Tolerance and Autoimmunity Flashcards
Define Immunological Tolerance
Unresponsiveness of the immune system to a particular antigen (self or non-self)
Define Autoimmunity
A failure of immunological tolerance resulting in an immune response to self-antigens (influenced by genetic and environmental factors)
Define Antigen
Any substance capable of inducing an immune response
Describe central tolerance
Immunological tolerance that develops in bone marrow and thymus, begins in foetal development and declines after birth.
Prevents immature foetal lymphocytes from initiating autoimmune response by clonal deletion (apoptosis) and clonal anergy (t lymphocyte regulation)
Describe peripheral tolerance
Immunological tolerance that develops in peripheral lymphoid tissues, prevents autoimmune responses of mature lymphocytes against foetus, gut flora, plant pollens.
Active throughout life.
Prevents autoimmune responses through clonal suppression by T lymphocytes.
What branch of specific immunity is most affected in loss of tolerance (autoimmunity)?
B-cells
Variations in what proteins are associated with autoimmune conditions?
Class I and II MHC proteins
Why does B-cell mediation make autoimmune conditions easier to diagnose?
Can be diagnosed through measurement of autoantibodies.
What is the negative aspect of B-cell mediation being responsible for autoimmune conditions?
Autoantibodies can cross the placenta causing babies to be born with autoimmune conditions (e.g. neonatal lupus)
What specific autoantibody is associated with RA?
Rheumatoid factor (RhF)
What specific antibody is associated with systemic lupus?
Anti Nuclear Antibody (ANA) (95% specificity)
double stranded DNA (dsDNA) (50% sens, 99% spec)
What specific antibody is associated with Hashimoto’s Thyroiditis?
Thyroid Peroxidase
What specific antibody is associated with Grave’s disease?
TSH receptor
Explain molecular mimicry
Immune system responds to antigens and produces immune response but also produces response against self-antigens similar to the initial insulting antigen.
Give examples of infectious molecular mimicry
Streptococcal infection- rheumatic fever
Campylobacter gastroenteritis- Guillan Barre syndrome
Urethritis/gastroenteritis- reactive arthritis
How does autoimmunity occur?
Through genetic recombination T and B cells are pre-programmed to recognise infinite number of antigens, including self antigens. Autoimmunity occurs when control of T and B cells that recognise self antigens fails- loss of immunological tolerance.
How do steroids help treat autoimmune conditions?
Anti-inflammatory and immunosuppressive: Decrease cytokines and decrease the action of cell mediated and humoral immunity.
Name 3 disease modifying drugs used in autoimmune conditions
Methotrexate
Azathioprine
Sulfasalozine
Name 2 monoclonal antibody drugs used in autoimmune conditions
Infliximab
Rutiximab
Which genes are most associated with autoimmunity?
Major Histocompatilibity Complex
human leukocyte antigen
What diseases are the HLA-B27 gene associated with?
Ankylosing spondylitis
Reactive arthritis
What disease is the HLA-DR2 gene associated with?
Systemic Lupus Erythematosus
What diseases are the HLA-DR4 gene associated with?
Rheumatoid arthritis
T1DM
How does the environment contribute to autoimmunity?
Infection
Chemicals
Neoplasms
Trauma
What gene is associated with rheumatoid arthritis and T1DM?
HLA-DR4
What gene is associated with Sjogren’s syndrome, T1DM, SLE and autoimmune hepatitis\
HLA-DR3
What gene is associated with ankylosing spondylitis and reactive arthritis?
HLA-B27
What gene is associated with systemic lupus erythematosus?
HLA-DR2
What is the more specific autoantibody for rheumatoid arthritis?
anti-CCP
anti-cyclic citrullinated peptide
What autoantibody is associated with Sjogren’s syndrome?
ANA
What autoantibody is associated with coeliac disease?
Anti-gliadin and anti-endomysial
How does central tolerance prevent immune responses to self antigens?
Controls immature T-lymphocytes that recognise self antigens by:
- Clonal deletion (apoptosis)
- Clonal anergy (regulatory T-lymphocytes)
How does peripheral tolerance prevent immune responses to self-antigens?
Controls mature T-lymphocytes that recognise self or benign antigens by clonal suppression (regulatory T-lymphocytes)
Give examples of some chemical molecular mimicry
Anticonvulsants/antibiotics -> Drug-induced lupus
Halothane -> liver necrosis
Give examples of a neoplastic molecular mimicry
Teratoma -> autoimmune encephalitis
How can trauma cause molecular mimicry?
Exposure of self-antigens in protected sites (e.g. eyes, testes)
Explain the mechanism of Grave’s disease
What would you expect the blood results to be?
Autoantibodies towards TSH receptor result in persistent stimulation of the thyroid gland.
Increased thyroid hormones (T3 and T4) = Increased basal metabolic rate and sensitivity to catecholamines
Autoantibodies against ophthalmic muscles= exophthalmos.
Bloods: High T3 and T4, low TSH, presence of anti-TSH receptor antibodies.
