Autoimmunity Flashcards
What is the range of autoimmune disorders?
β systemic
β organ specific
What are 2 examples of an organ specific autoimmune disease?
β Graves disease
β Type 1 diabetes
What is Graves disease?
β an antibody response to the TSH receptors in the thyroid
Why do you get bulging eyes in Graves disease?
β Low level of TSH receptors in the fibroblasts in the eye
β immune deposition of antibodies in the eye
What are the 6 types of HLA B27- associated spondyloarthropathies?
β Ankylosing spondylitis β undifferentiated spondyloarthropathy β reactive arthritis β psoriatic arthritis β urethritis β iritis
What is usually associated with HLA B27- associated spondyloarthropathy?
β bowel inflammation
What is the cause of systemic lupus erythematous (SLE)?
β Autoantibodies to nuclear antigens :
β double stranded DNA
What are the 8 signs of SLE?
β discoid lesions β alopecia β butterfly rash β pericarditis β arthritis β proteinuria βRaynauds β mucus membrane ulceration
What is autoimmunity?
β Failure of the regulatory controls in the immune system that prevent it attacking itself
What is central tolerance?
β Destroy self-reactive T or B cells before they enter the circulation
What is peripheral tolerance?
β Destroy or control any self reactive T or B cells which do enter the circulation
How does central tolerance of B cells occur?
β Immature B cells in bone marrow encounter an antigen in a form which can cross-link their IgM then apoptosis is triggered
What happens if a T cell binds to MHC too weakly?
β it may not be enough to allow signalling when foreign peptides are in the groove
What happens if a T cell binds to MHC too strongly?
β it may allow signalling irrespective of whether self or foreign peptide is in the groove
What types of T cells get selected in the thymus and which get destroyed?
β T cells that donβt bind to any MHC - death by neglect
β T cells that bind to MHC too strongly - apoptosis triggered- negative selection
β T cells that bind self MHC weakly - signal to survive
How do T cells in the thymus encounter MHC bearing peptides from other parts of the body?
β A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissue
What is AIRE and what is its function?
β (autoimmune regulator)
β it promotes self tolerance by allowing the thymic expression of genes from other tissues
What do mutations in AIRE result in?
β multi organ autoimmunity
What are the three steps in peripheral tolerance?
β Ignorance
β anergy
β regulation
Why does the ignorance step happen in peripheral tolerance?
β the antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
β e.g immunologically privileged sites such as the eye or the brain
β T cells will not come across the antigen
What is anergy?
β Exposure to antigen without appropriate co-stimulatory signals
How does anergy occur?
β Naive T cells needs co-stimulatory signals to be activated
β most cells lack co-stimulatory proteins and MHC class II
β if a naive T cell sees its MHC/peptide without appropriate co-stimulation it becomes anergic
What does anergic mean?
β less likely to be stimulated in the future even if co-stimulation is present
What cells are involved in the regulation step in peripheral tolerance?
β Treg cells
How do Treg cells work?
β The Treg cells bind to an antigen on an APC they can send a negative signal to any other cells that are recognising antigens on that cell via TGF beta and IL-10
What two conditions cause a varying of Treg numbers?
β Cancer - increased Treg
β autoimmune - decreased Treg
What do Treg cells express?
β Transcription factor FOXP3
What do mutations in FOXP3 lead to?
β IPEX disease
β immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome
On what chromosome is MHC located?
β chromosome 6
How many genes are there for MHC class I and II?
β 3 for each
What is MHC associated with in terms of disease?
β the most disease compared to other regions in the genome
In what gender is SLE more common in?
β 10x more common in females than males
In what gender is MS more common in?
β 10 times more common in females than males
In what gender is diabetes common in?
β equally common in both
in what gender is ankylosing spondylitis more common in?
β 3 times more common in males than females
What is the hygiene hypothesis?
β If you keep a (non obese diabetic mouse) in a pathogen free environment it doesnβt get diabetes
What 3 diseases become more apparent when you move from a rural environment to a more urban one?
β type 1 diabetes
β MS
β SLE
What disease is smoking linked with and what is the proof?
β rheumatoid arthritis
β 13 pairs of identical twins where 1 of the pair smokes, 12/13 cases the twin with arthritis was the smoker
What are the 4 things that can trigger a breakdown of self tolerance?
β Loss of or a problem with regulatory cells
β release of a sequestered antigen
β modification of self
β molecular mimicry
What is citrulline?
β an amino acid not coded for by DNA
What is citrullination?
β arginine converted into citrulline as a post translational modification
What enzyme causes citrullination?
β peptidylarginine deaminase (PAD)
What can citrullination be increased by?
β inflammation
What link does citrulline have with rheumatoid arthritis?
β Autoantibodies to citrullinated proteins are seen in rheumatoid arthritis
How is rheumatic fever caused?
β Disease is caused by infection with streptococcus pyogenes
β antibodies to the streptococcus cell wall antigens may cross react with cardiac muscle
How can hyperthyroidism arise?
β autoantibodies bind TSH receptor and stimulate it
What is Hashimotos disease?
β autoantibodies bind TSH receptor and cause inflammation
What happens in myasthenia gravis?
β Autoantibodies bind to AcH receptor and block the ability of Ach to bind
β leads to receptor internalisation and degradation
β results in muscle weakness
What types of autoimmune diseases can be transferred across the placenta and why?
β Diseases mediated by IgG
β IgG is small enough to cross the placenta
What are the 5 diseases that can be transferred across the placenta?
β Myasthenia gravis β Graves disease β Thrombocytic purpura β Neonatal lupus rash/congenital heart block β Pemphigus vulgaris
How can you βcureβ a baby from an autoimmune disease transferred from the mother?
β Plasmaphorese the baby and remove all the IgG
Which cytokine induces self destruction?
β TNF alpha
What are the 4 ways in which T cells are involved in autoimmune pathologies?
β direct killing by CD8+ and cytotoxic T cells
β self destruction by TNF alpha
β recruitment and activation of macrophages leading to bystander tissue destruction
β CD4 cells can activate antibodies and cytotoxicity
What two conditions are caused by T cells malfunctioning?
β Insulin dependent diabetes
β Multiple sclerosis
What do TH17 helper cells produce?
β IL-17
What is the function of TH17 cells?
β Produce cytokines which are involved in the recruitment, migration and activation of immune system
What are 3 therapeutic strategies for autoimmune diseases?
β Anti-inflammatories
β T & B cell depletion
β Therapeutic antibodies
What are two examples of anti-inflammatories?
β NSAID
β corticosteroids
What is used to deplete T & B cells in rheumatoid arthritis?
β anti CD4
β anti CD20
What are two therapeutic antibodies?
β anti TNF
β anti VLA-4
What is the function of anti VLA-4?
β blocks adhesion
Why does anti TNF only work for a short while?
β the body makes antibodies to the antibodies
What drug increases Treg?
β glatiramer acetate
