Self, Non-Self Discrimination Flashcards
What is the site for central tolerance?
Thymus for T cells
Bone marrow for B cells
What is the site for peripheral tolerance?
Secondary lymphoid organs
Peripheral tissues
What are the mechanisms that induce tolerance?
Deletion
Anergy
Ignorance
Regulation
Which uncommitted progenitor gives rise to the development of B cells?
Common lymphoid progenitor (CLP)
Where do B cells develop?
Bone marrow
Also in neonatal spleen and liver
When does the generation of new B cells end?
Continues through life
What is the configuration of the BCR in a CLP?
In germline configuration
What happens in BCR development during the early pro-B cell stage?
DJ heavy chain rearrangement
How are genes chosen to make a BCR/TCR?
Enzymes come in and randomly chop DNA
Recombined via RAG
What happens in BCR development during the pre-B cell stage?
Heavy mu chain produced by combining V, D, and J segments
How many chances does a pre-B cell get to make a functional heavy mu chain?
2 because of 2 alleles
What happens to a pre-B cell that cannot make a functional heavy mu chain?
Die
How is a pre-B cell saved from death?
Heavy mu chain tested for functionality by pairing with surrogate chains > pre-BCR
Functional pre-BCR signalling engaged by dimerisation/oligomerisation - no Ag needed
What is the significance of pre-BCR testing?
Important checkpoint for transition of pro-B cell to pre-B cell
What enzyme is needed for pre-BCR signalling, and what disease occurs when this enzyme is not present?
Bruton’s tyrosine kinase
Disease: Bruton’s X-linked agammaglobulinaemia
How many chances does an immature B cell get to make a functional light chain?
4 because of 2 loci: kappa and lambda - on 2 alleles
Do BCRs on a B cell express both a kappa and lambda light chain?
No, only one type is used by a single B cell = isotypic exclusion
What is the transition between a small pre-B cell to an immature B cell?
Light chain and heavy chain forming IgM
What is the default response of lymphocytes during development?
To die - must be actively saved from apoptosis via signals
How does central tolerance of B cells work?
No self reaction in bone marrow > migrate to periphery > mature B cell
Multivalent self molecule binding > clonal deletion/receptor editing > apoptosis/generation of non-autoreactive mature B cell
Soluble self molecule binding (smaller signal) > migrates to periphery > anergic B cell
Low-affinity non-cross-linking self molecule binding > migrates to periphery > mature B cell (clonally ignorant)
Are there any self-reactive B cells in the periphery?
Yes, a little bit of self-reactivity goes through because of low signal or low affinity binding
Why is an anergic state of lymphocytes maintained in the periphery?
In case receptor strongly recognises foreign molecule
Is B cell central tolerance of equal stringency as T cell central tolerance?
No, B cell tolerance less stringent
By when does the thymus fully develop?
Fully developed by birth
When does the thymus start to involute?
During puberty
What effect does DiGeorge syndrome have on the thymus?
Thymic aplasia because 3rd and 4th pharyngeal arches don’t develop properly
Does T cell development continue throughout life?
Yes, but it sharply drops during puberty when thymus starts to involute
What are the three main fates of thymocytes entering the thymus?
Alpha/beta T cells
Gamma/delta T cells
Invariant NKT cells
What are alpha/beta T cells?
Conventional T cells
Further differentiate into CD4 helper T cells and CD8 killer T cells
What are gamma/delta T cells?
Primarily located in epithelial and mucosal sites
Don’t have CD4 and CD8
Don’t undergo positive and negative selection
Produced earlier in embryonic development than conventional T cells
What happens to double negative (DN)1 thymocytes?
TCR genes still in germline configuration
What happens to DN2 thymocytes?
Become responsive to IL-2
Beta chain rearrangement starts
What happens to DN3/4 thymocytes?
Rearrangement of beta chain continues
Pre-TCR testing determines whether cell expresses CD4 and CD8
What happens to double positive (DP) thymocytes?
Rearrangement starts at alpha chain locus
Single beta chain can associate with many different alpha chains
How many times can a thymocyte try and make a functional beta chain?
2 times because of 2 alleles
What is positive selection?
Ensures thymocytes can recognise and bind to MHC
Determines whether or not cell will be CD4 or CD8
Which cells do thymocytes bind to in negative selection?
Professional antigen presenting cells expressing self-Ag
What is negative selection?
Thymocytes that recognise self-Ag strongly are deleted
What does death by neglect involve in the thymus?
Thymocytes bind too weakly to MHC so they die because of too weak a signal
What is the role of Tregs in peripheral tolerance?
Have intermediate self-reactivity
Suppress function of other T cells
What do Tregs express?
CD25
Foxp3
What do Tregs secrete?
IL-10
TGF-beta
What is the defect in immunodysregulation polyendocrinopathy X-linked syndrome (IPEX)?
Foxp3
What happens to mice who don’t express Foxp3, and what does this illustrate?
Develop autoimmune diseases
Removing just one peripheral tolerance mechanism causes autoimmunity > peripheral tolerance important
What are the symptoms of Grave’s disease?
Tachycardia Loss of weight Heat intolerance Exophthalmos = abnormal protrusion of eyeballs Sleep disturbances Hot flushes Agitated nervousness
How is Grave’s disease mediated?
Autoimmune Abs produced against TSH receptor on thyroid gland > stimulates thyroid to produce hormone
Thyroid hormones shut down TSH production but have no effect on autoAb production > excessive thyroid production > hyperthyroidism
How is myasthenia gravis mediated?
Ab blocks Ach receptor at NMJ
What are the symptoms of myasthenia gravis?
Progressive weakness following diurnal pattern
Why does decreasing the amount of Ach activity at the NMJ have such profound effects?
Small minute changes in fine control muscles have large effects
Eg: levator palpebrae superioris > person can’t keep eye open when looking up after a while
What is the treatment in severe cases of myasthenia gravis?
Can elute Abs from blood but it’s not Ag specific
Danger of becoming vulnerable to other infections and diseases
What is multiple sclerosis (MS)?
Loss of myelin sheath through autoimmune process
Debilitates nerve conduction
Can affect any part of CNS > people present with variety of symptoms
Which immune cell is believed to be implicated in MS?
Th17 cells
What is one possible treatment in development for MS?
Trying to trap autoreactive T cells in periphery
What is molecular mimicry?
Pathogen derived Ags resemble self tissues
What are two examples of where molecular mimicry occurs?
Rheumatic feveer
Guillain-Barre syndrome
What are some possible environmental risk factors that cause tolerance failures?
Industrialisation Small family sie Affluent, urban homes Stable intestinal microflora High antibiotic use Low/absent helminth burden Good sanitation > low orofaecal burden
