Autoimmune Disease Flashcards
What is the definition of autoimmunity?
Autoimmunity can be defined as the presence of immune responses against self-tissue. This may be a harmless phenomenon detected only by the presence of low-titre autoantibodies or autoreactive T cells. However, if these responses cause significant organ damage, autoimmune diseases occur. These are a major cause of chronic morbidity and disability, affecting up to 1 in 30 adults at some point during life.
What is central tolerance?
Autoimmune diseases result from the failure of immune tolerance, the process by which the immune system recognises and accepts self-tissue. Central immune tolerance occurs during lymphocyte development, when T and B lymphocytes that recognise self-antigens are eliminated before they develop into fully immunocompetent cells. This process is most active in fetal life but continues throughout life as immature lymphocytes are generated.
What is peripheral tolerance?
Some autoreactive cells inevitably evade deletion and escape into the circulation, however, and are controlled through peripheral tolerance mechanisms. Peripheral immune tolerance mechanisms include the suppression of autoreactive cells by regulatory T cells; the generation of functional hyporesponsiveness (anergy) in lymphocytes that encounter antigen in the absence of the co-stimulatory signals that accompany inflammation; and cell death by apoptosis. Autoimmune diseases develop when self-reactive lymphocytes escape from these tolerance mechanisms.
What factors contribute to the development of autoimmune disease?
Autoimmune diseases are much more common in women than in men, for reasons that remain unclear.
Many are associated with genetic variations in the HLA loci, reflecting the importance of HLA genes in shaping lymphocyte responses.
Other important susceptibility genes include those determining cytokine activity, co-stimulation (the expression of second signals required for full T-cell activation) and cell death. Many of the same gene variants underlie multiple autoimmune disorders, reflecting their common pathogenesis.
Several environmental factors may be associated with autoimmunity in genetically predisposed individuals, including infection, cigarette smoking and hormone levels.
How does infection trigger autoimmunity?
Several mechanisms have been invoked to explain the autoimmunity that occurs after an infectious trigger (e.g. rheumatic fever). These include cross- reactivity between proteins expressed by the pathogen and the host (molecular mimicry), such as Guillain–Barré syndrome and Campylobacter infection; release of sequestered antigens from tissues that are damaged during infections that are not usually visible to the immune system; and production of inflammatory cytokines that overwhelm the normal control mechanisms that prevent bystander damage
What are the clinical features of autoimmunty?
The clinical presentation of autoimmune disease is highly variable. Autoimmune diseases can be classified by organ involvement or by the predominant mechanism responsible for tissue damage. The Gell and Coombs classification of hypersensitivity is the most widely used, and distinguishes four types of immune response that result in tissue damage.
What is type I hypersensitivity?
This is relavent in allergy but is not associated with autoimmune disease.
It is caused by IgE mediated mast cell degranulation.
What is type II hypersensitivity?
This causes injury to a single tissue or organ and is mediated by specific autoantibodies. Binding of cytotoxic IgG or IgM antibodies to antigens on cell surface causes cell killing.
Examples include autoimmune haemolytic anaemia, ITP, Goodpasture’s disease, ABO blood transfusion reaction, hyperacute transplant rejection.
What is type III hypersensitivity?
This results from deposition of immune complexes, which initiates activation of the classical complement cascade, as well as recruitment and activation of phagocytes and CD4+ lymphocytes. The site of immune complex deposition is determined by the relative amount of antibody, size of the immune complexes, nature of the antigen and local haemodynamics. Generalised deposition of immune complexes gives rise to systemic diseases such as SLE.
IgG or IgM antibodies bind soluble antigen to form immune complexes that trigger classical complement pathway activation.
Examples include serum sickness, Farmer’s lung, SLE and cryoglobulinaemia.
What is type IV hypersensitivity?
This is mediated by activated T cells and macrophages, which together cause tissue damage.
Examples include acute cellular transplant rejection, Nickel hypersensitivity, type 1 diabetes, Hashimoto’s thyroiditis.
How should suspected autoimmune diseases be investigated?
1) Autoantibodies
2) Complement
3) Cryoglobulins
How are autoantibodies detected?
Many autoantibodies have been identified and are used in the diagnosis and monitoring of autoimmune diseases.
Antibodies can be quantified either by titre (the maximum dilution of the serum at which the antibody can be detected) or by concentration in standardised units using an enzyme-linked immunosorbent assay (ELISA) in which the antigen is used to coat microtitre plates to which the patient’s serum is added.
Qualitative tests are also employed for antinuclear antibodies in which the pattern of nuclear staining is recorded.
Why are complement levels measured in certain autoimmune conditions?
Measurement of complement components can be useful in the evaluation of immune complex-mediated diseases. Classical complement pathway activation leads to a decrease in circulating C4 levels and is often also associated with decreased C3 levels. Serial measurement of C3 and C4 is a useful surrogate measure of disease activity in conditions such as SLE.
What are cryoglobulins?
Cryoglobulins are antibodies directed against other immunoglobulins, forming immune complexes that precipitate in the cold. They can lead to type III hypersensitivity reactions, with typical clinical manifestations including purpuric rash, often of the lower extremities, arthralgia and peripheral neuropathy. Cryoglobulins are classified into three types, depending on the properties of the immunoglobulin involved.
How do cryoglobulins need to be measured?
Testing for cryoglobulins requires the transport of a serum specimen to the laboratory at 37°C. Cryoglobulins should not be confused with cold agglutinins; the latter are autoantibodies specifically directed against the I/i antigen on the surface of red cells, which can cause intravascular haemolysis in the cold.
