Autoimmunity (Findlay) Flashcards
CD4+ T Cell Activation Process?
APC recognizes a pathogen
internalization and antigen processing
peptide presented via MHC class II
Interaction of the TCR complex with the peptide.
A danger signal/ co-stimulation
T cell proliferation/cytokine response
T cell signal to B cells and CD8 T cells to launch an immune response
What causes autoimmunity?
Autoimmune diseases occur when:
- The usual control processes are interrupted, allowing lymphocytes to avoid suppression
- When there is an ‘alteration’ in cells/tissue so that it is no longer recognised as “self” and is thus attacked.
What is “Tolerance”?
Tolerance is the prevention of an immune response against a particular antigen
For instance, the immune system is generally tolerant of self-antigens, so it does not usually attack the body’s own cells, tissues, and organs
The immune system also usually ignores (is tolerant to) food antigens
When this “tolerance” to self breaks down it can give
rise to autoimmunity
What are the two types of tolerance?
Central tolerance
- Thymic selection and regulation
Peripheral tolerance
- Post-thymic selection and regulation
Steps of T cell selection in the thymus?
Must Express TCR (T Cell Receptor):
- T cells must express a functional TCR to progress in their development
- The TCR is essential for recognising peptide antigens presented by Major Histocompatibility Complex (MHC) molecules on other cells
Positive Selection:
- This process ensures that T cells with TCRs capable of recognising self-MHC molecules (either Class I or Class II) are selected to survive
- T cells that cannot recognise MHC molecules fail to receive necessary survival signals and die by apoptosis (programmed cell death)
Negative Selection:
- Negative selection involves the elimination of T cells that bind too strongly to self-antigens presented by MHC
- Also eliminates T cells that recognise self-peptide in self-MHC
- This process prevents autoimmune responses by deleting T cells that could potentially recognise and attack the body’s own tissues.
How does positive selection work?
Thymic T cells live 3-4 days unless rescued by TCR engagement
Only small % of all generated TCRs will ever be able to functionally recognise MHC molecules - these are chosen to continue
Mouse thymus produces 50 million DP thymocytes per
day - 10% survive positive selection
Want to find cells which recognise self-MHC
Self-MHC presented by cortical thymic epithelial cells
(cTECs)
How are T cells activated?
TCR recognises peptides in the cleft of MHC molecules on surface of APCs and then signals through associated CD3 complex proteins
Peptide + MHC class I:
- CD8+ T Cells
Peptide + MHC class II:
- CD4+ T Cells
What does negative selection do?
Following positive selection, we have T cells which we know can signal through CD3 and recognise MHC. We need to have a way to reject cells which:
- Recognise self MHC strongly
- Recognise self peptide
As these cells are likely to induce autoimmunity in the periphery
What is AIRE?
Autoimmune Regulator (AIRE)
Promotes the expression of diverse self-antigens in the thymus
What this means is that in a normal human thymus, on epithelial cells, every single type of antigen that you might ever have inside your body, can be expressed on the MHC
Essential for the negative selection of T cells
Helps eliminate T cells that are reactive to the body’s own tissues, reducing the risk of autoimmune diseases
Maintains immune self-tolerance and prevents the immune system from attacking the body’s own cells
What is APS1/APECED?
It is an autoimmune disease
“Autoimmune Polyendocrine Syndrome type 1” /
“Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy”
Caused by mutations in the AIRE gene
Patients present in childhood or teenage
Requires person to have 2/3 of the following:
- Candidiasis
- Addison’s disease
- Autoimmune hypoparathyroidism
Antibodies structure
Y-shaped molecule composed of four polypeptide chains.
Two identical heavy chains and two identical light chains.
Variable (V) Regions: Located at the tips of the Y, specific to each antibody, determine antigen binding specificity
Constant (C) Regions: Part of the chains that determine the antibody’s class and its role in the immune response
Disulfide bonds link the chains together and stabilise the antibody structure
Contains a flexible hinge region which allows flexibility and variability in positioning when binding to antigens
Five classes:
- IgG, IgM, IgA, IgE, IgD, classified based on differences in the constant region of the heavy chains
What is B cell central tolerance?
Occurs in the bone marrow, where B cells mature
Involves negative selection of B cells that bind strongly to self-antigens
2 Processes:
- Receptor Editing: B cells that recognise self-antigens may rearrange their receptor genes to alter specificity.
- Clonal Deletion: B cells with receptors that still recognise self-antigens are eliminated
Binding of self reactive IgM to self antigen in the bone marrow leads to death of the cell. Estimated to be approx. 75% of B cells killed in this way
What happens when a B cell encounters a multivalent self molecule during central tolerance?
A multivalent self molecule has multiple identical epitopes.
Strong cross-linking of the B cell receptor (BCR).
Typically leads to strong signalling for negative selection, such as clonal deletion or receptor editing, to prevent autoimmunity.
What is the effect of encountering a soluble self molecule on B cell central tolerance?
Soluble self molecules are unattached and free-floating in the bone marrow environment.
May bind to BCR without cross-linking.
Often results in receptor editing to change specificity or, if the interaction is of high affinity, clonal deletion.
How does a B cell respond to a low-affinity non-cross-linking self molecule during central tolerance?
These molecules bind weakly and do not cause significant receptor clustering.
May lead to B cell anergy, where the cell becomes functionally inactive but is not deleted, or the B cell may escape deletion due to insufficient signalling for negative selection.
What occurs if a B cell does not react with any self molecule during central tolerance?
B cell receptors do not recognise or bind to any self antigens.
The B cell is considered non-self-reactive and successfully matures, exiting the bone marrow to participate in the peripheral immune response, enhancing immune diversity and readiness.
What is the major control mechanism in the periphery?
T regulatory cells (Tregs)
Natural Tregs are called nTregs
Thymus derived Tregs are called tTregs
These are a bridge between central tolerance and peripheral tolerance
They are cells that are generated in the thymus but which act in the periphery
Tregs can catch the damaging self-reactive T and B cells which escape negative selection
What is CD25+?
CD25 is notably expressed on regulatory T cells (Tregs) and is used as a marker to identify these cells
Tregs are essential for maintaining immune tolerance and preventing autoimmune responses.
When CD25+ cells are knocked out of mice, 100% get autoimmune disease
What is foxp3?
FOXP3 is a transcription factor that is crucial for the development and function of Tregs
It regulates the expression of genes that are necessary for the suppressive activity of Tregs`
The expression of FOXP3 essentially defines Tregs and is required for their development and suppressive functions
It acts to modulate the immune response and maintain self-tolerance
When FOXP3 is knocked out of mice models, their organs filled up with T cells and they die
How do Tregs work?
They make suppressive inhibitory cytokines
They can directly kill cells by releasing granzyme (cytolysis)
They can produce adenosine to cause metabolic disruption
They can prevent dendritic cells from maturing
What happens with a FOXP3 mutation?
A disease called IPEX
“Immune dysregulation polyendocrinopathy X-linked”
Mutation in foxp3 causes no natural Treg cells
Suffer from:
- Severe allergic inflammation
- Polyendocrinopathy
- Enlargement of lymphoid organs
- Diabetes
- Anaemia
- Early death
What is the T cell effector functions?
Main targets:
- Clears pathogens
- Kills infected cells
- Recruits and activates other immune cells to clear up damage
But can also result in:
- Attacks on self antigen
- Releases cytokines which damage host tissue
- Occurs in inappropriate sites
- Over reacts to innocuous challenge
So needs to be kept in careful balanceW
What are the 5 main mechanisms to keep T cells in control?
- Ignorance
- Anergy
- Negative co-stimulation
- Activation induced cell death
- T regulatory cells
What is ignorance?
Ignorance (immune privilege)
Immune privileged sites which do not spark immune responses
Grafts in these sites are not rejected
Have barriers that exclude naïve T cells
Produce anti-inflammatory cytokines eg TGFbeta
Lymphocytes which do enter are killed (Fas)
- E.g. brain, eye, testis, foetus
What is sympathetic autoimmune opthalmia?
Eye usually experiences ignorance, with no T cells present in the eyes, so any antibodies in the eyes are never detected and immune response never occurs
Sympathetic autoimmune opthalmia is trauma to one eye resulting in the release of sequestered intraocular protein antigens
Released intraocular antigen is carried to lymph nodes and activates T cells
Effector T cells return via bloodstream and encounter antigen in both eyes
What is induction of anergy?
Induction of anergy refers to the process where immune cells, particularly T cells, become non-responsive to their specific antigen, preventing an immune response even in the presence of that antigen
Some autoreactive T cells escape the thymus e.g. Multiple
Sclerosis
The requirement for co-stimulation in the T cell activator process in the periphery means T cells are not activated by continual self antigen presentation by DC
This requirement is also harnessed to suppress self-reactive T cells through induction of ANERGY
Anergy defined as ‘ failure to proliferate or produce IL-2
following presentation of cognate antigen’
Anergy in T cell mechanism
Naive T cells which recognise self antigen in the absence of co-stimulation enter state of anergy because there is no inflammation driving DC maturation, so no need to respond
What is negative co-stimulation?
It is the switching off of T cell activation via negative co-stimulation
Some co-stimulatory molecules are negative rather than positive signals
PD-1 ,CTLA-4 are the main ones
What is CTLA-4?
CTLA4 is a major negative regulator
It is initially intracellular but moves to cell surface after TC signalling
It binds to the same ligands as CD28, but with a higher affinity for CD80 / CD86 than CD28
It binds all the CD80/86 so prevents CD28 signalling
These negative co-stimulators are the target of cancer therapies - where we want lots of very activated anti-tumour T cells
What is activation induced cell death? (AICD)
After the effector T cells have activated other cells or killed
their targets, they must be removed
This is done by Fas / Fas ligand interaction - called activation induced cell death
T cells express Fas as they are activated. When T cells bind other Fas presenting cells (can be T cells), Fas is trimerized and activates the apoptosis pathway
T cells can also express FasL and kill each other
What is Autoimmune Lymphoproliferative Syndrome ALPS?
It is a autoimmune disease caused by mutations of Fas or downstream Fas pathway
Leads to build up in lymph
Can lead to lymphoma
What mechanisms are used by infections to induce autoimmune responses in the host?
- Molecular mimicry
- Epitope spreading
- Bystander activation
- Cryptic antigens
What is molecular mimicry?
Molecular mimicry is where the antigens of a pathogen resemble the body’s own proteins, causing the immune system to attack its own tissues, triggering autoimmune diseases
E.g.
- Streptococcus pyogenes infection can trigger cardiac pathology
- T cell clones from heart lesions can recognise
BOTH heart-specific proteins and streptococcus M protein
What is bystander activation
Bystander activation is a mechanism where immune cells are activated indirectly due to the inflammatory environment created by an immune response
This can lead to the activation of immune cells that have not encountered their specific antigen
Some of these may be auto-reactive T cells
Inflammation also temporarily suppresses Treg
What is hashimoto thyroiditis?
Is is the first disease to be recognised as an autoimmune disease
Autoreactive antibodies and T cells that attack the thyroid:
- Inflammation
- Enlargement of thyroid
- Gradual destruction of follicles in thyroid
Blocking antibodies
- Stimulate the thyroid-stimulating hormone (TSH) receptor,
- Thyroid peroxidase and or thyroglobulin
Resulting in inadequate iodine uptake and thyroid hormone production and secretion
Most commonly affects middle age females
Genetics : HLA-DR5, CTLA4
Symptoms:
- Weight gain
- Depression
- Mania
- Sensitivity to cold
- Fatigue
- Panic attacks
- Tachycardia
Hashimoto’s thyroiditis is often misdiagnosed as depression
Testing for-thyroid antibodies can resolve any diagnostic difficulty.
What is graves disease?
Hyperthyroidism
Graves’ disease is an autoimmune disease characterised by the overproduction of thyroid hormones due to the immune system producing antibodies that stimulate the thyroid gland
Ordinarily, TSH is secreted by the pituitary gland that binds TSH receptors and stimulates the thyroid to secrete thyroid hormone, which acts on the pituitary gland and shuts it down
With graves disease, the pituitary gland is still shut down by the secreted thyroid hormone, however, the antibodies continue to stimulate the thyroid, endlessly producing thyroid hormone
Symptoms include:
- Enlarged thyroid (goiter)
- Bulging eyes
- Increased heart rate
- Weight loss
Treatment often involves medications to reduce thyroid hormone production, radioactive iodine, or surgery.
What is systemic lupus erythematosus?
Lupus is a systemic autoimmune disease that attacks many tissues.
More common in women than men (9:1).
Symptoms include:
- Fever, arthritis
- Skin rash
- Pleurisy
- Kidney dysfunction
Caused by auto-antibodies to DNA, histones, RBCs
Leads to formation of immune complex and complement activation leading to vasculitis.
What are some treatments for autoimmune diseases?
Steroids
Symptomatic treatment e.g. insulin
Induce anergy - block T cell co-stimulation
Shut off T cell activation - PD1, CTLA4
Suppressive cytokines
Infuse Treg
How do we treat Crohns disease
Corticosteroids are used as short-term treatments for disease flares.
They act quickly to reduce inflammation by inducing lymphocyte death and reducing T cell activation and cytokine production
BUT they suppress the entire immune system and have significant side effects
So the ‘biologic’ class of therapy has now been developed
Anti-TNF (infliximab and newer versions) was a game-changer when it was developed
This induces and maintains remission as it prevents release of TNF, the key pro-inflammatory cytokine
BUT this blocks all TNF
Patients are at risk of infections - some severe, including an increased risk in Tuberculosis susceptibility
The Holy Grail is finding a population of pathogenic cells with a marker that can be specifically blocked
