Lec 4 - autoimmunity Flashcards
Define the mechanisms by which immunological tolerance arises.
Define Autoimmune Disease.
Illustrate the factors involved in the aetiology of autoimmune disease.
Describe the pathogenetic mechanisms involved in autoimmune disease.
Contrast organ-specific and non-organ specific autoimmune disease.
Define the role of HLA molecules in autoimmune disease.
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What is immune tolerance
unresponsiveness to an antigen that is induced by previous exposure of that antigen
Antigens that induce tolerance are called
tolerogens
Define self tolerance
Tolerance to self antigens; fundamental property of immune system to be unresponsive to a harmless antigen
To avoid autoimmune disease, the T and B cells bearing self-reactive molecules must be
eliminated or downregulated
2 major mechanisms by which immunological tolerance arises
Central tolerance
What is central tolerance
Also known as negative selection, is the process of eliminating any developing T or B lymphocytes that have receptors specifically reactive to self antigens at an early stage
What is peripheral tolerance
Secondary mechanism to ensure that T and B cells are not self-reactive once they leave primary lymphoid organs (thymus and bone marrow)
–> either become deactivated or die by apoptosis
Central tolerance occurs where (2)
Peripheral tolerance occurs where (2)
Generative (PRIMARY) lymphoid organs
- Thymus
- Bone marrow
Secondary lymphoid organs
- spleen
- lymph nodes
Mechanisms of central tolerance
B cell tolerance (in bone marrow)
-those with high affinity to self antigens undergo negative selection and are eliminated via apoptosis
T cell tolerance (in thymus)
- T cells undergo positive and negative selection
- those that have low affinity to self antigens go on to differentiate into single positive CD4 or CD8 T lymphocytes
- some CD4+ T cells with moderate affinity for self antigens receive a survival signal (+ve selection) and differentiate into T regulatory cells
Mechanisms of peripheral tolerance (3)
Anergy (a state of inactivation in which the lymphocytes remain alive but are unable to respond to antigen)
Antigen recognition without co-stimulation
Treg suppression - block activation of lymphocytes
Apoptosis - induce death of self-reactive lymphocytes
Overcoming peripheral tolerance is a contributing factor to the process of autoimmunity; in what ways is peripheral tolerance overcome (3)
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 the immune system
Breakdown of peripheral tolerance is more likely to happen when what is present
Inflammation/tissue injury due to increased activity of proteolytic enzymes –> increased protein breakdown –> high concentrations of peptides being presented to responsive to T cells
Apart of overcoming peripheral tolerance, there’s another immunopathological mechanism that can contribute to autoimmune disease which involves structural similarity between self antigens and antigens of microbes - what is this called + what things can cause this
Molecular mimicry, e.g. infections, drugs, UV
Oncetolerancehas broken down, the resulting inflammation may allow presentation of further peptides.
The immune response broadens and local tissue damage accelerates
What is this called
Epitope spreading
Illustrate the factors involved in the aetiology of autoimmune disease
Genetic predisposition - inherit HLA polymorphisms
Immune regulatory factors - defective tolerance
Environmental factors - infection, drugs, UV
ALL CONTRIBUTE TO BREAKDOWN OF TOLERANCE
Define autoimmune disease
Adaptive immune responses to self antigens
Autoimmune disease occurs when autoreactive T cells or autoantibodies cause tissue damage through which hypersensitivity reaction types
II, III and IV
Genetic predisposition to autoimmunity is usually due to polymorphisms of what gene
+ mutation of what gene
HLA polymorphisms
AIRE gene mutations
What conditions are associated with HLA-B27 polymorphism
Ankylosing spondylitis
Reiter disease
What condition is associated with HLA-DR2 polymorphism
Goodpasture syndrome
What conditions are associated with HLA-DR3 polymorphism
Addison disease
Hashimoto’s disease
Myasthenia gravis
What condition is associated with HLA-DR4 polymorphism
T1DM
What is the AIRE gene
Transcription factor expressed mainly by medullary epithelial cells in the thymus that is an AUTOIMMUNE REGULATOR
Proposed sequence of events in autoimmunity
INITIATING (environmental) EVENT (e.g. infection) + GENETIC SUSCEPTIBILITY (e.g. HLA polymorphism, AIRE mutation)
–> BREAKDOWN OF SELF-TOLERANCE
–> Autoreactivity
–> Unnecessary cellular + humoral activity
–> Tissue damage
Almost all types of autoimmune diseases are more common in women except which
Ankylosing spondylitis
Organ specific autoimmune diseases often affect which system
Endocrine - thyroid, adrenal, kidney
List some organ specific autoimmune diseases
Endocrine
- Type 1 DM
- Hashimoto’s disease
- Grave’s disease
- Primary myxedema
- Addison’s disease
Muscle
-Myasthenia
GI
-pernicious anaemia
Neuro
-MS
List some non-organ specific autoimmune disease
Dermatomyositis
SLE
Scleroderma (systemic sclerosis)
Rheumatoid arthritis
In type 1 DM, autoantibodies are directed against what cells
Islet of langerhans –> defective insulin production
Treatment options of autoimmune disease
Immunosuppressants
Organ transplant (ONLY if organ specific)
Immunotherapy - Treg cell therapy
