Inflammation science pharmacology. Flashcards
How do cells achieve self tolerance?
Self-tolerance is achieved in three ways.
1. Antigen segregation: Here, there are some physical barriers and immune-privileged sites that are not accessible by the immune cells.
2. Central tolerance: Here, there is a reduction in the development of autoreactive immune cells during their development which mainly occurs in the bone marrow (B-cells) and thymus (T-cells).
3. Peripheral tolerance: Here, there is regulation of autoreactive immune cells in the circulation.
Why is there the need for both central and peripheral tolerance.
As it is already known, central tolerance which is present earlier on during the development of immune cells is there to reduce the production of autoreactive immune cells.
However, the central tolerance process is not full proof.
1. This is because there may be some expression of self-antigen later on after the development of the immune cells meaning they eventually become autoreactive.
2. Another key factor is that there is a specified binding interaction threshold that needs to be exceeded by immune cells towards self-antigen for them to be deemed as autoreactive. As such, any weakly autoreactive immune cells may escape central tolerance and be present in the circulation.
Describe Central T lymphocyte tolerance.
Central T lymphocyte tolerance is a process that occurs in the thymus during the development stage of T-cells. In central T lymphocyte tolerance, the immature T cells are exposed to self-antigens. There are then 4 possible outcomes relating to the type of binding.
1. Strong binding which means negative selection hence they die by apoptosis.
2. No binding which also means negative selection where they also die by apoptosis.
3. Weak binding which means positive selection and hence development of the T cells are encouraged.
4. Intermediate binding which means the T cells are differentiated into T-regulatory cells via the expression of the transcription factor FOXP3.
Describe the process of Central B lymphocyte tolerance.
Central B cell tolerance is a process that mainly occurs in the bone marrow during the development of B cells. The outcome of B cells during central B cell tolerance is dependent on the strength of binding to self-antigen.
1. High avidity: Here, there will be receptor editing where new light chains replace old ones. In the case where there is still high avidity, then the B cell dies by apoptosis.
2. Low avidity: Here, due to this, there is reduced receptor expression and the B cell-cell becomes anergic.
It should be noted that with B cell, no binding is deemed as good and development is encouraged.
Describe the process of peripheral T lymphocyte tolerance.
In peripheral T lymphocyte tolerance, as the self-antigen binds, there is the prevention of the production of co-stimulatory signals which are needed for activation. This is mainly done by the T-reg cells.
There will then be 3 possible outcomes.
1. Anergy –> Which is functionally unresponsiveness mainly due to lack of co-stimulation.
2. Suppression: This is a block in activation that is caused by T-regs.
3. Deletion: The autoreactive T cells then die by apoptosis.
Describe peripheral B lymphocyte tolerance.
In peripheral B lymphocyte tolerance, the helper t cells which are needed before the B cells are able to differentiate into plasma cells and eventually produce antibodies do not become activated.
As such, there will again be 3 possible outcomes.
1. Anergic.
2. Regulation by inhibitory receptors.
3. Apoptosis.
What are the multiple layers of self tolerance, their mechanisms and site of action?
- Central tolerance - The mechanism is via deletion, and editing, and the site of action is the bone marrow and the thymus.
- Antigen segregation - The mechanism is via a physical barrier to self-antigen access to the lymphoid system. The site of action is the peripheral organs such as the thyroid and pancreas.
- Peripheral anergy: Mechanism is by cellular inactivation by weak signal without co-stimulation. The site of action is the secondary lymphoid tissue.
- Regulatory cells: Mechanism is by suppression via cytokines as well as intercellular signals. The site of action is the secondary lymphoid tissue and the site of inflammation.
- Cytokine deviation: Mechanism is by differentiation into TH2 cells thereby limiting inflammatory cytokine secretion. the site of action is the lymphoid tissue and the site of inflammation.
- Clonal deletion: Mechanism by apoptosis post-activation. The site of action is the secondary lymphoid tissue and the site of inflammation.
What is the overview autoimmune diseases?
Autoimmune disease is where the body begins to attack and damage self-tissues. This is due to the fact that multiple layers of self-tolerance become dysfunctional. Since these self-antigens cannot be eliminated, the response is sustained.
Autoimmunity mainly stems from the combination of genetic susceptibility, environmental triggers, and breakdown of natural tolerance.
Sufferers of autoimmune diseases have high levels of circulating auto-antibodies.
Studies have shown that autoimmune disease is much more common in females when compared to males and this may be attributed to the estrogen which influences the immune system to predispose autoimmune diseases.
Also, the presence of one autoimmune disease increases the chance of developing another autoimmune disease.
Describe the two main postulated mechanisms of autoimmunity.
The two main postulated mechanisms of autoimmunity are gene susceptibility to and infection.
1. Gene susceptibility –> There is a strong genetic component in autoimmune diseases. That is a genetic predisposition to autoimmune diseases. This is shown in studies relating to twins which showed an increase in incidence in twins. Much more so in monozygotic twins than in dizygotic twins. Also, most autoimmune diseases are polygenic and affected individuals mainly inherit multiple genetic polymorphisms that contribute to the disease susceptibility. There is also a strong association of MHC class II genes.
2. Infections –> Infection may trigger an autoimmune reaction.
In terms of infection, it may lead to autoimmunity after an infection has been eradicated,
Also, studies have shown that infection may prevent autoimmune diseases and this could be related to the hygiene hypothesis seen in diabetes.
What are the challenges associated with genes in autoimmune diseases?
In autoimmunity, it is difficult to relate complex genotypes to phenotypic and functional abnormalities to better understand the pathogenesis.
Identified disease polymorphisms have small effects and therefore little predictive value.
Because of this small effect of any one gene, targeting these genes therapeutically is unlikely to have a significant benefit.
Describe the mechanism by which infection may lead to autoimmunity.
In self-tolerance, resting tissue APC presents self-antigens to T cells, and eventually through central and peripheral tolerance, self-tolerance may be achieved.
In infection:
1. There could be induction of co-stimulators on APC. Here, a microbe infects an APC which is presenting self-antigens to the T cells in the circulation. Due to the infection, there is the expression of co-stimulatory molecules on the APC (B7). This co-stimulatory molecule will then interact and activate the T cell.
2. Molecular mimicry: Here, certain microbial antigens may resemble that of self-antigens. This means as an immune response is mounted against those microbes, tissues containing these self-antigens may also be attacked by the immune system.
Describe the mechanisms of autoimmune damage.
- Circulating autoantibodies.
Where these autoantibodies may be involved in:
complement lysis as seen in hemolytic disease.
Interaction with cell receptors as seen in myasthenia gravis and thyrotoxicity.
Toxic immune complexes as seen in SLE.
Antibody-dependent cellular cytotoxicity as seen in organ-specific autoimmune disease.
Penetration into living cells. - T-lymphocytes.
Here: CD4 cells polarised towards Th1 responsiveness via cytokines as seen in RA, multiple sclerosis, and type 1 diabetes.
Also, CD8 is activated to become cytotoxic T cells and directly cause cytolysis. - Non-specific which is mainly due to the recruitment of inflammatory leukocytes into autoimmune lesions as seen in synovitis.
Overview of Organ-specific autoimmunity.
Organ-specific autoimmunity accounts for about 5-10% of all diabetes cases.
Autoantibodies against nicotinic acetylcholine receptors are made.
The autoantibodies mimic a ligand and therefore lead to the continual stimulation of the thyroid cells.
The initiation of the disease is unknown but it may be attributed to viral infections.
Autoantigens have been implicated, including glutamic acid decarboxylase (GAD) and insulin itself.
Ion channels which functions such as receptor in muscle, receives input from motor neurons at the neuromuscular synapse and induces muscle contraction.
Autoantibodies prevent the binding of acetylcholine to the receptor and induce internalization and degradation of the receptor.
Cell-mediated attack on the islet of Langerhans in the endocrine pancreas results in the death of the insulin-producing beta-cells.
Examples of immune privileged sites
- Brain
- Eye
- Testes
- Uterus.
- Hamster Cheek pouch
Describe the process involved in inflammation and fever.
Fever is a positive response that arises as a result of an immune response. Here, a gram-negative bacteria that has endotoxins particularly LPS gets into the body where they are engulfed by macrophages. The macrophages then degrade the gram-negative bacteria in a vacuole thereby releasing the endotoxins. These then trigger the macrophages to produce IL-1 which travels through the bloodstream into the hypothalamus of the brain. There, IL-1 induces the hypothalamus to produce prostaglandins which then restarts the body’s thermostat to a higher temperature, producing fever.
