Autoimmunity Flashcards
why are women more likely to have an autoimmune disease
a larger number of genes originate from the X chromosome creating a far greater possibility of mutations occurring - women have two X chromosomes where males have one.
higher levels of female hormones and lower male ones may contribute
what causes autoimmunity
an inability to recognise self from non self (the antigens and molecules presenting them) - when tolerance to self breaks
Bacteria, viruses, toxins, and some drugs may play a role in triggering an autoimmune process in someone who already has a genetic (inherited) predisposition to develop such a disorder.
autoimmune diseases occur when…
- the usual control process are interrupted, allowing lymphocytes to avoid suppression
- when there is an ‘alteration’ in cells/tissue so that it is no longer recognized as “self” and is thus attacked.
what is tolerance?
• Tolerance is the prevention of an immune response against a particular antigen. For instance, the immune system is generally tolerant of self-antigens, so it does not usually attack the body’s own cells, tissues, and organs. Also recognition of MHC cells
what cells do t cells specifically eliminate/bind to (different from b cells)
t cells only eliminate viral infected cells, not free virus or antigens
what did Peter C Doherty and Rolf M Zinkernagel win the Nobel Prize in 1996
for their discoveries concerning “the specificity of the cell mediated immune defence”.
T cells have to interact with MHC molecules and peptides
what are the two types of tolerance
central and peripheral tolerance
what two types of molecules are recognised in t cell activation (autoimmunity)
self MHC + foreign antigen
what is central tolerance
When T cell mature in the thymus, they are checked for their reactivity against self. T cells which react against self are destroyed.
what is positive selection
- occurs when double positive T cells bind cortical epithelial cells expressing Class I or Class II MHC plus self-peptides with a high enough affinity to get the survival signal. (but not too high) (death to those who do not interact with MHC molecules)
what is negative selection of t cells
- occurs when the TCR of a thymocyte engages a peptide–MHC ligand with very high affinity, leading to the apoptotic death of the cell
Deletes potentially self-reactive thymocytes (any cells with high affinity for self), thereby generating a repertoire of peripheral t sells that is largely self-tolerant
T cells with low affinity for self are allowed to maturate
what occurs to T cells that have an intermediate affinity for self
-> upregulation of transcription factor foxp3 turning them into T regulatory cells
these Treg cells suppress reaction to self antigens (cells activated in the periphery)
what is peripheral tolerance
- deletion or anergy of lymphocytes that recognize self antigens in peripheral tissue
T cells in the circulation must receive signals from normal cellular tissue to survive. When this control system fails, the immune system can react against our own molecules
what may cause anergy or inactivation of t cells in the periphery
Lack of accessory signals in presence of TCR engagement with MHC-peptide may lead to anergy or inactivation. -If presentation without co-stimulation
what is a t regulatory response/ what causes it?
T regulatory cells will respond to Ag (antigen) but induce an inhibitory response (regulation) (suppressive activity, no activate)
what is escape tolerance
Ignorance to self - lymphocytes with low affinity for self antigens make no response to the antigen (not highly activates providing self tolerance)
at what stage in b cell development does central tolerance occur
immature b cells
what is negative selection of b cells
If antigen receptor is crosslinked in the bone marrow it will die by apoptosis
Cross linking of IgM on immature B cells can cause cell death
– Binding of self-reactive IgM to self-antigen
what are the two broad categories of autoimmune disease
Organ specific autoimmunity
target antigen is unique to a single organ or gland, manifestations largely limited to that organ: cellular damage, over-stimulation, or blockade
Systemic autoimmunity
Most of the body
what cells drive multiple sclerosis
(hypothesised) cytotoxic CD4+ T cells (CTL) drive progression of MS and have prognostic value.
what causes autoimmune hemolytic aneamia
increased RBC destruction triggered by autoantibodies reacting against a single self antigen on red blood cells
what is pernicious anaemia
an autoimmune disease caused by auto-antibodies reacting against membrane bound intestinal proteins on gastric parietal cells. blocks B12 absorption (needed for hematopoiesis). Causes down regulation of RBCs, weakness, fatigue, peripheral nerve damage and jaudice. treatment: b12 replacement therapy
what are the two main thyroid hormones synthesised in the thymus gland
T4 (thyroxine) and T3 (triiodothyronine)
major hand in your energy levels, internal temperature, hair, skin, weight, and more
what causes Hashimoto’s disease/thyroiditis
autoreactive antibodies HLA-DR5 and t cells CTLA4 that attack the thyroid - causes inadequate iodine uptake and thyroid hormones production and secretion
what are the symptoms of Hashimotos thyroiditis and how can you test for the disease
Symptoms: weight gain, depression, mania, sensitivity to cold, fatigue, panic attacks
Testing for-thyroid antibodies can resolve any diagnostic difficulty.
what causes Graves disease
LATS long acting thyroid stimulating antibodies
autoimmune b cells make antibodies against the TSH receptor that also stimulates thyroid hormone production
thyroid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production - increases metabolic rate by 60-100%
factors include genetics (HLADR3), sex age and stress
what are the symptoms of Graves disease
Symptoms include anxiety, irregular heartbeat, fatigue, tremor, exophthalmos
what is sytemic lupus erthematosus (SLE)
a systemic autoimmune disease that attacks many tissues. caused by autoantibodies to DNA, histones and RBCs etc. Immune complex formation and complement activation lead to vasculitis. (glomerular basement membrane particularly targetted by the autoantibodies)
what are the symptoms of systemic lupus erythematosus (SLE)
Symptoms include fever, arthritis, skin rash, pleurisy, kidney dysfunction. because its systemic not every patient has the same symptoms.
characterised by a butterfly rash on the face
what is multiple sclerosis
an autoimmune disease of the central nervous system (brain, spinal cord and optic nerves) - white matter lost a s aresult of the inflammation. triggered by t cell response
what causes multiple sclerosis
t cell mediated autoimmune attack of myelin of nerves and oligodendricytes causes inflammation and damage of the myelin
what are the possible causes of autoimmune diseases
Release of sequestered antigen (CNS, eye)
Molecular mimicry (infectious agents, neoplasms)
Inappropriate activation of MHC Class II
Polyclonal activation of B-cell e.g. by infectious agent
Unlikely to be a single cause - Complex interplay between genetic and environmental factors
what causes type 1 diabetes
an effector t cell recognises peptides on beta cells in the pancreas and kills the beta cell. Glucagon (alpha cell) and somatostatin (delta cell) are still produced but isulin is NOT made
resulting in higher glucose levels in the blood
what therapeutic interventions are available for autoimmune diseases
Immunosuppresion - corticosteroids, azathioprine, cyclophosphamide - cyclosporin
Immunomodulation - beta-interferon.
Anti-inflammatory drugs - alpha4beta1, TNF-alpha blockade.
Selective blockade of TCR or MHC
Re-establish tolerance -oral antigens, mucosal antigens.
what are the symptoms of type 1 diabetes
Increased thirst. Frequent urination. Bed-wetting in children who previously didn't wet the bed during the night. Extreme hunger. Unintended weight loss. Irritability and other mood changes. Fatigue and weakness. Blurred vision. (caused by macula edema)
