Autoimmunity

Question 1

What is autoimmunity?

Answer 1

A process by which the immune system reacts against the body’s own tissues.
Chronic and or excessive autoimmune responses can result in autoimmune diseases.
Everyone has a certain level of autoimmunity, but when it is over threshold it develops into autoimmune disease.

Question 2

Why do we need to maintain immune tolerance?

Answer 2

There is a range of antigen specific receptors carried by T and B cells which are generated by random processes.
Some of these B and T cells receptors recognise self-cells.
Without effective mechanisms to maintain tolerance against these cells, we are at risk of autoimmunity.

Question 3

How do we maintain T cell tolerance?

Answer 3

Central - thymic negative selection - transcription factor AIRE randomly switches on genes and their expression in the thymus, any T cell that recognises these is deleted.
Peripheral - ignorance, cell death/anergy, regulation.

Question 4

What are the peripheral mechanisms for T cell tolerance?

Answer 4

Ignorance - antigens hidden from the immune system e.g. in the eye.
Cell death/anergy - if antigens activate T cells in the absence of co-stimulatory signals, the T cell undergoes apoptosis or switches itself off to be anergic.
Regulation - regulatory T cells switch off activatory signals to T cells. These Tregs might have been initially recognised as self-reactive, then switched to be regulatory.

Question 5

How do we maintain B cell tolerance?

Answer 5

Central - early antigen encounter in bone marrow or early antigen encounter after being released that results in deletion or anergy.
Peripheral - a lack of T cell help, as B cell tolerance is affected by T cell tolerance. In germinal centres, T cells input to help maturation and optimisation of the B cell receptor. So if self-antigen specific T cells have been removed already, it helps with B cell tolerance.

Question 6

What is a defect in central T cell tolerance?

Answer 6

Genetic deficiency in expression of transcription factor AIRE, develop autoimmune polyendocrine syndrome type I.
Autoimmunity against all organ systems.
Low life expectancy.

Question 7

What is a defect in regulatory T cells?

Answer 7

Genetic mutation in transcription factor FoxP3, so is deficient.
FoxP3 is responsible for generating Tregs, so without it, causes high autoimmunity - IPEX - immunodysregulation polyendocrinopathy enteropathy X-linked.

Question 8

What is the mechanism of a loss of T cell tolerance due to ignorance?

Answer 8

T cells are normally not able to enter the eyes, so eye-specific antigens are hidden.
If one eye is damaged, the specific antigens raise an immune response, which activates T cells in the lymph nodes.
Activated T cells travel in the blood and are free to enter tissues, so it can enter the eyes and cause inflammation in both eyes.

Question 9

What is the mechanism of a loss of T cell tolerance due to activation?

Answer 9

Dendritic cells present antigens to T cells, but T cells are not activated unless the dendritic cell is fully stimulated through other signals.
When a dendritic cell is excessively activated, the T cell becomes more receptive to signals and is activated inappropriately.
e.g. a strong immune response to a bacterial infection highly activates dendritic cells and therefore T cells, which would not normally be activated by these antigens.
It causes a loss of selectivity of T cell activation.

Question 10

What is the mechanism of a loss of T cell tolerance due to regulation?

Answer 10

Tregs can produce cytokines IL-10 and TGF-b which limit the activation of effector T cells.
Tregs can sequester (remove) IL-2 which is co-stimulatory, by having a high expression of IL-2 receptors. They outcompete the signal of IL-2 by removing it from activating effector T cells.
Inhibit co-stimulation by removing co-stimulatory molecules from dendritic cells, so prevents the interaction with TCR.

Question 11

How does a loss of tolerance occur?

Answer 11

Genetic factors increase the risk of developing a certain autoimmune disease e.g. type I diabetes, or rheumatoid arthritis.
The interaction of genes with infection and environmental exposure increases the risk and removes immune regulation and develops autoimmunity.

Question 12

How is autoimmunity associated with genetic predisposition?

Answer 12

The genetic risk is found on the HLA region of the short arm of chromosome 6.
The HLA region encodes for class I and class II regions needed to present the antigens to T cells.
Class II encodes MHC II molecules, which present antigens to CD4.
Class I encodes MHC I, which presents antigens to CD8.
There is such a range of alleles, which combine to form a great genetic variability of MHC molecule.

Question 13

What is the structure of the MHC II molecule?

Answer 13

2 chains come together to form a groove in which the peptide is inserted.
The peptide which is inserted is defined by the shape and charges of the amino acids in the MHC proteins.
So certain peptides are more likely to bind to MHC depending on the MHC alleles.
This is seen in rheumatoid arthritis.

Question 14

How is auto-immunity characterised by auto-antibodies?

Answer 14

Antibodies to erythrocytes cause haemolytic anaemia as they cause phagocytosis of the RBC.
Antibodies to acetylcholine receptor causes myasthenia gravis. This is because it blocks the neuromuscular end plate, so blocks receptor signal transmission and leads to muscle weakness.
Antibodies to heart muscle develop after myocardial infarction, but have no effect.

Question 15

How do autoantibodies cause damage by opsonisation?

Answer 15

Coat the cells in autoantibody or complement proteins to aid phagocytosis.
The macrophages have receptors for the Fc region of antibodies and complement proteins, so can recognise them and easier bind the pathogen.
e.g. in haemolytic anaemia.

Question 16

How do autoantibodies cause damage by complement mediated lysis?

Answer 16

Autoantibodies bind to the cells and fixes the complement factors on.
The autoantibodies bind to self-antigens which activate the classical complement pathway, leading to membrane attack complex (MAC) formation.
MAC is inserted into the host cell and causes it to rupture.

Question 17

How do autoantibodies cause damage by forming immune complexes?

Answer 17

Autoantibodies bind to self-antigens to form immune complexes, which are large and abundant.
They deposit in the blood vessels and tissues, and then fix complement, which triggers neutrophil recruitment and MAC formation, which causes inflammation.
Neutrophils attempt to phagocytose the complexes, but cannot as they are stuck to basement membranes, so release proteases, reactive oxygen species and cytokines which cause inflammation and destruction.

Question 18

How do autoantibodies differ in binding to receptors?

Answer 18

Depending on where the autoantibody binds, the antibody will either lead to stimulation or inhibition of a receptor.
It can cause completely different diseases despite binding to the same ligand.

Question 19

How do autoantibodies cause Grave’s disease?

Answer 19

Autoantibody binds directly to the binding site of the Thyroid stimulating hormone (TSH) receptor.
This mimics the effect of TSH, which causes the thyroid to proliferate and excessively produce thyroxine, so causes hyperthyroidism and Grave’s disease.

Question 20

How do autoantibodies cause Hashimoto’s disease?

Answer 20

The autoantibody binds to a different site of the TSH receptor and prevents TSH from binding.
This blocks the function of the receptor, so less thyroxine is produced, and it induces tissue destruction.

Question 21

How do autoantibodies cause Myasthenia Gravis?

Answer 21

Autoantibodies specific to the acetylcholine receptor bind and prevent Na+ influx into the synapse, and therefore prevents muscle contraction.
The acetylcholine receptors are internalised and degraded.
Can also cause inflammation of the neuromuscular junction sites.

Question 21

How do maternal autoantibodies affect their offspring?

Answer 21

In autoimmune disease e.g. myasthenia gravis or Graves’ disease, the autoantibodies transfer to the placenta and the baby is born with anti-TSHR antibodies, which means they also suffer from Grave’s disease.
Plasmapheresis removes the maternal anti-TSHR antibodies to cure the disease.
Or, if the disease is only mild, the maternal autoantibodies are naturally removed over a period of time (10 months).

Question 22

What are the differentiations of autoimmune disease?

Answer 22

Organ specific - type 1 diabetes (kills beta cells), multiple sclerosis, Grave’s disease, myasthenia gravis.
Systemic autoimmunity - rheumatoid arthritis, systemic lupus erythematosus - which has autoantibodies against a range of cell proteins.

Question 23

What is rheumatoid arthritis?

Answer 23

A chronic inflammatory joint condition.
Associated with autoantibodies, though not the only factor.
Inflammation leads to joint damage by erosions.

Question 24

What is the pathway to developing rheumatoid arthritis?

Answer 24

Accumulate genetic and environmental risk factors e.g. smoking, chronic bacterial infections can cause RA in the gums. Genetic - HLA alleles for MHC. Develop autoantibodies to modified protein - citrullinated proteins. After some time develop swollen joints, have undifferentiated arthritis. Then might develop rheumatoid arthritis.

Question 25

What are the genes that are a risk factor for rheumatoid arthritis?

Answer 25

MHC PTPN22 PAD14

Question 26

What are citrullinated proteins?

Answer 26

Modification of peptidyl arginine proteins to peptidyl citrulline using peptidyl arginine deaminases (PADs), which removes the positive charge of arginine.

Question 27

What are anti-citrullinated protein antibodies?

Answer 27

Citrullinated proteins can become auto-antigens, because the immune system has not been tolerised to them. The autoantibodies against citrulline are associated with rheumatoid arthritis. Having both the antigen and autoantibody is associated with severe, erosive disease.

Question 28

What is the gene-environment interaction for rheumatoid arthritis?

Answer 28

No alleles for HLA-DRB1 means only 1% risk for developing RA. Single allele, increased risk, further increased by PTPN22 allele, and further still increased by smoking. Homozygous HLA-DRB1 (double) - high risk, even more exacerbated by PTPN22 and smoking. But this is only for CCP (cyclic citrullinated proteins) positive RA, which have anti-citrullinated antibodies.

Question 29

How are neutrophils activated?

Answer 29

Smoking, mucosal inflammation e.g. in gums, infections or microtrauma activate neutrophils. This is why gum inflammation, chronic bacterial infection and smoking has increased risk for RA.

Question 30

How do neutrophils lead to rheumatoid arthritis?

Answer 30

Activated neutrophils causes a calcium influx which switches PAD enzymes on, which citrullinate proteins - vimentin, fibrinogen, enolase, collagen II and histones. PAD4 citrullinates histones to loosen chromatin and enable NETosis, which releases citrullinated proteins. The immune system is not tolerised, so the citrullinated proteins are auto-antigens, and causes development of autoantibodies.

Question 31

What is systemic lupus erythematosus?

Answer 31

SLE is an autoimmune disease which affects most of the body, as the autoantibodies recognise double stranded DNA. Triggered by UV light, viral or bacterial infections, hormonal factors. Systems affected are nervous, ophthalmic (eyes), oral, dermatologic (skin), renal, cardiopulmonary, gastrointestinal, reproductive, haematologic (vasculature inflammation), musculoskeletal.

Question 32

What is the mechanism of systemic lupus erythematosus?

Answer 32

When apoptotic debris is not cleared efficiently - DNA, RNA, nuclear material becomes accessible to the immune system, and develops autoantibodies against it. Bind nuclear antigens and form immune complexes which deposit in skin, kidneys, joints and blood vessels which then activate complement. This leads to neutrophil recruitment, MAC formation and increased inflammation. Chronic inflammation leads to glomerulonephritis, vasculitis, arthritis, cytopenias (less blood cells), serositis, and CNS involvement.

Question 33

How are high affinity anti DNA antibodies generated in SLE?

Answer 33

DNA cannot be presented on MHC to T cells. In SLE, damaged cells release nucleosomes, DNA wrapped around histones, which are recognised by B cells. The B cell processes the antigen and presents the histone component to MHC II, allowing the T cell and B cell to interact despite recognising different antigens. This drives the germinal centre reaction and produces high levels of antibodies with a high affinity for DNA.

Question 34

How does type I diabetes occur?

Answer 34

In type I diabetes, have cytotoxic activated T cells specific for antigens expressed on islet cells - glucagon (a), insulin (b), somatostatin (delta) cells. Effector T cells specifically recognise insulin producing cells - beta cells, not glucagon or somatostatin producing cells. Specific killing mechanism by self-reactive cytotoxic T cells to beta cells, leading to destruction of the b-islets and leading to diabetes.

Question 35

How can autoimmunity be treated?

Answer 35

Limit inflammation, generally using glucocorticoids to reduce symptoms, but limit beneficial inflammatory events so have side effects. Antibodies to block specific pro-inflammatory cytokines - TNF, IL-17, IL-23 and IL-6. Target B cells - removing B cells from circulation using anti CD20 antibody, although plasma cells that produce antibodies are not affected. Target T cell activation - block co-stimulatory signals between antigen presenting cell and T cell.