Week 5 Flashcards
pro-B cell
- earliest identifiable cell of B cell lineage
- CD34 is found on undifferentiated precuros cells of hematopoetic origin
Pro-B cell rearrangement
- rearrangement of heavy chain only uses one chromosome
- if non-productive rearrangements are made with both chromosomes then the B cell will go through apoptosis
Pre-B cell and Ig heavy chains
- pre-B cell assess quality of the Ig heavy chain
- VpreB and gamma 5 proteins make up a surrogate light chains that binds to mu heavy chains to mimic the light chain and test out whether it is functional
re-arrangement of light chain
- uses VDJ recombinase
- reaarangement success rate is increased because there are two genes that can be used; kappa and lambda
kappa vs lamba
- the body always uses kappa genes first but if it cannot rearrange those then it will move on to lambda
- because kappa is used first they are used more than lambda
- the only Ig that predominately uses lambda chains is IgD
Checkpoints of B cells
- Checkpoint 1: occurs at the late pro-B-cell stage with formation of a functional pre-B-cell receptor; involves whether cell is able to make mu chains that can assemble a functions pre-B cell receptor
- Checkpoint 2: at the stage of the small pre-B cell, is dependent on whether the cell is able to make a function light chain that can bind to the heavy chain
t-cells and the thymus
T cells have to migrate to the thymus to mature and once matured they move to the lymphnode
two lineages of b cells
- α:β T cells and γ:δ T cells.
- these cells will begin to express CD4 and/or CD8 during their development
thymus
- made of
- later in life
- made of epithelial that is colonized by bone marrow progenitor cells which give rise to thymocytes and dendritic cells
- involution: fat cells claim area that were once packed with thymocytes and thymus is no longer able to produce as many T-cells; this does not effect t-cell immunity because T cells are long lived
DiGeorge Syndrome
genetic disease where the thymus fails to develop so T cells are absent but B cells are present. This leaves patient open to opportunistic infections
Thymocytes commit to T-cell lineage
- lymphoid progenitor cells express CD34 but with interaction of thymic stromal cells the progenitor cells will divide and differentiate
- the cell will begin to express CD2 and CD5 showing that they have committed to T4 lineage
Double negative thymocytes
-the t cell does not have CD4 or CD8 yet on cell
Double positive thymocytes
- the t cells have both CD4 and C8 on cell surface
- need to
Notch 1
-transcription factor that binds to the nucleus and initiates transcription of T cell genes
thymocyte lineage
- commitment to α:β or a γ:δ is a race; whichever gene can rearrange and make a functional receptor first will be the lineage that the receptor will go down
- if beta chain is made before a γ:δ receptor is made then it becomes a pre-T cell receptor
- Pre-T cell receptor will express CD4 and CD8 then alpha chain will be allowed to rearrange while still competing with γ:δ to make a successful receptor
- if γ:δ make a succeessful receptor before the cell can make a beta chain then the cell is committed to γ:δ lineage
pre-TCR complex
- tests for ability of beta chain to bind surrogate alpha chain whcih will bind with CD3 complex forming the pre-T cell recptor
Thymocytes attempts at rearrangement
- thymocytes have four attempts to re-arrange beta cell before it goes through apoptosis
- thymocytes have multiple attempts at re-arragning alpha chain
why do we favor α:β lineage over γ:δ lineage
commitment to α:β lineage requires only one productive gene rearrangement, whereas commitment to the γ:δ lineage requires a minimum of two productive rearrangements.
alpha chain rearrangement and delta locus
- When an α-chain gene is rearranged, the δ locus situated within the α locus will be automatically deleted
- greatly reduces the probability that a T cell committed to the α:β lineage will end up expressing a γ:δ receptor as well as an α:β receptor
positive selection
- mediated by the complexes of self peptides and self-MHC molecules present on the surface of the cortical epithelial cells
- If a peptide:MHC complex is bound within 3–4 days after the thymocyte first expresses a functional receptor, then a positive signal is delivered to the thymocyte, which permits its maturation to continue.
- double-positive CD4 CD8 T cell interacts through its α:β receptor with a particular peptide:MHC complex. When the interacting MHC molecule is class I, CD8 molecules are recruited into the interaction, whereas CD4 molecules are excluded. Conversely, when the selecting MHC molecule is class II, CD4 is recruited and CD8 excluded
negative selection
-deletes T cells whose antigen receptors bind too strongly to the complexes of self peptides and self-MHC molecules presented by cells in the thymus
How negative selection occurs
- development of central tolerance: AIRE transcription factor will induce transcription of tissue specific genes in the thymus and if developing B cell binds too tightly to self antigen it will induce apoptosis
- development of peripheral tolerance: after development if a t-cell binds to self antigen too tightly it will become anergic and eventually die
autoimmune disease
- CTLA-4
- defecive AIRE alleles
- FOXP3
- arises when tolerance to self antigens in lost
- CTLA-4 will compete with CD28 for binding with B7; when 28 is bound the T cell is activated when 4 is bound the T cell is inactivated; if CTLA4 is inhibited then the T cell will always be activated (Ipilimumab)
- common in Finns, Sardiniansm and Iranian jews; will have incomplete deletion of sef–reactive T-cells
- FOXP53 only used by T-reg cells to cause annergy to t-cells activated by self antigen after maturation
Endocrine glands and autoimmunity
- contains tissue specific proteins not expressed in other tissues and are well vascularized
- Thyroid gland, islets of langerhans and adrenal gland
Autoimmunity and infections
- some antibodies made in infection can react with epitopes present in human tissue (molecular mimicry)
- ex: rheumatic fever; antibodies specific for cell-wall components of S. pyogenes are made and react with epitopes present on human heart, joint, and kidney tissue causing inflammation in those tissues
autoimmunity being caused by environmental factors
- smoking: Alveoli in the lungs of smokers are chronically damaged from their daily exposure to cigarette smoke. This lack of integrity gives circulating antibodies access to the basement membranes, where deposition of immune complexes activates complement, causing blood vessels to burst and hemorrhage.
- punched in the eye: proteins unique to the eye drain from the anterior chamber to the local lymph node and there induce an autoimmune response which can cause blindenss to both eye unless treated
Immunogen
elicits an immune response
Toleragen
Does not ellicit an immune response
What is self-tolerance
body’s non-response to antigens that are normally seen in the body where as a failure of that would be an autoimmune disease
Mechanisms of by which the immune system develops tolerance to self during development
○ T-cells: May undergo apoptosis OR CD4 cells may differentiate to Treg cells (which will have an effect in regulating peripheral responses to self antigens)
○ B-cell: engages with self antigen while being developed the BCR undergo receptor editing (gene rearrangements) OR undergo apoptosis
