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110 Cards in this Set

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The surrogate light chain operating during pre-Bcell development is made up of?
1) VpreB:/\5.
The surrogate light chains expression with u on the pre-B cell surface represents ?
1) an important checkpoint in B-cell maturation
Name the T-cell analog of VpreB:/\5.?
1) preTa (pTa)
pre Tcell receptor consists of ?
pre Bcell receptor consists of?
1) Pre Tcell
a) pTa
b) Tcell receptor B-chain,
2) preBcell
a) VpreB:/\5
b) Ig H-chain
Tcell receptor B-chain?
1) which is the first of the two Tcell receptor chains to be expressed
The B chain, is like the Ig ?
1) H-chain,
2) 1st to be rearranged
a) contains V, D and J segments.
complete complex of pre Tcell receptor?
pre Bcell receptor?
1) Pre Tcell
a) pTa
b) B-chain
c) CD3 and zeta components to this complex
2) Pre B cell receptor
a) VpreB:/\5
b) H-chain
c) Iga and IgB
and the assembly of the complete complex induces ?
1) pre Tcell receptor
a) Tcell proliferation and
b) the cessation of rearrangement at the TCRB loci.
2) Pre B cell receptor
a) similarly prevents further rearrangement of the H-chain loci
cessation of rearrangement of TCRB loci and Tcell proliferation leads to ?
1) allelic exclusion
pre Tcell
pre Bcell
Tcell receptor
Bcell receptor
successive gene rearrangements at the Tcell receptor?
the immunoglobiulin?
1) a- and B-chain loci can rescue unproductibely rearranged VJ and VDJ segments, respectively.
2) k and /\ L-chain loci can also undergo successive gene rearrangements
Ig H-chain genes are only permitted ?
1) one rearrangement per locus
What aspects of the arrangement of gene segments at these loci make successive gene rearrangements possible for ?
1) TCRa,
2) TCRB,
3) light chain k
4) light chain /\ loci
5) but not for the heavy chain locus
Successive gene rearrangement is possible at the TCRa locus ?
1) because there are numerous V and J gene segments available.
a) As long as there are V segments upstream and J segments downstream of the initial unproductive rearrangement,
(i) a second rearrangement can occur.
What does the second rearrangement of TCRa locus involve?
1) deletion of the unproductive rearrangement.
If the second rearrangement is productive?
1) then rearrangement at this locus terminates
If second rearrangement is unproductive?
1) then another rearrangement is permitted,
a) providing there are V and J segments still available.
If the V and/ or J segment pool is depleted at one locus?
then the other TCRa locus can begin to rearrange
a-chain rearrangements
1) because there are numerous V and J gene segments available.
a) As long as there are V segments upstream and J segments downstream of the initial unproductive rearrangement,
(i) a second rearrangement can occur.
Successive gene rearrangement is poss. At the TCRB locus because ?
1) there are two sets of D, J, and C gene segments down stream of the cluster of V gene segments:
a) (VB)n…DB1…(JB1)n…CB1…DB2…(JB2)n…CB2.
if a first rearrangement involving DB1 and JB1 segment is unproductive?
1) upstream V gene segment can rearrange to the second D gene segment and an associated J segment.
If this is unproductive?
1) no more rearrangements can be made
B chain rearr
1) there are two sets of D, J, and C gene segments down stream of the cluster of V gene segments:
a) (VB)n…DB1…(JB1)n…CB1…DB2…(JB2)n…CB2.
successive gene rearrangement is possible at the k L-chain locus b/c ?
1) there are numerous V and J gene segments available.
a) As with the TCRa locus,
b) as long as there are available V and J segments,
(i) further rearrangements can take place
further rearrangments of k L-chain result in ?
1) the excision of the unproductive rearrangement product.
Each k locus has the potential of rearranging a maximum of ?
1) five times
a) because there are five J segments
k L-chain rearrangements
1) there are numerous V and J gene segments available.
a) As with the TCRa locus,
b) as long as there are available V and J segments,
(i) further rearrangements can take place
successive gene rearrangement is possible at the /\ L-chain locus b/c ?
1) there are four sets of one J and one C gene segment cluster:
a) (V/\)-29…J/\1…C/\1…J/\2…C/\2…J/\3…C/\3…J/\4…C/\4.
each /\ locus thus has the potential to make a max. of ?
1) four rearrangements
/\ L-chain rearrangments
1) there are four sets of one J and one C gene segment cluster:
a) (V/\)-29…J/\1…C/\1…J/\2…C/\2…J/\3…C/\3…J/\4…C/\4.
H- chain locus has the following configuration: ?
1) (V)n-heptamer…23 spacer..nonamer…nonamer…12 spacer…heptamer-(D)n-heptamer…12spacer…nonamer…nonamer…23spacer…haptamer(j)n…Cu.
After the first DJ rearrangement, ?
1) the intervening D segments b/t the chosen D and J will be deleted
Following VDJ rearrangements?
1) the D segments that lie b/t the chosen V and DJ will be deleted.
2) Therefore, no un-rearranged D segments remain following these two rearrangement events
V and J cannot rearrange directly b/c ?
1) the recombination signal sequences are not paired appropriately and do not follow the 23/12 rule,
a) but rather they both contain 23-spacers with their recombination signal sequences.
b) Successive gene rearrangement is thus not possible at a H-chain locus
H--chain rearrangement
1) (V)n-heptamer…23 spacer..nonamer…nonamer…12 spacer…heptamer-(D)n-heptamer…12spacer…nonamer…nonamer…23spacer…haptamer(j)n…Cu.
MHCclass II expression is restricted to?
a limited number of cell types
what are the MHC class II expression cell types?
a) the professional antigen presenting cells
b) thymic epithelial cells,
c) neural microglia, and
d) activated Tcells (in humans)
the professional antigen presenting cells?
1) Bcells,
2) macrophages and
3) dentritic cell
which of these cell types populate the thymus or ciculate through it?
1) Macrophages,
2) dendritic cells, and
3) thymic epethialial cells
what role do MHC class II expression cell types play in mediating positive and/or negative slection?
1) positive selection
a) Cortical thymic epithelial cells participate
b) Only Tcells that have Tcell receptors that can interact with self MHC are positively selected
2) Negative selection
a) Cortical and
b) medullary thymic epithelium may also participate
c) Thymic epithelium,
d) circulating macrophages and
e) dendritic cells
How do Cortical thymic epithelial cells participate in positive selection ?
1) by presenting MHC class I and II molecules w/ self peptides to double positive (CD4+/CD8+) thymocytes
What is a double positive thymocytes?
1) These are developing T cells that have successfully rearranged the TCRa and TCRB genes.
2) Express CD4, CD8 and the a:B Tcell receptor in assoc w/ CD3
Only Tcells that have ? are positively selected?
1) Tcell receptors that can interact with self MHC
a) thus shaping a tcell repertoire that is specific for self-MHC molecules.
if the affinity for self MHC:self peptide is too weak?
1) the Tcells will die by neglect through apop.
Cortical and medullary thymic epithelium may also participate in negative selection by ?
1) inducing apop of thymocytes
a) that bear a Tcell receptor w/ high affinity for self MHC, self peptide or a comination of the two.
Thymic epithelium, circulating macrophages and dendritic cells that are found primarily at the?
participate in?
aid?
1) cortico-medullary junction
2) negative selection and
3) aid in the elimination of potentially self reactive T cells
Potentially self reactive Tcells bear?
1) high affinity Tcell receptors for complexes of self MHC:self peptides.
b/c Potentially self reactive Tcells are circulating b/t tissues, organs and the thymus?
1) a heterogenous array of self peptides will be transported to the thymus and displayed
why is it important for a heterogenous array of self peptides will be transported to the thymus and displayed ?
1) b/c there are some self peptides that are expressed in locations other than the thymus and which may be encountered in secondary lymphoid organs
Circulating dentritic cells and macrophages are effective at ?
1) endocytosing cellular debris
a) in extra thymic locations and
2) then presenting self peptides (derived from this debris) to thymocytes
Although circulating dentritic cells and macrophages are effective at endocytosing cellular debris and then presenting self peptides to thymocytes, there are some self proteins that are
1) Excluded from this housekeeping function.
a) these are located in immunologically privileged sites
(i) where leukocytes do not usually circulate.
These immunologically privileged sites are
1) normally MHC class II negative
What is the importance of these immunologically priviledged sites being MHC II negative?
1) b/c this avoids the presentation of self peptides with MHC class II
a) that were not presented in the thymus during negative selection.
Some of these tissues can be induced to
1) express MHC class II molecules
a) under the influence of certain cytokines,
example of cytokines that can influence the tissues
interferon-y,
a) during an inflammatory response
This is believed to be one mechanism by which
tolerance can be broken, resulting in autoimmunity
can you explain why it would be detrimental for non-circulating cells that populate tissues and glands, to express MHC class II?
1) Although cellular debris is usually endocytosed in extra thymic locations and presented as self proteins to thymocytes,
a) some self proteins are excluded from this housekeeping function.
(i) located in immunologically privileged sites
(a) These sites are normally MHC class II negative and
b) this is important b/c this avoids the presentation of self peptides with MHC class II that were not presented in the thymus during negative selection.
2) some of these tissues can be induced to express MHC class II molecules.
resulting in autoimmunity
in Tcells allelic exclusion of the a- chain locus ?
1) is relatively ineffective,
a) resulting in the production of some Tcells w/ 2 Tcell receptors
these two receptors are of ?
1) differing antigen specificity on their cell surface
will both the Tcell receptors have to pass positive selection for the cell to survive?
1) only one of the receptors have to be positively selected
a) Even if the other receptor does not react with self MHC this will have no effect.
Will both receptors have to pass negative selection for the cell to survive?
1) both receptors will have to pass the negative selection test for the Tcell to survive,
a) if only one of them fails > the cell will die
is there a potential problem having T cells with dual specificity surviving these selection processes and being exported to the periphery?
1) Yes.
a) Activated effector Tcell
(i) 2nd self peptide
b) Interferon-y
(i) Non-prof. APC
how would an tcells with dual specificity become activated?
1) during an infection by an APC + foreign antigen 1
a) using Tcell receptor 1
how would an activated effector tcells with dual specificity respond to 2nd peptide?
1) using tcell receptor 2 (could be self-peptide)
a) without requiring the co-stimulatory signals only professional antigen presenting cells deliver.
2) Thus it could cause a reaction against a self tissue
reactions against a self tissue, either ?
1) directly if it is a CD8T cell or
2) indirectly if it is a CD4 Tcell,
a) by activating potentially autoreactive B cells
interferon-y produced in the response against foreign antigen 1 could activate?
1) nonprofessional antigen-presenting cells nearby,
what would activation of nonprofessional antigen-presenting cells induce?
expression of MHC class II
a) with presentation of the self peptide above.
b) Effector Tcells with T cell receptor could make an autoimmune response against it.
mature B cells undergo?
1) somatic hypermutation following activation
when somatic hypermutation follows activation which follows affinity maturation, it results in ?
1) the production of antibody with higher affinity for antigen than in the primary antibody response
Since Tcells drive almost all immune responses, once activated,?
1) their receptors must continue to recognize the exact complex of foreign antigen and MHC molecule that activated them.
b/c of the requirement for dual recognition, somatic hypermutation would more likely than not ?
1) change the Tcell receptor to make it unable to recognize either the peptide or the MHC molecule, or the combination of both,
if the Tcell receptor was unable to recognize either the peptide or the MHC molecule, or both, it would render it?
1) unable to give help the B cells or to attack infected cells,
a) depending on the type of Tcell.
if the Tcell was unable to give help the B cells or to attack infected cells, This would?
destroy both the primary immune response and the development of immunity
Even changes that simply increased the affinity of the t cell for its antigen ?
1) would have no real advantage,
a) as it would not make the immune response any stronger or improve immunological memory in the same way that affinity maturation of Bcell does.
if somatic hypermutation changed the specificity of the Tcell receptor so that it now ?recognized a self peptide, this could result in ?
1) an autoimmune reaction
why do These considerations not apply to B cells?
1) they require Tcell help to produce antibody and
2) will only receive it if their Bcell receptor still recognizes the original antigen.
MHC class II deficiency is inherited as ?
and involves?
1) an autosomal recessive trait and
2) involves a defect in the coordination of transcription factors
What are the transcription factors involved in ?
1) the regulation of all MHC class II gene expression
a) (HLA-DP, HLA-DQ and HLA-DR)
what is the effect of MHCclass II defiency?
1) it affects the development of CD4 Tcells in the thymus
How does MHCclass II defiency affects the development of CD4 Tcells in the thymus?
If the thymic epithelium lacks MHC class II,
a) then positive selection of CD4 Tcells will not take place
Why are CD8 Tcells not affected ?
1) b/c MHC class I expression is unaffected by this defect.
explain why hypogammaglobulinemia is associated with this deficiency?
1) in order to produce antibody B cells require tcell help
In what form is the Tcell help?
1) The form of cytokines
a) produced by CD4 TH2 cells
what is hypogammaglobulinemia ?
1) Low Ig levels
what are the low levels of Ig attributed to?
1) the inability of B lymphocytes to p/d into plasma cells
a) in the absence of TH2 cytokines
what can be used to treat several types of Tcell tumors, ?
1) allogeneic bone marrow transplantation
example of a type of Tcell tumors?
1) acute lymphoblastic leukemia ((T-ALL)
describe in general terms how an allogeneic bone marrow transplant is carried out.?
a) Following irradiation and chemotherapy,
b) the patient would be infused with bone marrow
(i) obtained from a donor with the best HLA match possible.
we learned in chapter 3 that the benefit of polygeney in the MHC class I and class II genes and the expression of multiple isotypes is the ?
1) resulting increase in the number of potential peptide-binding motifs for antigen presentation to Tcells.
three isotypes for MHC class I ?
1) HLA-A,
2) -B and
3) –C
three isotypes for MHC class II ?
1) HLA-DP,
2) -DQ, and
3) –DR
If more is better, then why hasn’t natural selection favored more than three isotypes each for MHC class I and MHC class II
and driven the expansion of polygney further in the MHC?
1) Beyond a certain number of isotopes, the t cell repertoire will be decreased,
Beyond a certain number of isotopes, the t cell repertoire will be decreased owing to?
1) the disproportionate increase in negative selection events as the number of different isotypes increases
Each additional isotype will
1) decrease the number of t cells exported to the periphery,
2) compromising the diversity of the tcell population
see notes about transplantation?
chapter 5 questions flashcards
discuss why there are Tcell tumors corresponding to early and late Tcell developmental stages but no to intermediate stages?
1) Thymocytes do Not undergo significant prolif. b/t early and late progenitor stages
a) and there is little opportunity for maturations to accumulate at intermediate stages
Why do thymocytes not undergo significant proliferation between the early and late progenitor stages of development ?
1) thymic maturation of tcell occurs within a short time period;
2) thymocytes not rescued promptly during positive selection in the cortex are destined to
a) die by apop
When do transformation of tcells occur? examples?
either at an early lymphoid progenitor stage of thymocyte differentiation in the thymus or
a) common acute lymphoblastic leukemia (C-ALL)
2) at the post maturation stage in the periphery,
a) chronic lymphocytic leukemia (CLL)
explain how southern blotting could be used to identify a Tcell tumor expressing a rearranged Tcell receptor B gene?
Southern blotting is a ?
1) molecular technique based on DNA hybridization,
Southern blotting can be used to detect and characterize a t cell tumor by?
1) by demonstrating that the transformed cells all contain the same rearranged tcell receptor gene.
In southern blotting DNA is ?
1) endonuclease to generate DNA fragments of varying lengths,
2) electrophoresed in an agarose gel,
3) denatured and
4) transferred to a nitrocellulose filter or nylon membrane
b/c the tumor cells all contain the same rearranged B gene, ?
1) a distinct band can be visualized
a) corresponding to the rearranged gene,
How is the band visualized?
1) after hybridizing the nitrocellulose filter with a radioactive, single-stranded probe
a) complementary to the Tcell receptor B-locus C-region
2) followed by autoradiography.
What is also visible?
1) bands corresponding to the unrearranged B locus
what result would you expect when comparing DNA extracted from spermatocytes?
1) They will all contain Tcell receptor B-loci in the germline configuration,
2) and so the sample will only give the two bands
a) corresponding to the CB1 and CB2 genes in the unrearranged locus when probed with a C-region probe.
what are PBMCs?
1) peripheral blood mononuclear cells
normal PBMCs?
1) contain Tcells in addition to other monoculear cells
what result would you expect when comparing DNA extracted from normal (PBMCs)?
1) will give the same two bands and
2) a barely detectable smear
a) corresponding to the numerous different rearranged B genes in the heterogenous polyclonal pop. Of T cells
what result would you expect when comparing DNA extracted from PBMCs of patient with Tcell leukemia?
1) will contain a much larger proportion of T cells than normal,
a) and the majority will harbor the same rearranged B gene,
(i) as a result of outgrowth of a single transformed Tcell.
2) a discrete band migrating at a location distinct from the band s representing the germline configuration.
a) This band represents the numerous identical rearranged B genes in the sample.
b) The intensity of the band will correlate with the proportion of transformed cells in the sample