Autoimmunity Flashcards
What is immunologic tolerance?
Unresponsiveness to an antigen that is induced by previous exposure to that antigen
- Remember that the same antigen may induce an immune response or tolerance, depending on the conditions of exposure (timing etc) and the presence or absence of other stimuli.
What do you call antigens that induce immune tolerance?
Tolerogens
How does autoimmunity come about?
Failure of self-tolerance results in immune reactions against self (autologous) antigens => such reactions are called autoimmunity.
Autoimmune disease occurs when autoreactive T cells or autoantibodies cause tissue damage through hypersensitivity reaction types II, III and IV.
- Most healthy individuals produce some autoantibodies (very low level and low affinity) but the levels are increased in patients with autoimmune disease
Very generally, how can autoimmune diseases be avoided?
- The T and B cells bearing self-reactive molecules must be eliminated or downregulated.
- There are several mechanisms involved in this but the main ones are central tolerance and peripheral tolerance.
What is central tolerance?
Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self.
- The thymus plays an important role in eliminating T-cells with high affinity to self-antigens
- The bone marrow is important in B-cell tolerance
What is peripheral tolerance?
This happens after central tolerance in the immune periphery (after T and B cells egress from primary lymphoid organs).
This is the process by which mature T or B lymphocytes that are reactive to self antigens in peripheral tissues become incapable of activation or die by apoptosis.
Mechanisms of peripheral tolerance:
- Anergy (functional unresponsiveness)
- Antigen recognition without co-stimulation
- T-reg suppression (block activation of T cells)
- Deletion (cell death)
When can peripheral tolerance be broken down/not work?
Sometimes due to exposure to certain environmental factors or infection on top of having genetic susceptibility => peripheral tolerance can be broken resulting in an immune reaction against self antigens. This can happen because of:
- Inappropriate access to self-antigens: protected antigens are no longer protected and are exposed to the immune system
- Alterations or enhancement in the ways self molecules are presented to the immune system
This is more likely to happen when there is inflammation or tissue damage present due to the increased activity of proteolytic enzymes which cause breakdown of intra- and extracellular proteins, leading to high concentrations of peptides being presented to responsive T cells. Also, the structures of self-peptides may be altered by viruses, free radicals or ionising radiation, thus bypassing previously established tolerance.
So what factors contribute towards the development of autoimmune disease?
- Genes
- Infections
- Environmental factors
They all cause breakdown of tolerance
- What are natural antibodies?
- Which types of cells secrete them?
- Natural antibodies are produced spontaneously in the body without prior antigenic experience. They are usually IgM antibodies and are present in the gut lining (fight bacteria), they bind DNA released from apoptotic cells and other cellular debris and also bind to A or B antigens on RBCs.
- They are secreted by B1 cells - a sub-class of B cells that are involved in the humoral immune response.
How is T cell tolerance broken down?
- Genetic predisposition such as HLA mutation or the self antigen is missing from the thymus
- Fewer autoreactive T cells are deleted and more escape to the periphery
- DNA may leak out of dying cells and is not cleared if complement is defective
- Physical barriers around cells may become defective
- T-regulation is missing
- Environmental factors such as infections or drugs - if a tissue becomes infected, cells of the innate immune system express costimulatory molecules and secrete cytokines
What are some genetic factors that result in autoimmunity?
- Autoimmune diseases show clustering within families
- Alleles of major histocompatibility complex (MHC) - cell surface proteins
- Almost all types of autoimmune diseases are more common in women
- 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
- If AIRE gene is mutated then central tolerance cannot take place
What are some environmental factors that result in autoimmunity?
Infections
- Molecular mimicry
- Upregulation of co-stimulation
- Antigen breakdown and presentation changes
Drugs
- Molecular mimicry
- Genetic variation in drug metabolism
- SLE
UV radiation
- SLE
- Modification of self-antigen
What does the term ‘molecular mimicry’ mean?
Structural similarity between self-proteins and microbial antigens may trigger an autoimmune response.
Organ specific vs non-organ specific autoimmune disease
Non-organ specific - affects multiple organs, associated with autoimmune responses against self-molecules which are widely distributed throughout the body
Organ specific - restricted to one organ
Systemic Lupus Erythematosus (SLE)
Genetic factors in SLE = inheritance of HLA and inheritance of impaired DNA clearance.
- These cause DNA-specific T cells to escape the thymus
Environmental factors in SLE = Drugs (reduce DNA clearance), pregnancy, exposure to UV light, infection leading to apoptosis and interferon secretion
- T cell help and low-level antibodies against DNA result in DNA/antibody complexes
