Introduction to immune disease Flashcards
110 slides
Where are different immune cells made in the body?
Stem cells in our bone marrow divide and differentiate into Myeloid progenitor cells and lymphoid progenitor cells.
- Lymphoid progenitor cells differentiate into:
- Small lymphocytes -> B lymphocytes (plasma cells) and T lymphocytes
- Natural killer cells
- Myeloid progenitor cells differentiate into:
- Megakaryocytes -> Thrombocytes
- Erythrocytes
- Mast cells
- Myeleoblast -> Basophils, neutrophils, eosinophil, monocytes (which become macrophages)
What is autoimmunity? (ESSENTIAL)
It is an immune response against self (autologous) antigens.
Autoimmunity results from some failure of the hosts immune system to distinguish self from non-self.
- Sufferers have high circulating levels of ‘auto-antibodies’ - hence antibodies that recognise self.
- Autoimmune diseases are more frequent in women than men. May be due to the oestrogen levels in females that may influence immune system to predispose to autoimmune diseases.
- The presence of one autoimmune disease increases chance for developing another simultaneous autoimmune disease.
What is an immunogen?
A substance capable of eliciting/causing an immune response
What is a Tolerogen?
Antigens that induce tolerance rather than immune reactivity.
Meaning our immune system can identify them but it doesn’t mount an immune response against them.
Can the same compound be an immunogen and tolerogen?
Yes, but it depends on how and where it is presented to the immune system.
How do we achieve self tolerance?
- Segregation of antigens
This is achieved by physical barriers and immune privileged sites like for example the eyes.
- Our eyes are in an immune privileged site so cells of our immune system, so our B and T cells can’t ever get there so therefore it doesn’t matter what antigens we have in the eyes because it will never be exposed to the immune system.
- Central tolerance
Limits the development of auto reactive B and T cells - Peripheral tolerance:
Regulates auto reactive cells in the circulation
Why do we have both central and peripheral tolerance?
- Not all self antigens are expressed in the central lymphoid organs where negative selection occurs
- There is a threshold requirement for affinity to self antigens before deletion is triggered- some weakly self reactive antigens survive
What happens to T cells in the central tolerance? (ESSENTIAL)
- We have the immature T lymphocytes in the thymus and they’re exposed to self-antigens during development.
- They are exposed to these self- antigens via the antigens presenting cells (APC).
- The APC is presenting them via the MHC complex to the self-antigens.
- CD4 or CD8 receptors also play a role here
- This interaction leads to different kinds of reactions from the cell:
STRONG INTERACTION: It will undergo negative selection and undergo apoptosis.
WEAK INTERACTION: We take it for positive selection
NO INTERACTION / NOT RECOGNISED: Undergoes apoptosis
INTERMEDIATE INTERACTION: Might become a regulatory T cell
What do T regulatory cells do?
It governs how our T cells will actually react.
What happens to B lymphocytes in the central tolerance? (ESSENTIAL)
- Immature B lymphocytes will mature in the bone marrow and they become exposed to self antigens during development.
- We have the B cell with a B cell receptor and the self antigen will bind to the B cell receptors
- There will be different interactions depending on how the IgE antibody on the B cell reacts to the self antigen:
HIGH AVIDITY:
- Cell might undergo RECEPTOR EDITING and express a new light chain and this new light chain will bind to the self antigen with high avidity, then we get rid of the B cell and it undergoes apoptosis.
LOW AVIDITY:
- Reduces receptor expression and the cell becomes anergic. Meaning the B cell will never react towards this self antigen ever again.
What does anergic mean and why is it preferred in central tolerance of B cells?
Anergy or to be anergic is a condition in which the body immune system fails to react to an antigen. This is needed hence low avidity reaction is preferred as we don’t want an immune response to self-antigens if not it’ll lead to an autoimmune disease.
What happens in the peripheral tolerance of T lymphocytes? (ESSENTIAL)
- T cell Normal Response (non-self antigen)
- In normal response the T cells become exposed to an antigen and become activated. Co-stimulation occurs
- Resulting in: Effector T cells and Memory T cells.
- Response to self antigen
- T cell exposed to self-antigen
- T regulatory cells come along and ensure the T cell doesn’t become activated.
- This can then lead to 3 conclusions:
ANERGIC: Hence functionally unresponsive, without the necessary costimulatory signals
SUPPRESSION: The regulatory T cell will suppress/block the activation
DELETION: If it still becomes activated, the T cell will be killed off - apoptosis
What happens in the peripheral tolerance of B lymphocytes? (ESSENTIAL)
- B cell Normal response (non-self antigen)
- Our B cells are exposed to non-self antigens and they become activated.
- The helper T cells are releasing cytokines which will help the activation of T cells
- Results in the production of plasma cells and produce antibodies.
- Response to self antigen
- Self antigen binds to the B cell receptor.
- There’s no T cell activation hence no helper T cells releasing any cytokines.
- Without the help of T cells, the B cells can result in 3 conclusions:
ANERGIC: Functionally unresponsive
APOPTOSIS: Killed off
INHIBITORY RECEPTORS: Can be prevented from becoming activated by inhibitory receptors.
What is required in order to have B cell activation? (ESSENTIAL)
Activation of T cells
- Maintaining T cell tolerance enforces B cell tolerance to the same antigens.
- WE ONLY GET B CELLS ACTIVATED TOWARDS A SELF ANTIGEN IF YOU ALREADY HAVE A T CELL ACTIVATION TO THE SAME SELF-ANTIGEN
What is the mechanism of action of cytokine deviation in terms of self tolerance? (ESSENTIAL)
There is differentiation to the Th2 cells hence limiting the inflammatory cytokine secretion hence no immune response activation.
What is the mechanism of action of clonal deletion in terms of self tolerance? (ESSENTIAL)
Where apoptosis occurs post activation. So even after activation occurs it can be killed off by clonal deletion hence stopping the immune response.
So when does autoimmune disease occur? (ESSENTIAL)
Although we have central and peripheral tolerance, autoimmune disease happens when the tolerance actually fails (multiple layers of self tolerance become dysfunctional).
- May be due to having the wrong genes or wrong environment and when these 2 factors come together (combination) we usually end up with autoimmune disease.
What may occur to break/fail the self tolerance? (ESSENTIAL)
- There are susceptibility genes present and they might lead to the production of self reactive lymphocytes causing self-tolerance to fail.
- At the same time if you have an infection or inflammation occurring, that might mean we have activation of tissue antigen presenting cells (APCs) and at the same time we may get an influx of self-reactive lymphocytes into the tissues.
- When these 2 things come together, it might lead to the activation of self-reactive lymphocytes.
- Hence leading to TISSUE INJURY -> Autoimmune disease.
How do genes play a role in autoimmune diseases? (ESSENTIAL)
- There is a genetic predisposition of autoimmune disease, and research shows high incidence in twins (more in monozygotic twins (identical) than in dizygotic twins (non-identical)).
-Most autoimmune diseases are polygenic and affected individual multiple genetic polymorphism (so not only one gene determining immune disease but usually a whole cluster of different genes) that contribute to disease susceptibility.
- There is a strong association of MHC Class 2 genes with disease.
What role do infections play in autoimmunity? (ESSENTIAL)
Infections can trigger autoimmune reactions.
- Autoimmunity may develop after infection if done/finished. Meaning the autoimmune disease is triggered by the infection but is not directly caused by the infection.
- Some autoimmune diseases are prevented by infections. Mechanism is unknown but similar to the “hygiene hypothesis” -> If we are exposed to more antigens/infections, our body is better capable of differentiating between self and non-self.
What are the different mechanisms of autoimmune damage? (ESSENTIAL)
- Circulating autoantibodies
- There are circulating autoantibodies that can do anything such as compliment lysis, interacting with cell receptors, formation of toxic immune complexes, antibody dependent cellular cytotoxicity and even penetration into living cells.
- T Lymphocytes
- CD4 cells polarised towards Th1 responses via cytokines which can drive the inflammatory response.
- CD8 cells activated to become cytotoxic T cells and cause direct cytolysis (Burst due to osmotic imbalance)
- Non-specific mechanisms
- Recruitment of inflammatory leucocytes into autoimmune lesions
What are some common autoimmune diseases?
Systemic autoimmune diseases:
- Rheumatoid arthritis
Organ specific autoimmune diseases:
- Myasthenia gravis
- Grave’s disease
- Autoimmune diabetes
What is organ-specific autoimmunity? (ESSENTIAL)
- Autoantibodies are made against nicotinic acetylcholine receptors
- The antibodies work by mimicking a ligand which causes the continuous stimulation of the thyroid cells
- Cause of disease is unknown, maybe viral infections are involved in triggering this immune response.
- Autoantigens have been implicated, including glutamic acid decarboxylase (GAD) and insulin itself.
- Ion channel which functions as a receptor in muscles, receives input from motor neurone at the neuromuscular synapse and induces muscle contraction.
- Autoantibodies are directed against the receptor for thyroid-stimulating hormone (TSH)
- Autoantibodies prevent binding of acetylcholine to the receptor and include internalisation and degradation of the receptor.
- Cell mediated attack on the islets of Langerhans in the endocrine pancreas results in the death of the insulin-producing beta-cells
- Causes severe muscle weakness
Which sites in the body are immunologically privileged?
- Brain
- Eyes
- Testis
- Uterus (fetus)
- Hamster cheek pouch
What conventional therapies available for autoimmune diseases?
As most of the time, we have an inflammatory disease underlying the autoimmune disease, we can use:
- Anti-inflammatory drugs
- Aspirin, ibuprofen
- Corticosteroids (can block TNF and IL-1 production)
We can also use:
- Immunosuppressive drugs
- For inhibition of lymphocyte proliferation
- E.g. Ciclosporin A - Non-specific control of autoantibodies in the blood
- IV immunoglobulin (IV-IG): antibodies of multiple specificity from a group of healthy donors. Mechanism of action unsure.
- Plasmapheresis (removal of circulating antibodies from the bloodstream, short term) - Organ specific
- Insulin to treat diabetes
- Acetylcholinesterase inhibitors in Myasthenia Gravis
What is happening overall in inflammation?
There is an invasion of bacterium, through the epithelial cell layer (can occur elsewhere) and the bacterium will be recognised by mast cells or macrophages in our skin. These cells will then start to release different types of mediators:
- lipid mediators:
Prostaglandins
Leukotrienes
Platelet-activating factor - Chemokines
- Cytokines:
TNF
IL-1
IL-6
What happens in inflammation (step by step) when macrophages release cytokines to result in a fever?
- Macrophage engulfs a gram-negative bacterium via endocytosis.
- The bacterium contains endotoxins and the endotoxins are released and will activate the macrophage to release IL-1.
- IL-1 is released and get into the blood vessels and travels to the hypothalamus of the brain.
- In the hypothalamus, IL-1 induces the production of prostaglandins. Prostaglandins will the RESET your body “thermostat” to a higher temperature, resulting in a fever.
What are main symptoms of inflammation?
- Rubor - Redness (blood rushing to the area)
- Dolour - Pain
- Calor - Heat, fever
- Tumour - Swelling (fluid leakage)
- Function laesa - loss of function (severe cases)
What causes an inflammation?
Inflammation is a response to cellular insults which may be caused by infectious agents, toxins or physical stresses.
Inflammation is a protective response from our body, the ultimate goal being to remove the initial cause of injury and consequences of injury such as the necrotic cells and tissues hence to protect our body.
What is the step-by-step process that occurs during an inflammatory response? (ESSENTIAL)
- Insult by trauma or pathogen causing release of cytokine and acute phase reaction occurs. Where TNFa, IL-1 and IL-6 is released.
- Platelet adhesion, transient vasoconstriction of efferent vessels
- Cytokine-induced vasodilation of afferent vessels (increased heat and blood flow to the area). Vasodilation and increased vascular permeability, hence more blood rushing to the site of inflammation, which causes the redness, heat and swelling.
- Activation of complement system, coagulation, fibrinolytic and kinin systems
- Leukocyte adhesion
- Increase vascular permeability and extravasation of serum proteins (exudate) and leukocytes (-> neutrophils -> macrophages -> lymphocytes) which results in tissue swelling. Inflammatory cells migrate into tissues, releasing inflammatory mediators (NK cells and macrophages) causing pain. These inflammatory mediators attract more and more cells to the site of inflammation.
- Phagocytosis of forge in material with pus formation
- Wound healing and remodelling
