Autoimmunity Flashcards
What is immunological tolerance?
Immunological tolerance = unresponsiveness to an antigen that is induced by previous exposure to that antigen
The same antigen may induce tolerance or immune response depending on..?
- Conditions of exposure
- Absence of other stimuli
What are tolerogens?
Tolerogens = antigens that induce tolerance
What is self-tolerance?
Self-tolerance = tolerance to self-antigens:
- Failure of this is called autoimmunity, and diseases they cause are autoimmune diseases
What is done by the body to avoid autoimmune disease?
- T and B cells bearing self-reactive molecules must be eliminated
- Achieved by central and peripheral tolerance
What are important organs for central tolerance?
- Thymus
- Eliminates T cells with high affinity to self-antigens
- Bone marrow
- B cell tolerance
Describe the mechanism of central tolerance?
- Within cortex of thymus, T cell progenitors are tested against antigens
- If they do not react at all they die – death by neglect
- If they have strong recognition for self-antigens they die – negative selection
- If this does not happen they develop further – positive selection
- If low affinity to self-antigens they can develop into Treg cells still
- Cells go into periphery
Where does central tolerance occur for T cells?
Cortex of thymus
Where does central tolerance for B cells occur?
Bone marrow
What is peripheral tolerance?
Safety mechanism encase some reaction cells escape primary tolerance:
- Mature lymphocytes that recognise self-antigens in peripheral tissues become incapable of activation or die by apoptosis
- Can happen due to absence of certain antigens within thymus/bone marrow
What are some of the different mechanisms of peripheral tolerance?
- Anergy (functional unresponsiveness)
- Stimulation without co-stimulation, which is required
- Antigen recognition without co-stimulation
- Treg suppression
- Autoreactive T cells inhibited by Treg cells
- Deletion (cell death)
- Self-antigens hidden from immune system by anatomical barriers
Overcoming peripheral tolerance can result from?
- Inappropriate access of self-antigens
- Inappropriate or increased local expression of co-stimulatory molecules
- Alterations in the ways in which self-molecules are presented to immune system
What increases the risk of overcoming peripheral tolerance?
- Inflammatory or tissue damage
- Due to increased activity of proteolytic enzymes, leading to high concentrations of peptides being presented to responsive T cells
- Infection
- Structure of self-peptides altered by viruses, free radicals or ionising radiation thus bypassing previously established tolerance
How can inflammation or tissue damage allow peripheral tolerance to fail?
- Due to increased activity of proteolytic enzymes, leading to high concentrations of peptides being presented to responsive T cells
How can infection cause peripheral tolerance to fail?
- Structure of self-peptides altered by viruses, free radicals or ionising radiation thus bypassing previously established tolerance
What does autoimmunity occur due to?
Occurs due to breakdown of tolerance, where autoreactive T cells or autoantibodies cause tissue damage through hypersensitivity reactions types II, III and IV, could be due to:
- Genes
- Infections
- Environmental factors
What is autoimmunity?
Autoimmunity = adaptive immune responses to self-antigens
What are autoantibodies?
Autoantibodies = antibodies directed at normal cellular components, referred to as autoantigens
Does the presence of autoantibodies always indicate disease?
Most healthy people produce low amounts of autoantibodies, with low affinity
What do natural antibodies do?
B1 cells secrete natural antibodies that are major source of autoantibodies (part of innate immune system):
- Bind with low affinity to antigens on a variety of bacteria, activating complement to help clear bacteria rapidly
- Cross-react with inherited A and B antigens of red cells
- Unless inherited either A or B antigens, people make IgM anti-A and anti-B antibodies even if they have never been exposed to red cells from another person
- Can bind to normal cellular constituents such as nuclear proteins and DNA
What can breakdown of T cell tolerance occur due to?
- Genetic predisposition
- Poor expression of self-antigen in thymus
- HLA with poor binding for self-antigen
- Alleles of MHC – common polymorphisms rather than rare mutations implicated in breakdown of immune tolerance leading to disease
- Environmental factors
- Infections
- Molecular mimicry – mimic self-molecules, so immune system reacts to autoantigens as well as infection/drugs
- Upregulation of co-stimulation
- Antigen breakdown and presentation changes
- Drugs
- Molecular mimicry
- Genetic variation in drug metabolism
- UV radiation
- Trigger for skin inflammation
- Modification of self-antigen
- Infections
What is molecular mimicry?
- Molecular mimicry – mimic self-molecules, so immune system reacts to autoantigens as well as infection/drugs
What are some genetic predispositions to breakdown of T cell tolerance?
- Poor expression of self-antigen in thymus
- HLA with poor binding for self-antigen
- Alleles of MHC – common polymorphisms rather than rare mutations implicated in breakdown of immune tolerance leading to disease
What are some diseases that HLA gene alleles are associated to?
What does HLA stand for?
Human leukocyte antigen
What are some microbial antigens that are similar to self-antigens and so can cause molecular mimicry?
What are some risk factors for autoimmune disease?
Describe the epidemiology of autoimmune disease?
(prevalence, age, sex)
- Prevalence 3%
- Clustering within families
- Peak onset 15-65 years (exception T1 diabetes)
- Almost all more common in woman (exception ankylosing spondylitis)
How can autoimmune disease be classified?
- Non-organ specific
- Affect multiple organs
- Associated with autoimmune responses against self-molecules that are widely distributed
- Intracellular molecules involved in transcription and translation
- Organ specific
- Restricted to one organ
- Endocrine glands
What are examples of autoimmune diseases?
What is the self-antigen involved in the following diseases:
- hyper/hypothyroidism
- hyper/hypoglycaemia
- myasthenia graves
- acquired haemophilia
- haemolytic anaemia
- SLE
and SLE is double stranded DNA and histones
Describe the mechanism behind type 1 diabetes?
What does SLE stand for?
Systemic lupis erythematosus
What is the antigen involved in SLE?
DNA
Describe the mechanism behind SLE?
Describe the treatment goals for autoimmune disease?
- Suppression of damaging immune response
- Before irreversible tissue damage
- Problems with specificity of treatments and toxicity
- Replacement of the function of the damaged organ
- Such as hypothyroidism and insulin dependent diabetes mellitus
