L24 - Autoimmunity Flashcards
What is meant by Immune Tolerance?
Immune system does not attack self proteins or cells. It is tolerant to them
Describe Central Tolerance?
Central tolerance – destroy self-reactive T or B cells before they enter the circulation
B-cells:
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered
T-cells:
- Bind too strongly to MHC, they are killed. Only positive selection for those that bind weakly/moderately
- promotes self-tolerance by allowing the thymic expression of genes from other tissues
Describe Peripheral Tolerance?
Peripheral tolerance – destroy or control any self reactive T or B cells which do enter the circulation
Describe the Ignorance mechanism of Peripheral Tolerance?
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
Describe the Anergy mechanism of Peripheral Tolerance?
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
Describe the Regulatory mechanism of Peripheral Tolerance?
A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells
How does MHC influence Autoimmune disease?
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
How does Endocrine factors influence Autoimmune disease?
The immune system is highly receptive to endocrine signals due to the expression of hormone receptors on immune cells.
How does Environmental factors influence Autoimmune disease?
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
Modification of self
Molecular mimicry
Describe how Modification to Self may cause breakdown of Self-tolerance
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
Looks less like self peptide
Describe how Molecular Mimicry may cause breakdown of Self-tolerance
Disease is triggered by infection with Streptococcus pyogenes
Antibodies to strep cell wall antigens may crossreact with cardiac muscle
Describe Graves Disease as an Autoimmune disease?
Auto-antibodies bind Thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism
Disease can be transferred with IgG antibodies
Describe Myasthenia Gravis as an Autoimmune disease?
Autoantibodies bind to acetylcholine receptor and block the ability of acetyl choline to bind
Also lead to receptor internalisation and degradation
Results in muscle weakness
What are the roles of T-cells in Autoimmune Pathology?
Direct killing by CD8+ CTL
Self-destruction induced by cytokines such as TNFa
Recruitment and activation of macrophages leading to bystander tissue destruction
CD4 cells providing help for Ab and cytotoxicity
Multiple sclerosis
Insulin dependent diabetes mellitus
