Autoimmunity Flashcards
name some autoimmune diseases?
myasthenia gravis
graves disease
Addison’s disease
hashimoto’s thyroiditis
example of an organ-specific autoimmune disease?
Type 1 Diabetes
– insulin producing pancreatic beta cells are destroyed, reducing insulin production and mediated by T cells
HLA B27-associated spondyloarthropathies
Arthritis in the knees and joints
Spectrum of severity
Associated with bowel inflammation
psoriatic arthritis, urethritis, iritis
Systemic autoimmune pathologies – Systemic lupus erythematosus (SLE)
Multi-system disease, autoantibodies to nuclear antigens eg double stranded DNA
Relapse and remission
Proteinuria, ends of fingers go white with lack of circulation, ulceration of mucous membranes
What is autoimmunity?
The immune system has various regulatory controls to prevent it from attacking self proteins and cells.
Failure of these controls will result in immune attack of host components – known as autoimmunity.
Immune tolerance
Immune system does not attack self proteins or cells – it is tolerant to them
Tolerance
Central tolerance – destroy self-reactive T or B cells before they enter the circulation
Peripheral tolerance – destroy or control any self reactive T or B cells which do enter the circulation
Central tolerance – B cells
if immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM (eg. a stromal cell), apoptosis is triggered
T cells need to be able to recognise what?
foreign peptides that are bound to self-MHC
T cell receptor and MHC binding - why is weak binding or too strong binding dangerous?
If binding to self MHC is too weak, may not be enough to allow signalling when binding to MHC with foreign peptides bound in groove
If binding to self MHC is too strong, may allow signalling irrespective of whether self or foreign peptide is bound in groove
T cell selection in the thymus
Is it useless?
Doesn’t bind to any self-MHC at all
Death by neglect (apoptosis)
Is it dangerous?
Binds self MHC too strongly
Apoptosis triggered – negative selection
Is it useful?
Binds self MHC weakly
Signal to survive – positive selection
How can a T cell developing in the thymus encounter MHC bearing peptides expressed in other parts of the body?
A specialised transcription factor
- AutoImmune REgulator (AIRE) - promotes self tolerance by allowing the thymic expression of genes expressed in peripheral tissues
- Mutations in AIRE result in multi-organ autoimmunity, eg. Autoimmune Polyendocrinopathy Syndrome type 1
What happens to autoreactive T cells that survive central tolerance control?
some autoimmune T and B cells get out of the thymus and bone marrow, so we need to have a second way of dealing with these cells
If they escape central tolerance, they become under the control of peripheral tolerance.
3 areas of Peripheral tolerance?
Ignorance - don’t see the antigen and you are not aware of it
-either the antigen is too low a concentration to reach the threshold for TCR triggering or they are in an immunologically privileged sites e.g. eye, brain, so the T cell will never come across them
Anergy - T cell will recognise the antigen but won’t respond to it as it doesn’t have the right signals, lack costimulatory proteins and MHC class II -Less likely to be stimulated in future even if co-stimulation is then present
Regulation - A subset of helper T cells known as Treg (T regulatory cells) that inhibit other T cells
- express FOXP3
- IL10, a cytokine that dampens the immune response
when are Treg numbers increased or decreased?
cancer - increase in Treg numbers
autoimmune disease - not enough Treg’
Mutation in FOXP3
leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
The major histocompatibility complex - where is it encoded?
Each copy of ch 6 carries 3 different MHC class I and II genes (HLA- A, B, C)
High levels of genetic variation (polymorphism) - why? Because you need the ability to recognise a huge range of peptides/antigens
MHC is associated with more disease than any other region of the genome
Genetics of autoimmunity – other genes
not just MHC, other genes involved
Endocrine factors?
MS is approximately 10 times more common in females than males
Diabetes is equally common in females and males
environmental factors?
Hygiene hypothesis: NOD mice and SPF conditions. Migration and T1D, MS and SLE
Smoking and rheumatoid arthritis -
13 pairs of identical twins where 1 of each pair smoked and 1 of each pair had RA
In 12/13 cases the twin with RA was the smoker
What might trigger a breakdown of self tolerance?
Loss of/problem with regulatory cells
Release of sequestered antigen - in immunologically privileged sites where an immune response will not occur, trauma then causes the antigen to come into contact with the immune system
Modification of self
Molecular mimicry
Modification of self - Citrullination
Citrullin is an amino acid, not coded for by DNA
Arginine can be converted to citrulline as a post-translational modification by peptidylarginine deiminase (PAD) enzymes
Citrullination may be increased by inflammation
Autoantibodies to citrullinated proteins seen in rheumatoid arthritis. Now used for clinical diagnosis
Molecular mimicry – rheumatic fever
Disease is triggered by infection with Streptococcus pyogenes
Antibodies to strep cell wall antigens may crossreact with cardiac muscle
Antibodies in autoimmune pathology (1) – Graves disease
Graves disease – TSH receptors in thyroid
- auto antibodies bind to and stimulate TSH receptors leading to hyperthyroidism or thyrotoxicosis
- inflammation of the eyes (Graves opthalmopathy) - fibroblasts in the eye may express TSH leading to inflammation
Disease can be transferred with IgG antibodies
Antibodies in autoimmune pathology (2) – Myasthenia Gravis
Autoantibodies bind to acetylcholine receptor (post synaptic receptor) and block the ability of Ach to bind
Receptor internalisation and degradation, muscle weakness and nerve paralysis
Antibodies in autoimmune pathology (3) – Immune complexes in SLE (Systemic lupus erythematosus) and vasculitis
Autoantibodies to soluble antigens form immune complexes
Deposited in tissue e.g. blood vessels, joints, renal glomerulus
Can lead to activation of complement and phagocytic cells
Immune complexes depositing in kidney can lead to renal failure
how do we know autoimmune diseases are mediated by IgG?
they can be transferred across the placenta
- IgG is one of the only antibodies that can get across the placenta. Antibodies from the mother can protect the baby in the first few months of life.
If the mother has graves disease, the antibodies in the mother can transfer across the placenta and the baby can get graves disease. So you do plasmapherisis and remove all the IgG from the baby and it get cured.
T Cells in autoimmune pathology
Direct killing by CD8+ CTL
Self-destruction induced by cytokines such as TNFα
Recruitment and activation of macrophages leading to bystander tissue destruction
CD4 cells providing help for Ab and cytotoxicity - autoimmune CD4 positive T cell can activate CD8 to become killers against an autoantigen
Multiple sclerosis
Insulin dependent diabetes mellitus
TH17 cells (helper T)
produce the cytokine IL-17 involved in the recruitment, migration and activation of immune cells
implicated in autoimmune diseases including MS and diabetes
Highly inflammatory
Therapeutic strategies
Anti-inflammatories: NSAID, corticosteroids
T & B cell depletion (RA: anti-CD4, anti-CD20)
Therapeutic antibodies (anti-TNF; anti-VLA-4 (blocks adhesion))
Antigen specific therapies, in development. Glatiramer acetate, increases T-regs.
