Autoimmunity Flashcards
Organ-specific autoimmune diseases
Graves disease – TSH receptors in thyroid
Type 1 Diabetes – insulin producing cells of the pancreas
HLA B27-associated spondyloarthropathies - describe effects/associations
Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis
Spectrum of severity and HLA B27 association
Associated with bowel inflammation
Systemic autoimmune pathologies – Systemic lupus erythematosus (SLE) - describe
Multi-system disease
characterised by autoantibodies to nuclear antigens eg double stranded DNA
Relapse and remission
What is autoimmunity?
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.
Central tolerance - define
Central tolerance – destroy self-reactive T or B cells before they enter the circulation
Peripheral tolerance - define
Peripheral tolerance – destroy or control any self reactive T or B cells which do enter the circulation
Explain the effect on B cells if immature
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered
T cell receptor and MHC binding - explain effects if too weak/strong
Need to select for T cell receptors which are capable of binding self MHC
BUT
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?
Is it useless?
Doesn’t bind to any self-MHC at all
Death by neglect (apoptosis)
T cell selection in the thymus - is it dangerous?
Is it dangerous?
Binds self MHC too strongly
Apoptosis triggered – negative selection
T cell selection in the thymus - is it useful
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 allows thymic expression of genes that are expressed in peripheral tissues
AutoImmune REgulator (AIRE) - function
promotes self tolerance by allowing the thymic expression of genes from other tissues
Mutations in AIRE result in
Mutations in AIRE result in multi-organ autoimmunity
Autoimmune Polyendocrinopathy Syndrome type 1
Peripheral tolerance - Ignorance - describe
Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
Immunologically privileged sites e.g. eye, brain
Peripheral tolerance - anergy - describe
Naive T cells need costimulatory signals in order to become activated
Most cells lack costimulatory proteins and MHC class II
If a naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic – i.e. Less likely to be stimulated in future even if co-stimulation is then present
Peripheral tolerance - regulation - desribe
A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells
Treg express what and describe the effect of a mutation in this
Treg express transcription factor FOXP3
Mutation in FOXP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
The major histocompatibility complex - characteristics
Each copy of chromosome 6 carries 3 different MHC class I and 3 different MHC class II genes
High levels of genetic variation (polymorphism)
MHC is associated with more disease than any other region of the genome
What might trigger a breakdown of self tolerance?
Loss of/problem with regulatory cells
Release of sequestered antigen
Modification of self
Molecular mimicry
Modification of self - Citrullination, describe how it is formed and what is it increased by
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
Explain molecular mimicry with an example
Disease is triggered by infection with Streptococcus pyogenes
Antibodies to strep cell wall antigens may crossreact with cardiac muscle
Immune complexes in SLE and vasculitis - describe the steps that lead to them depositing
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
T Cells in autoimmune pathology - direct killing by?
Direct killing by CD8+ CTL
T Cells in autoimmune pathology - self destruction by?
Self-destruction induced by cytokines such as TNFα
T Cells in autoimmune pathology - role of macrophages
Recruitment and activation of macrophages leading to bystander tissue destruction
T Cells in autoimmune pathology - role of CD4 cells
CD4 cells providing help for Ab and cytotoxicity
Th17 - define
Th17 cells are helper T cells that produce the cytokine IL-17
Th17 - characteristics
Highly inflammatory
Produce cytokines which are involved in the recruitment, migration and activation of immune cells
Th17 - implicated in which diseases
Implicated in autoimmune diseases including spondyloarthropathy, MS and diabetes
Describe therapeutic strategies for AI diseases
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.
