Autoimmunity Flashcards
(37 cards)
Types of autoimmune diseases
Organ specific
Systemic
Grave’s Disease
Organ-specific autoimmune disease characterised by an antibody response (autoantibodies) against TSH receptors in the thyroid (excess stimulation)
-excess thyroxine produced causing hyperthyroidism
*disease can be transferred into animals with IgG antibodies
Type I Diabetes
Type 1 Diabetes –organ specific autoimmune=immune system attacks the pancreatic β cells, reducing the amount of insulin produced by the pancreas
Myasthenia gravis
Autoimmune disease caused by autoantibodies which bind to nicotinic Ach receptors at neuromuscular junction and block them
- leads to receptor internalisation and degradation
- results in muscle weakness
Describe an example of MHC-specific autoimmunity.
HLA B27-associated spondyloarthropathies are an example of MHC-specific autoimmunity.
The spondyloarthropathies include:
- ankylosing spondylitis
- undifferentiated spondyloarthropathy
- reactive arthritis
- psoriatic arthritis
- urethritis
- iritis
There is a spectrum of severity and HLA B27 association.
It is associated with bowel inflammation.
Describe lupus as a systemic autoimmune pathology.
SLE (systemic lupus erythematosus). It is a multi-system disease.
It’s characterised by autoantibodies to nuclear antigens e.g. double stranded DNA. forming immune complexes deposited in tissues (e.g. blood vessels, joints, renal glomerulus)
You get devascularization of the fingers, membrane ulcerations, and alopecia are all manifestations of SLE.
Can lead to activation of complement and phagocytic cells
Immune complexes depositing in kidney can lead to renal failure
It is a disease of relapse and remission.
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.
What is immune tolerance?
Immune system does not attack self proteins or cells – it is tolerant to them.
To do this, we need to be able to identify what is self and what is not self.
Define the two mechanisms of tolerance.
Central tolerance: destroy self-reactive T or B cells before they enter the circulation.
Peripheral tolerance: destroy or control any self reactive T or B cells which do enter the circulation.
Central tolerance of B cells
If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered.
If immature T-cells recognise the self-antigen presented by AIRE (AutoImmunty REgulator), it is destroyed.
Central tolerance of T cells
T Cell selection in the thymus:
Is it useless?
- doesn’t bind to any self-MHC at all → useless
- death by neglect (apoptosis)
Is it dangerous?
- binds self-MHC too strongly
- apoptosis triggered → negative selection
Is it useful?
- binds self MHC weakly→ apoptosis
- binds self MHC with a high enough affinity, receiving survival signal → positive selection
How do we control TCR and MHC binding?
We need to be able to select for T cell receptors which are capable of binding self MHC.
If binding to self MHC is too weak, it 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, it may allow signalling irrespective of whether self or foreign peptide is bound in groove
We need to find that intermediate level of affinity.
How can a T cell developing in the thymus encounter MHC bearing peptides expressed in other parts of the body?
A specialised transcription factor (AIRE) allows thymic expression of genes that are expressed in peripheral tissues → promotes self-tolerance
*AIRE= autoimmune regulator
What is the consequence of AIRE mutations?
Mutations in AIRE result in multi-organ autoimmunity
-Autoimmune Polyendocrinopathy Syndrome type 1
What happens to autoreactive T cells that survive central tolerance control?
Some autoreactive T cells and B cells do escape central tolerance and get out of the thymus/bone marrow. We need to have a second way of dealing with these cells.
-if they escape central tolerance, they come under the control of peripheral tolerance
What are the three parts of peripheral tolerance?
- ignorance
- anergy
- regulation
Describe ignorance in peripheral tolerance.
The antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering.
It could also be because the antigen is present in an immunologically privileged site e.g. eye, brain, where the immune system simply doesn’t go.
Describe anergy in peripheral tolerance.
T cells can be made non-responsive to antigens presented on APCs if the T cell engages an MHC molecule on an antigen presenting cell (signal 1) without engagement of co-stimulatory molecules (signal 2).
- Naïve T cell becomes anergic
*less likely to be stimulated in future even if co-stimulation is then present
Describe regulation in peripheral tolerance.
Suppression of self-reactive T cells by CD4 Tregs. Tregs use several different mechanisms to suppress autoimmune reactions:
- Bind antigen on an APC and produce cytokines (IL-10 and TGF-β) which send a negative signal to other self-reactive T cells
- Inhibit other self-reactive T cells by contact inhibition
Treg levels in some cases of cancer and autoimmune disease
In some cases of cancer, there are increased Treg cells.
In autoimmune diseases, there are too few Treg cells
- defective Treg cells have been observed in multiple sclerosis
What gives Tregs their function?
Tregs express transcription factor FOXP3. This molecule is expressed in CD4 T-regs and it gives them their effector function (regulatory T cell)
How can we identify Treg cells?
Tregs express transcription factor FOXP3.
A mutation in FOXP3 leads to a severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
Factors which contribute to autoimmunity
Genetic Factors
Environmental Factors
Endocrine Factors
Genetic Factors in autoimmunity
Major histocompatibility complex (MHC)
- Each copy of chromosome 6 carries 3 different MHC Class I and 3 different MHC Class II genes
- High levels of genetic variation (polymorphism) because it needs to be able to recognise a wide variety of peptides and non-peptide antigens
MHC genes (HLA) are the prevailing contributors of genetic susceptibility to autoimmune diseases.
-binding the wrong antigens on the peptide binding groove within MHC molecules increases risk of developing autoimmune disease.
