L25: Autoimmunity Flashcards
Give examples of organ specific autoimmune diseases
→Graves disease (thyrotoxicosis)
→Type 1 diabetes
What is Graves disease?
→Disease which manifests due to having stimulatory antibodies against thyroid-stimulating hormones (TSH) receptors in thyroid
→Antibodies cause overproduction of TSH
→symptoms: bulging red eyes
Why do people with Graves have bulging eyes?
→fibroblasts in the eye may express TSH leading to inflammation
Give examples of HLA B27-associated spondyloarthropathies
→reactive arthritis
→psoriatic arthritis
→bowel inflammation
→urehtritis
What molecule is implicated in ankolysing spondylitis?
→HLA B27
What is systemic lupus erythematosus (SLE) characterised by?
→by autoantibodies to nuclear antigens eg double stranded DNA
→relapse and remission
→Multi-system disease
What is central tolerance?
→destroy self-reactive T or B cells before they enter the circulation
What is peripheral tolerance?
→destroy or control any self reactive T or B cells which do enter the circulation (and have avoided the central tolerance)
Describe the mechanism of central tolerance
→If immature B cells in bone marrow encounter antigen in a form which can cross-link their IgM, apoptosis is triggered
so any immature B cell that gives rise to autoantibody in the form of IgM is removed.
What are rheumatoid factors?
→autoantibodies of IgM,IgG, IgA
What mutations can result in multi-organ autoimmunity?
→mutations in AIRE
What syndrome can be caused by mutations in AIRE?
→Autoimmune Polyendocrinopathy Syndrome type 1
What is involved in peripheral tolerance?
→ignorance
→anergy
→regulation
What is ignorance in peripheral tolerance?
→Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
→immune privilege sites
What is involved in anergy of peripheral tolerance?
→If a naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic –
→Less likely to be stimulated in future even if co-stimulation is then present
What is regulation in peripheral tolerance?
→Tregs inhibit other Tcells
→IL-10 and TGF-beta
What transcription factor do Tregs express?
→FOXP3
What can mutations in FOXP3 result in?
→Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome
→autoimmune disorder
Which gender is SLE more common in?
→females
Which gender is MS more common in?
→females
Which gender is diabetes more common in?
→females
Which gender is ankylosing spondylitis more common in?
→males
What might trigger a breakdown of self tolerance?
→Loss of/problem with regulatory cells
→Release of sequestered antigen
→Modification of self
→Molecular mimicry
What is citrullin?
→amino acid
→not coded for by DNA
How is citrullin is genrated?
→Arginine can be converted to citrullin as a post-translational modification by peptidylarginine deiminase (PAD) enzymes
What charge does arginine have?
→positive
What charge does citrullin have?
→neutral
→more susceptible to proteolytic degradation
How is citrullin implicated in rheumatoid arthritis?
→Autoantibodies to citrullinated proteins
How is rheumatic fever triggered?
→Antibodies to strep cell wall antigens may cross react with cardiac muscle
Which pathogen is implicated in rheumatic fever?
→Streptococcus pyogenes
Which Ab is pathogenic in arthritis?
→IgG
Describe mechanism of Myasthenia Gravis
→Autoantibodies bind to acetylcholine receptor and block the ability of acetyl choline to bind
→lead to receptor internalisation and degradation
→Results in muscle weakness
Describe the mechanism of SLE
→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 babies rid themselves of autoimmune Abs?
→plasmapheresis removes maternal anti-TSHR and antibodies
Which antibody aids in autoimmune disease transfer to babies?
→IgG
Examples of autoimmune disease transferred across placenta
→Myasthenia gravis
→Graves
→thrombocytoenic purpura
Which cytokines induce self destruction of cytokines?
→TNF-alpha
What is the role of CD4 cells in Tcell autoimmune pathology?
→providing help for Ab and cytotoxicity
What is the role of CD8 cells in Tcell autoimmunity?
→Direct killing by CD8+ CTL
Examples of Tcell implicate autoimmunity
→Multiple sclerosis
→Insulin dependent diabetes mellitus
Which cytokines do Th17 cells produce?
→IL-17
Which autoimmune diseases is TH17 implicated in?
→spondyloarthropathy,
→MS
→diabetes
What are the therapeutic strategies for autoimmune disease?
Anti-inflammatories: NSAID, corticosteroids
→T & B cell depletion (RA: anti-CD4, anti-CD20- Bcell marker)
→Therapeutic antibodies (anti-TNF; anti-VLA-4 (blocks adhesion))
→Antigen specific therapies, in development. Glatiramer acetate, increases T-regs.
What do B cells produce?
→Initially IgM
→Under influence of T cells IgG or other isotopes of antibody (development of humoral response)
