Flashcards in Autoimmuntiy Deck (24)
What are the events required for autoimmune disease?
Escape from autoreactive clones from the thymus
Encounter of autoreactive clones with self antigens
Failure of peripheral tolerance mechanism
Inflicting clinical damage by autreactive clones
What are the mechanisms of tolerance?
Clonal deletion with complete removal of the self-reacting cells this is the dominant mechanism for antigens that are expressed in primary lymphoid organs
Clonal anergy where self-reactive lymphocytes still exist but are usually resistant to stimulation this is important only for antigens found in the periphery
Immunological ignorance where self-reactive cells are present but do not mount a pathological response because the antigens to which they react are sequestered away in immunologically privileged sites or there is a lack of T cell help as the immune system needs to see antigens in a danger context to be interested
Suppression where self-reactive lymphocytes are present and potentially active but are kept in check by T regulator cells
What are natural autoantibodies?
Loss of self tolerance does not always lead to autoimmune disease with the healthy immune repertoire has some B cells which have the potential to produce auto autoantibodies which are usually IgM, low titre and/or low affinity, alternatively they are directed against antigens that are not normally accessible in significant amounts these are referred to as natural autoantibodies these are thought to have a regulatory role or help dispose of breakdown products
Why don’t natural autoantibodies cause disease?
The amounts or affinity are low perhaps they need help from a corresponding self-reactive T helper lymphocyte to get a stronger response going
The antibody is not pathogenic as many of the antibodies we associate with connective tissue disease don’t really cause the disease and are merely smoke from the fire with some other process causing the damage
The patina does actually have autoimmune disease but its subclinical
What are examples of autoimmune disease following the release fo sequestered antigens?
Symphathetic ophthalamia where there is immunological damage to the good eye due to exposure of eye antigens from the other eye which was damaged by trauma or surgery
Autoimmune orchitis where following mumps or testicular trauma there is immune damage to good testicle
What is molecular mimicry?
This is where tolerance can be bypassed through immunization with a closely cross-reacting antigen
What are examples of molecular mimicry caused autoimmunity?
Antibodies against viral RNA or DNA may cross react with self RNA or DNA which may explain the autoantibodies found in connective tissue disease
Infection with particular bacteria (Salmonella, Shigella, Chlamydia) can trigger reactive arthritis one postulated mechanism is that antigens on the bacteria cross-react with antigens in the joint
Rheumatic fever which is thought to be a result of cross reactions between antigens on streptococci and antigens in cardiac muscle
How can abnormal MHC expression lead to autoimmunity?
Viruses may have an analogous adjuvant-like effect
Viral infection leads to the release of IFN which causes upregulation of class II HLA most cells don’t normally express Class II HLA on their surface
These HLA antigens may present peptides which are derived from intracellular autoantigens that the immune system isn’t normally exposed to
T lymphocytes then respond to the HLA and sequestered-self so CD4 T cells can now provide help for B lymphocytes that previously ignored the intracellular antigen
There is an unresolved issue whether the increased expression of Class II help create the autoimmunity or if it is secondary to inflammation caused by the autoimmunity
What are examples of MHC II upregulation leading to autoimmunity?
Thyroid glandular cells in autoimmune thyroiditis
Islet cells in type 1 diabetes mellitus
Synovial endothelia and lining cells in rheumatoid arthritis
Keratinocytes in psoriasis
What is thyrotoxicosis?
This is caused by antibodies against the TSH receptor which mimic the action of TSH and stimulate the thyroid gland as seen in graves disease
What is pernicious anaemia?
This occurs as a result of malabsorption of vitamin B12 this can be due to autoimmune destruction of the gastric parietal cells which produce intrinsic factor or antibodies directed against intrinsic factor itself
What is idiopathic thrombocytopenic purpura?
This is caused by antibodies against platelets
What is addison’s disease?
Due to destruction of the adrenal cortex
What is myasthenia gravis?
This is due to autoantibodies blocking the acetylcholine receptor on the neuromuscular end-plate
What is pemphigus?
This is a bullous inflammatory skin disease caused by autoantibodies against the intercellular substance antigens (cadherins)
How might immunoglobulin genes lead to genetic predisposition?
These genes may be responsible for some autoantibodies are encoded in the germline, somatic hypermutation may also be responsible for producing autoantibody
What are systemic autoimmune disease?
These often involve soluble antigen and antibodies in optimal concentration this leads to precipitation and vessel deposition of the complex particularly in the kidneys where it causes glomerulonephritis, the skin where it causes a rash or the joints where it causes arthritis
What are the features of systemic lupus erythematosus?
This is a condition where there is inflammation in the skin, joints, blood, kidneys and potentially other regions due to the widespread nature of the disease
It may be brought on by photosensitivity
It shows the presence of anti-nuclear antibodies, anti DNA, antiRNA and anti-nuclear proteins
There is a raised erythrocyte sedimentation rate
Low levels of C3 due to complement activation
10 times more common in women
What is rheumatoid Arthritis?
This is a condition where there is the presence of rheumatoid factor which are IgM, IgG and IgA antibodies which bind the Fc region of IgG
This is present in 80% of rheumatoid arthritis patients though it is also seen in other autoimmune diseases
It is useful for diagnosis as the titre will correlate with disaeas activity however anti-CCP is a better test for rheumatoid arthritis due to its higher specificity
How can TcR genes cause susceptibility to autoimmune disease?
Some TcR genes are used preferentially by autoreactive T cells (this offers therapeutic prospects as specific antibodies targeting this receptor may be used)
Why might complement genes cause a susceptibility to autoimmune disease?
There is impaired immune complex clearance
What antigen presentation genes can cause susceptibility to autoimmune disease?
There are associations with class I (HLA-B27) and with class II (HLA-DR2,DR3,DR4)
What regulatory genes can cause susceptibility to autoimmune disease?
Cytokines and co-stimulators (this opens up treatment possibilities through things such as proinflammatory cytokine antagonists)
Autoimmune regulator element (Which plays a role in T cell development and may play a role in autoimmune polyglandular syndrome)