A6&7 - Autoimmunity and autoimmune diseases

What are autoimmune responses?

Immune responses which are targeted towards ‘self’

Auto/self-reactive lymphocytes (T/B) are found in many people not suffering from autoimmune disease

True or False.

True. These autoreactive cells are usually controlled by various mechanisms

In autoimmune diseases, the immune cells cause hypersensitivity to self despite these control mechanisms

How can autoimmune diseases be characterised? (Two groups)

Organ-specific

• Only impact one organ

• E.g. Autoimmune thyroid disease

Systemic

• Impact the whole body

• E.g. systemic lupus erythematosus

What is an example of an organ-specific autoimmune disease?

Autoimmune thyroid disease.

Antibodies against thyroid antigens (E.g. thyroglobulin and TSH receptor) are produced.

What is an example of a systemic autoimmune disease?

Systemic lupus erythematosus

Autoantibodies to nuclear antigens (histones) and/or DNA

Immune complexes form which can lead to type III sensitivity reactions in the skin, kidneys, joints, etc

How are autoimmune disease similar to normal immune responses?

They are initiated via innate cell activation (PAMPs?)

Causes generation of acquired antibody- or T-cell mediated responses.

What is Graves’ disease?

Over-active thyroid

This is due to autoantibodies which are specific for thyroid-stimulating hormone receptor (TSH-R)

Causes excessive secretion of thyroid hormones

What is Myasthenia gravis?

Autoantibodies specific for acetylcholine receptors (AChR)

Cause the receptor to be removed from muscle cell surfaces which means there’s no way to trigger muscle contraction leading to paralysis

How can you prove Myasthenia gravis is due to autoantibodies?

• Take blood and purify antibodies

• Perform immunoprecipitation to show the blood contained antibodies which bind proteins present in muscle cell

• Inject antibodies into a mouse and it will cause muscle paralysis

What are two type II hypersensitivity autoimmune diseases?

Autoimmune haemolytic anaemia

Immune thrombocytopenic purpura (ITP)

What is Autoimmune haemolytic anaemia?

Destruction of red blood cells due to autoantibodies

What is Immune thrombocytopenic purpura (ITP)?

Autoantibodies specific for platelets cause a reduced platelet count

Patients then suffer bruising and bleeding more easily.

What is an example of a type III hypersensitivity autoimmune disease?

3 Systemic lupus erythematosus (SLE)

What is 3 Systemic lupus erythematosus (SLE)?

Systemic disease which affects multiple organs.

Autoantibodies to nuclear antigens (including DNA) which forms ICs

ICs can then be deposited at susceptible sites leading to symptoms.

Why must mothers with antibody-mediated autoimmune diseases be careful getting pregnant?

The autoimmune disease could potentially be transferred across the placenta and to the foetus/new-born infant.

What animal models are often used for MS and type I diabetes?

Experimental autoimmune encephalomyelitis (EAE) mouse model

And

Non-obese diabetic (NOD) mouse model

What is Multiple Sclerosis?

CNS is affected due to the myelin sheath being damaged.

Immune cells infiltrate into the CNS and attack the myelin sheath

How can Multiple Sclerosis being T-cell mediated be shown using mice models?

Nervous tissue can be injected into a mouse which causes MS to develop

However, the disease can be transferred from a sick animal to a healthy animal just by transferring CD4+ T-cells

What is one of the ‘candidate autoantigens’ suggested for MS?

Myelin basic protein (MBP)

What occurs in type 1 diabetes?

The pancreas is deficient in insulin-producing beta cells.

This causes a reduction in secreted insulin which means a lack of control over blood glucose.

What are beta-cells destroyed by in type 1 diabetes?

Destroyed by autoreactive CD8+ cytotoxic T-cells with the help of autoreactive CD4+ T-cells.

What are NOD mice?

Non-obese diabetic mice.

Develop diabetes and so can act as an animal model for the disease

What can be transferred into a healthy mouse in order to induce loss of pancreatic beta-cells?

CD4+ T-cells from a diabetic mouse.

What is Rheumatoid arthritis?

Inflammation in synovial tissues which leads to damage of cartilage and bone in joints.

What is the role of synovial fibroblasts in RA?

They:

• Secrete Matrix Metalloproteases (MMPs) which damage tissues

• Express RANK ligand which activates osteoclasts to break down bone

What is Rheumatoid factor?

An autoreactive IgM antibody specific for IgG antibodies

Binding of self-antigens by developing B/T-cells can lead to death or inactivation. How can this potentially lead to autoimmunity developing?

The inactivated B/T-cells can cause problems as they are auto-reactive but have not been killed.

B-cells require at least to signals to trigger a response. What are these two signals?

Binding of BCR with an antigen

Binding of CD40 with CD40-L on an activated T-cell

T-cells require at least to signals to trigger a response. What are these two signals?

Binding of TCR with pMHC

Binding of CD28 with B7 on an activated APC

Which type of autoreactive B-cells rarely lead to disease?

B1 B-cells.

They produce autoreactive IgM which tends to have low affinity for self antigens are rarely cause disease.

Many disease-associated autoantibodies are from which isotype?

IgG

They are usually high affinity and show evidence of extensive somatic mutation

What is AIRE and what can defects of it cause?

Transcription factor expressed in the thymus

• Role in T-cell negative selection

Defect in AIRE can cause Autoimmune Polyendocrinopathy candidiasis ectodermal dystrophy (APECED)

What is Fas and what can defects of it cause?

Interaction of Fas with Fas-ligand induces apoptosis during immune regulation and tolerance induction

Defect causes autoimmune immunoproliferative syndrome (ALPS)

What is FoxP3 and what can defects of it cause?

Transcription factor important in development and function of CD4 cells

Defects can cause immunodysregulation polyendocrinopathy enteropathy X-linked syndrome.

What is CTLA-4 and what can defects of it cause?

Inhibits T-cells by competing with CD28 for it’s ligands.

Defects of it associated with numerous autoimmune disorders.

Why are autoreactive CD4+ T-cells normally absent or unresponsive?

Clonal deletion

• Body kills self-reactive cells to prevent autoimmunity

Clonal anergy

• T-cells encounter antigen but don’t have the necessary co-signals to activate

Suppression by Treg cells

Inadequate autoantigen presentation

How can a Group A Streptococci infection result in Rheumatic fever?

Some T and B-cells are specific for the M-protein of Group A Streptococci

• And so antibodies are produced

However, there are proteins in the heart which look similar to the M-protein and so these antibodies can cross-react with heart valve tissues and cause Rheumatic fever

How can DAMPs potentially indirectly activate self-reactive T-cells

DAMPs can bind to PRRs which will induce expression of co-stimulatory molecules on APCs

These APCs could then activate self-reactive T-cells

How can trauma to one eye cause an immune response in both eyes?

Antigens from the eye will be released and systemic immune cells will detect them.

The eyes are immuno-privileged sites and so the immune cells will attack both eyes, thinking the antigens are foreign

How can abnormal expression/post-translational modification of autoantigens lead to an autoimmune response?

Inflammation, for example, can induce post-translational modification

These altered proteins can potentially be recognised as non-self and invoke an immune response.

What are some treatments for autoimmune diseases?

Anti-inflammatory drugs

Immunosuppressive drugs

Cytokines and cytokine antagonists

Deletion of autoreactive lymphocyte subsets.

• E.g. Use of Anti-CD20 to deplete B-cells