Immunology 4 Autoimmunity Flashcards
Autoimmunity is a type of hypersensitivity reaction where there is a exaggerated immune response but specifically against ____ antigens and our own ________
self
tissues
what is immunological tolerance?
- Immunologic tolerance: unresponsiveness to an antigen that is induced by previous exposure to that antigen
- The same antigen may induce an immune response or tolerance, depending on the conditions of exposure and the presence or absence of other stimuli
Tolerance is when the immune system does not respond to an antigen even if it has been exposed to that antigen before
•Antigens that induce tolerance are called __________, or tolerogenic antigens
tolerogens
•Tolerance to self antigens, also called _______________, is a fundamental property of the normal immune system, and failure of self-tolerance results in ……..
self-tolerance
immune reactions against self (autologous) antigens
•Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases
- To avoid autoimmune disease, the T and B cells bearing self-reactive molecules must be ________ or _____________
- Several mechanisms are involved - what are they?
eliminated
downregulated
•Central and peripheral tolerance
During development of immune system, cells that react to self antigens e.g. in the thymus are eliminated to avoid damage to autoantibodies. B and T cells are downregulated if over reactive against self antigens
where does central tolerance occur?
- The thymus plays an important role in eliminating T cells with high affinity to self-antigens
- Bone marrow is important in B cell tolerance
what is the process of T cells central tolerance?
Start off as double negative then change to double positive
If they don’t react at all to any antigens then they die by death by neglect
If they have strong recognition of self antigens they die through negative selection
If they pass both those they pass to either CD8+ single positive or CD4+ single positive
If low affinity to self antigens then some change to regulatory T cells, important as low affinity to self antigens but in an inhibitory fashion then go into the periphery
what is peripheral tolerance?
•Mature lymphocytes that recognize self antigens in peripheral tissues become incapable of activation or die by apoptosis
Peripheral tolerance is for if some reactive cells (B or T) escape the central system
Many ways to ensure immunological tolerance against autoreactive T cells
what are the different mechanisms of peripheral tolerance?
- Anergy (functional unresponsiveness)
- Antigen recognition without co-stimulation
- Treg Suppression
- Deletion (cell death)
- Some self antigens are sequestered (hidden) from the immune system by anatomic barriers.
how can peripheral tolerance be overcome?
- Inappropriate access of self-antigens (protected antigens no longer protected and exposed to immune system)
- Inappropriate or increased local expression of co-stimulatory molecules (sometimes there is co-stimulation)
- Alterations in the ways in which self-molecules are presented to the immune system
when is peripheral tolerance more likely to be overcome?
- More likely to happen when inflammation or tissue damage is present due to the increased activity of proteolytic enzymes which can cause intra- and extracellular proteins to be broken down, leading to high concentrations of peptides (cryptic epitopes) being presented to responsive T cells
- The structures of self-peptides may be altered by viruses, free radicals or ionising radiation, thus bypassing previously established tolerance.
what things are responsible for causing a breakdown in tolerance?
what is the definition of autoimmunity?
•Adaptive immune responses to self antigens
Adaptive as either involves autoantibodies or T cells that are specific to autoantigens or self antigens
what are autoantibodies?
•antibodies directed at normal cellular components, referred to as autoantigens
Autoimmune disease occurs when what happens?
when autoreactive T cells or autoantibodies cause tissue damage through hypersensitivity reaction types II, III and IV
Type 2 – antibodies destroying specific cells that express the antigen
Type 3 – immune complexes which precipitate on tissues causing damage
Type 4 – delayed hypersensitivity reaction (already talked about RA and MS)
Most healthy individuals produce some ___________ (very low level and low affinity)
autoantibodies
what is the main source of autoantibodies?
Natural antibodies
what makes natural antibodies?
B1 cells secrete natural antibodies that are the major source of autoantibodies
what do natural antibodies do?
- Natural antibodies bind with low affinity to antigens on a variety of bacteria. This activates complement and helps clear invading bacteria rapidly
- Natural antibodies cross-react with the inherited A and B antigens of red cells. Unless they have inherited either A or B antigens, individuals make IgM anti-A and anti-B antibodies, even if they have never been exposed to red cells from another person
- Natural antibodies can bind to normal cellular constituents, such as nuclear proteins and DNA. (if breakdown of tissues due to infection or trauma or environmental factor then this can cause an exaggerated immune response against DNA if the patient has a predisposition for this autoimmunity)
diagram showing the role of natural antibodies
Protective mechanism against bacteria in the gut, act almost like the innate immune system, specificity and affinity is low
Can bind to blood cells - Important for blood transfusion and compatibility between donor and recipient
Cells with high affinity are normally eliminated
what causes the breakdown of T cell tolerance?
- Genetic predisposition
- Environmental factors
multiple mechanisms of peripheral tolerance but if that’s broken due to successive infections, drugs, UV light, other factors
Leads to effector autoreactive T cells capable of causing tissue damage and symptoms present themselves
We seen the mechanisms of peripheral tolerance and this is the same but shows how the tolerance is broken - how is tolerance broken?
If they have genetic predisposition, don’t express self antigens or the self antigens are not expressed highly enough and then can escape to periphery
- During infection or trauma DNA leaks out and if the complement system doesn’t clear it then the autoreactive T cells bind to it causing autoimmunity
- Barriers around protected tissues like the brain, if broken then autoreactive T cells can reach these tissues
- If suppressive function of Treg cells is missing then autoimmunity can progress
what are the genetic factors involved with a loss of tolerance?
- Clusters within families
- Alleles of MHC
- Common polymorphisms, rather than rare mutations, are implicated in the breakdown of immune tolerance that leads to these diseases.
- Some rare genetic diseases cause autoimmunity
- AIRE gene is mutated and central tolerance cannot take place
Not necessarily inheriting the same autoimmune disease but the enhanced risk of autoimmunity
environemntal factors causing a loss of tolerance:
how does infecitons lead to enhaced autoimmune reactions?
- Molecular mimicry (mimic self antigens so body reacts to both infection and body)
- Upregulation of co-stimulation (makes autoreactive T cells no longer anergic and now fully activated)
- Antigen breakdown and presentation changes (APCs which present self antigens with stimulation to the self reactive T cells)
environemntal factors causing a loss of tolerance:
how can drugs enhace autoimmune reactions?
- Molecular mimicry
- Genetic variation in drug metabolism (the way the drug is metabolised influences how the system reacts to the certain drugs)
environemntal factors causing a loss of tolerance:
how does UV radiation enhace autoimmune reactions?
- Trigger for skin inflammation
- Modification of self-antigen (may become more antigenic and the self reactive T cells become activated)
what is moleecular mimicry and what are some examples?
•Structural similarity between self-proteins and microbial antigens may trigger an autoimmune response
summary table showing risk factors for autoimmune disease:
what is the epidemiology of autoimmune disease?
- It is estimated that 3% of the population have some sort of autoimmune disease
- Autoimmune diseases show clustering within families
- Peak years of onset 15-65 years (exception; Type 1 Diabetes mellitus)
- Almost all types of autoimmune diseases are more common in women (Exception, ankylosing spondylitis)
what is Non-organ specific autoimmune diseases?
- They affect multiple organs
- Associated with autoimmune responses against self-molecules which are widely distributed throughout the body
- Intracellular molecules involved in transcription and translation
what are Organ specific autoimmune diseases?
- Restricted to one organ
- Endocrine glands
The ________ of the antigen determines where a disease lies in the spectrum
location
All depends on where and when the autoantigen is
Many organ specific autoimmune diseases affect endocrine glands
Examples of diseases and the self-antigens associated with the diseases, different categories
(cotinued) Examples of diseases and the self-antigens associated with the diseases, different categories
what is the process occuring in type 1 diabetes?
No co-stimulation
what is Systemic Lupus Erythematosus and how does it occur?
many symptoms
Autoantigens is the DNA
Anything that causes the breakdown of many cells leads to DNA spilling out and if it is not contained by complement system then may trigger autoimmunity in the patients with genetic susceptibility
Autoantibodies against the DNA begin to be produced and start to bind to the DNA to form complexes
Hypothetical case of what triggers SLE:
genetic factors in pink and environmental factors in blue
Once complexes have formed and precipitated into tissues they will start causing symptoms
what is the treatment of autoimmune diseases?
Suppression of the damaging immune response:
- Before irreversible tissue damage
- Early detection is a challenge
- Problem with specificity of treatments and toxicity
Replacement of the function of the damaged organ:
- Hypothyroidism
- Insulin dependent diabetes mellitus
