Introduction to inflammation, autoimmune disease, nsaids and Ra pathophysiology Flashcards
What is autoimmunity?
Autoimmunity is the immune response against the body’s self antigens. It occurs when the body’s self tolerance mechanisms fails.
How is self tolerance acheived?
- Segregation of antigens; physical barriers and immune privileged sites.
- Central tolerance: limits the development of B and T cells
- Peripheral tolerance: regulates autoreactive cells in circulation.
Why do we have both central and peripheral tolerance.?
- Not all self antigens are expressed in the central lymphoid organs where the negative selection occurs.
- There is a threshold requirement for affinity to self antigens before deletion is triggered so some weakly self reactive cells survive.
What is central tolerance for T lymphocytes?
As the self antigens are presented to the T cells, we need the weak binding. If the T cell binds strongly to the self antigens, it undergoes apoptosis as these are possible autoreactive T cells. If it binds moderately to it, it becomes a T regulatory cells. If it binds weakly to the self antigens, it survives. Central tolerance of T cells occurs in the thymus.
Describe central tolerance for B lymphocytes?
As the self antigens are presented to the B cells in the bone marrow, the one that binds to the antigen with high avidity undergoes receptor editing where they express new light chains in order to minimise it, if it still has high avidity, it undergoes apoptosis and dies. If the B cell binds to the self antigen with low avidity, it becomes anergic meaning it will not bind to that specific antigen again in its lifespan.
Describe peripheral tolerance for T cells?
As some autoreactive T cells escape the central tolerance in the thymus and finds their way into the blood circiulation, since they are auto-reactive they can bind to the self antigens found in the peripheral circulation but the body has a way of stopping this and this is through peripheral tolerance. When the autoreactive T cell binds to the self antigen, T regulatory cells come and prevent the co stimulation with the self antigen. It does this through three main ways
- Anergy: functional unresponsiveness without the necessary costimulatory signals.
- suppression: Block the activation by the T regulatory cells.
Deletion: apoptosis through the release of fas ligand which binds to the fas receptor and causes apoptosis.
Describe the peripheral tolerance for B cells?
As the autoreactive B cells bind to the self antigens, this prevents Th 2 cells from releasing cytokines which activate the B cell and the B cell to produce autoantibodies and hence either becomes anergic, die through apoptosis or is regulated through inhibitory receptors.
What causes autoimmune diseases ?
Autoimmune diseases occur as multiple layers of self tolerance fails or are dysfunctional. since antigen cannot be eliminated, response is sustained.
Is autoimmune disease more frequent in men or women and why?
Autoimmune diseases is more frequent in women than men and this has something to do with oestrogen levels in females which influences immune system to predispose to autoimmune diseases.
Does the presence of one autoimmune disease increase the chance for more autoimmune disease?
Yes; the presence of one autoimmune disease does increase the chance for another autoimmune disease to occur.
How are genes associated with autoimmunity?
There is a strong genetic component in autoimmune diseases. Most autoimmune diseases are polygenic and affected individuals inherit multiple genetic polymorphisms that contribute to disease susceptibility. Also there is a strong association of MHC class II with the disease.
What are the challenges in treating autoimmune diseases?
Because there is not only one gene involved;
- There is difficulty in relating complex genotypes to phenotypic and functional abnormalities to better understand pathogenesis.
- Identified disease-associated polymorphisms have small effects, therefore little predictive value.
- Because of small effects of any one gene, targeting these genes therapeutically is unlikely to have significant benefit.
Describe the multiple layers of self tolerance its site of action and mechanism?
- Central tolerance: its mechanism is deletion editing and it occurs at the thymus and bone marrow.
- Antigen segregation: its mechanism is barrier to self antigen access to lymphoid system and it occurs at the peripheral organs ( e.g.. thyroid, pancreas).
- Peripheral anergy: its mechanism is cellular inactivation by weak signalling without co-stimulus and it occurs at the secondary lymphoid tissues.
- Regulatory cells: its mechanism is suppression by cytokines, intercellular signals and it occurs at the secondary lymphoid tissue and sites of inflammation.
-Cytokine deviation: its mechanism is differentiation of th2 cells, limiting inflammatory cytokine secretion and it occurs at the secondary lymphoid tissues and sites of inflammation. - Clonal deletion: its mechanism is apoptosis post-activation and it occurs in the secondary lymphoid tissue and sites of inflammation.
Describe the postulated mechanisms of autoimmunity?
-Genetic susceptibility: Here the genes are affected and hence there is failure to self-tolerance which causes self-reactive lymphocytes to form and activation of these self-reactive lymphocytes cause tissue injury resulting in autoimmune diseases.
- Infection, inflammation: there is an infection or inflammation which occurs, this results in activation of APCs and influx of self-reactive lymphocytes into the tissues, activation of these self-reactive lymphocytes causes injury to the tissues and hence results in autoimmune diseases.
What are the different ways in which autoimmunity occurs?
-Induction of co-stimulators on APCs: here, an APC with a self antigen is affected by a microbe which then activates the APC to possess co stimulatory receptors like B7 which binds to the CD28 on the self-reactive T cells and B cells and cause autoimmunity.
- Molecular mimicry: A virus or a microbe resembles a self-antigen and hence activates a self-reactive immune cell causing autoimmunity.
Epitope spreading: autoantibodies spread and causes autoimmunity which leads to more inflammation and prolonged diseases in autoimmunity.
Describe the role of T lymphocytes in autoimmune damage?
- CD4 cells polarised toward TH1 responses via cytokines.
- CD8 cells activated to become cytotoxic T cells and cause direct cytosis.
What is the role of autoantibodies in immune damage?
Circulating autoantibodies can:
- activate the complement system leading to cell lysis.
- Interact with cell receptors.
- Cause toxic immune complexes.
-cause antibody dependent cellular toxicity.
- penetration into living cells.
Describe the non-specific way autoimmune damage occurs?
recruitment of inflammatory leukocytes into autoimmune lesions.
What are the common autoimmune diseases and examples
- systemic autoimmune disease; eg rheumatoid arthritis and lupus
-Organ specific autoimmune disease: eg myasthenia gravis, grave’s disease and autoimmune diabetes.
Describe the organ specific autoimmunity?
- Accounts for 5-10% of all diagnosed cases of diabetes.
-Autoantibodies against nicotinic acetylcholine receptors are made. - The antibodies mimic a ligand, which causes continual stimulation of the thyroid cells.
-What initiates this disease is not known.
-Maybe viral infections are involved in triggering this immune response. - Autoantibodies have been implicated including glutamic acid decarboxylase (GAD) and insulin itself.
-Ion channel which functions as a receptor in muscle, receives input from motor neurons at the neuromuscular synapse and induces muscle contraction. - Autoantibodies are directed against the receptor for thyroid-stimulating hormone (TSH)
- 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.
What are the conventional therapies autoimmune diseases?
- Anti-inflammatory drugs eg aspirin,
ibuprofen and corticosteroids. - Immunosuppressive drugs: inhibition of lymphocyte proliferation. Ciclosporin A
What are the non-specific ways to control autoantibodies?
- Infusion of intravenous immunoglobulin from a group of healthy donors.
- plasmapheresis: Removal of circulating antibodies but this is short term.
What are the symptoms of inflammation?
-Redness
-Heat
-swelling
- Pain
- Loss of function.
What are the causes of inflammation?
- Response to cellular insult by; infectious agents, toxins, physical stresses.
- Protective response: ultimate goal to remove initial cause of injury and consequences of injury- the necrotic cells and tissues.
What happens during inflammation? What are the different stages and what cells are involved?
Inflammation is made up of two main parts, vasculature and cellular.
During the vasculature phase, the toxin enters the cell and causes an acute phase reaction which causes transient vasoconstriction followed by cytokine mediated vasodilation of the afferent blood vessels which rashes a lot of blood to the site, as the blood vessel dilates, it becomes leaky and causes fluids to leak into tissues which shows the classic signs of inflammation, redness, swelling, heat, pain and in some serious ones loss of function. At this stage also there are release of po-inflammatory mediators like cytokines like il-1, il-6 and tnf a which causes acute phase proteins in the liver. Also Nf kB causes transcription of many pro – inflammatory mediators like adhesion molecules, mmps, chemokines and cytokines. As this is happening, activation of the complement, coagulation, fibrinolytic and kinin system also causes which then results in the attraction of leukocytes
During the cellular phase, chemoattractant are released from the endothelial cells which attracts the leucocytes to roll, slow roll and attach the adhesion molecules and causes transmigration into the site. Chemokines are released and the leukocytes find the microbes through chemotaxis . the phagocytes undergo phagocytosis and kill microbes releasing exudates which cause more swelling. After this there is tissues repair and release of anti inflammatory mediators to cause resolution. Eg solution adhesion molecules, timps, il-10, plasma molecules, resolvins and protectins.
Describe the vascular phase of inflammation including all the pro-inflammatory mediators and how they are involved?
A bacteria which contains an endotoxin (lipopolysaccharide) enters the body and it starts to damage the tissues and activates the mast cells. The mast cells release, histamine, prostaglandins and leukotrienes. kininogen is also converted to bradykinin, phospholipase A2 in response to the stimulus converts phospholipids to arachidonic acid which through lipoxygenases forms more leukotrienes and through cyclooxygenases forms prostaglandins. This causes an acute phase reaction which results in the transient vasoconstriction of the afferent vessels followed by cytokine mediated vasodilation of the blood vessels allowing the blood vessel to dilate and and become leaky. This forces more blood to the site causing leakage of fluid into the tissue at the site which then results in the classic symptoms of inflammation, redness, pain (through two ways of either the fluid pressing on the pain receptors of bradykinin activating the pain receptors), swelling, heat and loss of function. There is an activation of Nf KB which is a transcription factor that binds to the response elements in the nucleus causing the transcription and release of other pro-inflammatory mediators like adhesion molecules, cytokines (il-1, il-6 and TNF alpha), mmps. In addition to that there is activation of the complement, coagulation and fibrinogen systems. The cytokines IL-1, IL-6 and TNF alpha all can cause vasculature at the blood vessels, activate the release of acute phase proteins at the liver and in the bone marrow release more lymphoid cells ( B cells and T cells). Adhesion molecules like P selectins, ICAMS, e-selectins and PECAMS. Inflammatory peptides like C3a and C5a which are chemoattractant attract leukocytes to the site and once they get there they attach to the selectins, and ICAMS which are adhesion molecules and causes rolling, slow rolling completely stopping (Migration) As it stops, it squeezes through the gaps in between the blood vessels through a process of diapedesis by reacting with the PECAMS. The leukocytes are now in the tissue.
Also since the bacteria has an endotoxin, it is pyrogenic and can cause fever.
What is the process that leads to a fever?
A bacteria which contains an endotoxin comes inside the cell. Macrophages phagocytose the bacteria and in response releases IL-1.IL-1 travels to the hypothalamic site of the brain causing the release of prostaglandin (PGE2) which resets the thermostat of the brain causing a change in the temperature of the body to make it an unconducive environment for the bacteria.
