some of the foreign antigens from another mouse, then attempt a skin graft when the mouse is older, the graft won’t be rejected.
THIS SHOWS THAT TIMING OF ANTIGEN EXPOSURE IS CRITICAL TO BUILD IMMUNE TOLERANCE.
Give evidence to show that tolerance has specificity
Even if cells are given to a neonate mouse to introduce them to foreign antigens, if they are given a skin graft as an adult from a different strain, they will still reject it
Outline the mechanism behind central tolerance
CENTRAL TOLERANCE
All lymphocytes come from stem cells in the bone marrow
T-cell precursors go to the thymus where a selection process occurs after generation of the T-cell receptor based on the peptides being presented on the thymic epithelial cells and dendritic cells in the thymus
CD4+ T-Lymphocytes are selected on MHC II plus self peptide
CD8+ T-Lymphocytes are selected on MHC I plus self peptide
What happens to B-Cells and how do they develop tolerance?
IMMATURE B-CELLS = BONE MARROW
NO SELF-REACTION
- become a mature B-cell
- express IgG and IgM
REACT STRONGLY WITH MULTIVALENT SELF MOLECULE
- get deleted
- or receptor editing occurs to make a receptor that isn’t strongly self-reactive
REACT AGAINST SOLUBLE SELF-MOLECULES WITH INTERMEDIATE AFFINITY
- escape to periphery
- become anergic
- can’t receive T-cell help
- don’t become fully activated to produce antibodies
- reside in secondary lymphoid organs
- slowly turned-over and removed
REACT VERY WEAKLY WITH SELF-ANTIGEN BUT CAN REACT IF SELF-ANTIGEN IS IN HIGH AMOUNTS
- have receptors to bind to self-antigen
- “ignorant”
- if they escape to the periphery, they can cause autoimmune disease
- not deleted because they haven’t seen their antigen in the bone marrow
What causes APECED?
APECED result froma failure to delete T-cells in the thymus
- caused by mutations in the transcription factor AIRE (autoimmune regulator) gene
- AIRE is important for the expression of ‘tissue specific’ genes in the thymus
- involved in the negative selection of self-reactive T-cells in the thymus
- if the transcription factor doesn’t work, the auto-reactive T-cells escape to the periphery and cause multi-organ disease
Explain anergy
ANERGY - absence of costimulation
Naïve T-cells require costimulation for full activation: 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
Subsequent stimulation leads to a refractory state termed ‘ANERGY’
Outline an example of a failure of immunological ignorance
FAILURE OF IGNORANCE - ex: Sympathetic Opthalmia
Normally, immune cells do not enter the eye. Therefore, the proteins in the eye are not seen by immune cells.
Physical damage to eye causes a release of antigens that are only expressed in the eye via the lymphatics to the draining lymph node
If there’s some AP in the lymph node, the T-cells can get activated and cause immune response in both eyes
How are infections linked to autoimmune disease?
How could infections affect the tolerant state?
Molecular mimicry of self molecules
Induce changes in the expression and recognition of self proteins
Induction of co-stimulatory molecules or inappropriate MHC class II expression: 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
