Autoimmunity Flashcards
What are two examples of organ- specific autoimmune diseases?
Graves’ disease - TSH receptors in thyroid
Type 1 diabetes - insulin producing cells of pancreas
What is systemic lupus erythrematosus (SLE)?
Multi system disease
Characterised by autoantibodies to nuclear antigens
Eg. Double stranded DNA
What is auto immunity?
Immune attack or host components
What is immune tolerance?
Immune system does not attack self proteins or cells - its tolerant to them
Define central tolerance
Destroy self reactive T cell or B cells before they enter the circulation
Define peripheral tolerance
Destroy or control any self reactive T or B cells which do enter the circulation
What is central tolerance in terms of B cells?
If immature B cells in bone marrow encounter antigen in a form which can cross link their igM apoptosis is triggered
Any immature B cell will undergo apoptosis
What is central tolerance in term of T cells?
T cells recognise antigens that are presented to them by MHC - use be able to recognise foreign peptides that are bound to self-MHC
What is the correlation between T cell receptor and MHC binding?
If self MHC binding is too weak, my not be enough to allow signalling when bound with foreign peptides
If self MHC binding is too strong, may allow signalling irrespective of whether self or foreign is bound
When is a T cell determined as bing useless and what happens?
When the T cell doesn’t bind to any self-MHC at all
Death by neglect (apoptosis)
When is a T cell determined to be dangerous (NEGATIVE SELECTION)?
Binds to self-MHC too strongly
Apoptosis triggered - negative selection of T cell in thymus
When is a T cell determined as useful (POSITIVE SELECTION)?
Binds self MHC weakly
Signal to survive - positive selection
How can a developing T cell in the thymus encounter MHC bearing peptides expressed in other parts of the body?
A. Specialised transcription factor allows thymidine expression of genes that are expressed in peripheral tissues
Autoimmune regulator (AIRE)
What is the autoimmune regulator (AIRE)?
A Transcription factor that Promotes self tolerance by allowing the thymidine expression of gees from other tissues
Mutations in AIRE result in multi-organ autoimmunity
What are the three areas of peripheral tolerance?
Ignorance
Anergy
Regulation
What is the IGNORANCE of peripheral tolerance?
Antigen may be present in to low a concentration to reach the threshold. For T cell receptor triggering
Immunologically privalidged sites eg. Eye, brain - no T cells can enter this compartment
What is the ANERGY of peripheral tolerance?
Naive T cells need costimulatory signals in order to become activated
Most cells lack costimulatory proteins and MHC class 2 - if a naive T cell sees it MHC peptide without appropriate costimulatory protein it becomes anergic
What is the REGULATION of peripheral tolerance?
A subset of helper T cells known as Treg inhibit other T cells
What is expressed by Treg cells?
Transcription factor FOXP3
Mutation in this gene leads to severe and fatal autoimmune disorder - IPEX syndrome
Crucial in the CD4 T cell function
REVISION ACTIVITY
DRAW TREE DIAGRAM FROM LECTURE TO MAKE MINDMAP
What genetic factors can increase the chance of autoimmune disease?
Endocrine factors - some conditions are more common in one gender than another
MHC - highly polymorphic
What enviormental factors increase the risk of autoimmune disease?
Hygiene hypothesis - the environment no exposure to different pathogens - migration
Smoking and rheumatoid arthritis - study showed link
What might trigger a breakdown of self-tolerance?
Loss of/problem with regulatory cells
Release of sequestered antigen
Modification of self proteins
Molecular mimicry - autoimmune response to molecule
Describe what occurs during modification of self in citrullination
Citrullin is a amino acid not coded for by DNA
Arginine can be converted to citruline as a post-translational modification by PAD enzymes
Cirullinaation may be increased by inflammation
Autoantibodies to citrullinated proteins seen in rheumatoid arthritis - used for clinical diagnosis
Describe what occurs during modification of self in rheumatic fever
Disease is triggered by infection with streptococcus pyogenes
Antibodies to step cell wall antigens may cross react with cardiac muscle
What occurs during Graves’ disease?
Auto-antibodies bind thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism
Disease can be transferred with igG antibodies
What occurs during myasthenia gravis?
Autoantibodies find to acetylcholine receptor and block ability of acetyl choline to bind
Lead to receptor internalisation and degradation
Results in muscle weakness
What occurs in SLE and vasculitis?
Autoantibodies to soluble antigens form immune complexes
Deposited in tissue (eg. blood vessels, joints)
Can lead to activation of compliance and phagocytosis cells
Immune complexes depositing in kidney can lead to entail failure
How can newborn infants be cured from Graves’ disease?
Mother with Graves’ disease has anti-TSHR antibodies
Transfer of antibodies that mediate autoimmune diseases travel across placenta into fetus
Newborn infant also suffers from Graves’ disease
Plasmapheresis removed me tar all antibodies and cures the disease
How do T cells play a role in autoimmune pathology?
Direct killing of cells by CD8 + CTL
Self destruction induced by cytokines such as TNFalpha
Recruitment and activtion of macrophages leading to bystander tissue destruction
CD4 cells providing help for Ab and cytotoxicity
Multiple sclerosis
Insulin depends diabetes mellitus
What are TH7 cells?
Helper T cells that produce the cytokine IL-17
Implicate in autoimmune diseases including spondyloarthropathy, MS and diabetes
Highly inflammatory
Produce cytokines which are involved in the recruitment, migration and activation of immune cells
What are some therapeutic strategies to deal with autoimmune disease?
Anti inflammatories - NSAID, corticosteroids
T and B cell depletion
Therapeutic antibodies
Antigen specific therapies, in development - increases Tregs
