Exam 2 Flashcards
somatic hypermutation
how entire V region is diversified after B cell activated by antigen, AID makes point mutations
AID
activation-induced cytidine deaminase: converts cytosine to uracil and only active during B cell proliferation
affinity maturation
when B cells that bind better to antigen are positively selected for
IgM
first isotype made in primary immune response, secreted as a circular pentamer held by J Chain, strongly binds to antigen but limited in effector mechanisms thus need isotype switching
switch regions
flanks the 5’ side of C genes
isotype switching
involves recombination within cluster of C genes that removes a previously expressed C gene and brings a different one into its place
Steps of Isotype Switching
1) initiation of transcription of C region
2) Targeting of AID of cytosines in switch region
3) Uracil is removed (abasic nucleotide)
4) endonuclease removes nucleotide and leaves a nick
5) nicks in both switch regions facilitate recombination
(takes place between u and any other C region or can happen sequentially)
Hyper IgM immunodeficiency
patients lacking AID cannot undergo somatic hypermutation or isotype switching making them susceptible to pyogenic bacteria infection in sinuses, ears, lungs.
Neutralizing antibodies
inactivate pathogen or toxin and prevent interaction with human cells
Opsonizing antibodies
act as opsonins or complement activators - phagocytes have receptors for Fc component of antibody
IgG
more flexible and can wave, rotate, wag, bend to increase chance of binding 2 antigens and effector molecules. Susceptible to proteolytic cleavage so there are subgroups that differ in hinge and heavy chain.
IgG1
most protein antigen
IgE
recruits effector functions of mast cells
IgA
present at mucosal sufaces as dimeric form held together by J Chain. important in protecting mucosal surfaces and in total is most abundant antibody
IgG2
repetitive carbohydrate antigens
IgG3
best at complement activation
IgG4
can exchange heavy-light chain dimer with another IgG4 (can only neutralize) - anti-inflammatory
T Cell Receptors
beta chain like the heavy chain with VDJ and alpha chain like the light chain with VJ
T Cell Receptor Function
only involved in antigen recognition, not effector function, mainly recognizes proteins.
T Cell similarities to immunoglobulins
undergo rearrangement as well as junction diversity
T Cell differences to immunoglobulins
there is only one C(alpha) and two functionally identical C(beta), never soluble
Severe Combined Immunodeficiency Disease
rare disease where genetic defects result in absence of RAG proteins leading to lack of B and T lymphocytes. Babies die very quickly without immediate bone marrow transplant.
Ommen Syndrome
missense mutation in RAG proteins that lowers activity
Rage Genes and Evolution
Because RAG is essential in T and B development and without them babies die, RAG genes might be important in the evolution of adaptive immune systems. RAG genes don’t have introns and resemble the transposase gene of a transposon (mobile genetic element) which cleaves dsDNA
Self vs Non Self
the power of adaptive immunity is from infinite possible binding sites on receptors but there is the potential to recognize self antigens
Immunological Tolerance
when cells realize how to not attack the self - happens during lymphocyte development
positive selection
T Cells are selected that have antigen receptors that work effectively with MHC class I and class II
negative selection
T Cells that bind too strongly to self-MHC molecules die by apoptosis
B Cell selection
B Cells are dependent of T cells for activation so negative selection still happens but isn’t as critical
Regulatory T Cells
provide additional tolerance in peripheral tissues by being autoreactive to determine if other T cells are autoreactive
Functional T-Cell Receptor
TCR must associate with four invariant proteins in order to make it to the cell surface (CD3 complex, zeta chain)
CD3 complex
CDgamma, CDdelta, CDepsilon
Invariant Protein Purpose
important in transmitting signal of antigen binding into the cells (similar to Igalpha and Igbeta in immunoglobulins)
T Cell Receptor Classes
cand have alpha:beta or gamma:delta where a/g are similar and b/d are also similar.
T Cell Receptor Classes Only One or Other
can have a:b T-cell receptors or g:d T-cell receptors, never both because the delta gene locus resides in the middle of the alpha chain locus so rearrangement of the alpha chain deletes the delta chain locus
The enzyme responsible for both somatic hypermutation and aiding in isotype switching is
Activation-induced cytidine deaminase
Antibodies that bind to a pathogen or toxin and inactivate the molecule preventing interaction with human cells are
neutralizing antibodies
Each variable region of each T-Cell receptor subunit has how many hypervariable regions?
3
Which of the following is not a component of the T Cell Receptor?
Ig(alpha)
Which of the following is mismatched?
a. affinity maturation: isotype switching b. surface immunoglobulin: B-cell antigen receptor c. constant regions of antibodies: binding to complement proteins d. activation-induced cytidine deaminase: somatic hypermuation e. switch sequences: class switching
a) affinity maturation: isotype switching
Which of the following is mismatched?
a. affinity maturation: isotype switching b. surface immunoglobulin: B-cell antigen receptor c. constant regions of antibodies: binding to complement proteins d. activation-induced cytidine deaminase: somatic hypermuation e. switch sequences: class switching
a)IgA
Identify which of the following is not associated with activation-induced cytidine deaminase activity?
a) synthesized in prolifeating B cells during active immune responses
b) diversification of the Vh domain but not the Vl domain
c. somatic hypermutation
d. isotype switching
e. cytosine conversion to uracil
b) diversification of Vh domain but not the Vl domain
In contrast to immunglobulins, T-cell receptors recognize epitopes present on antigens.
a. carbohydrate and protein
b. lipid
c. carbohydrate and lipid.
d. protein
e. carbohydrate
d. protain
Which of the following characteristics is common to both T-cell receptors and immunoglobulins?
a. The antigen receptor is composed of two identical heavy chains and two identical light chains.
b. . Somatic recombination of V, D, and J segments is responsible for the diversity of antigen-binding sites
c. . Somatic hypermutation changes the affinity of antigen-binding sites and contributes to further diversification.
d. class switching enables a change in effector function
e. carbohydrate, lipid, and protein antigens are recognzied and stimulate a response
b. somatic recombination of V, D, and J segments is responsible for the diversity of antigen-binding sites
How many hypervariable regions contribute to antigen-binding site in an intact T-cell receptor?
a. 12
b. 4
c. 6
d. 2
e. 3
c. 6
In B cells, transport of immunoglobulin to the membrane is dependent on association with two invariant proteins, Ig and Ig. Which of the following invariant proteins provide this function for the T-cell receptor in T cells?
a. All of the given answers are correct
b. CD3gamma
c. CD3delta
d. CD3epsilon
e. zeta
all of them
Antigen Processing and Presentation
TCR recognize peptide bound to MHC which requires antigen processing and antigen presentation
Antigen Processing General
degradation of pathogen-derived proteins into peptides
Antigen Presentation General
peptides are loaded onto MHC molecules and peptide:MHC complexes are displayed on cell surfaces where TCRs can recognize them
MHC stands for
major histocompatibility complex
MHC class 1 (general)
antigens from intracellular pathogens
MHC class II (general)
antigens from extracellular pathogens
Types of effector T cells
Cytotoxic T Cells and Helper T Cells
Cytotoxic T Cells
intracellular infections, express CD8
Helper T Cells
extracellular infections, express CD4
T-Cell Co-Receptors
CD8 and CD4 allow effector T cells to recognize the correct MHC class molecules so T Cells will express a co-receptor but never both
MHC class I cells
most cells express this because any cell can be infected
MHC class II cells
only dendritic cells, macrophages, and B cells express this because they are professional phagocytes that attack extracellular pathogens
CD8 on Cytotoxic T Cells
recognize MHC Class I presenting intracellular
CD4 on Helper T Cells
recognize MHC class II presenting extracellular
Cytotoxic T Cells funtion
main effector function is kill cells infected with pathogen
Helper T cells function
main effector function is to help other cells respond to extracellular sources of infection (B cells and macrophages)
MHC Class I Structure
transmembrane alpha chain, beta2-microglobulin (not encoded by gene in MHC)
MHC Class II Structure
transmembrane alpha chain, transmembrane beta chain
Peptide binding groove structure
peptide binding groove of both MHCs is formed by two immunoglobulin-like domains which are also important in co-receptor binding
Promiscuous binding specificity
the peptide-binding site in an MHC can bind many different peptides
MHC class 1 peptide binding groove constraints
MHC class I binds peptides of 8, 9, 10 amino acids and the last amino acid is usually hydrophobic or basic
MHC class 2 peptide binding groove constraints
binds peptides of 13-25 amino acids (or longer)
MHC class 1 Antigen Presentation General
1) intracellular pathogen produces proteins using cellular machinery
2) some proteins naturally degraded and transported to the ER where they can bind MHC class 1
3) MHC class 1 bearing peptide leaves the ER and moves to the cell surface
4) cytotoxic T cells that have the proper T cell receptor and CD8 can recognize the MHC class 1:peptide complex and kill the affected cell
MHC class 1 Peptide Generation
intracellular pathogen uses cytoplasmic ribosomes to make protein but cells also have the proteasome. peptides are transported across ER membrane thought the protein TAP
Proteasome
how normal cells break down cellular protein and if the cell is responding to INF-gamma, the proteasome will adopt a function of making MHC class 1 peptides
TAP
transporter associated with antigen processing - lets MHC class 1 peptides into the ER
MHC Class 1 Peptide Loading Complex
1) class I heavy chain is stabilized by calnexin until b2-microglobulin binds
2) calnexin is released. the heterodimer of class 1 heavy chain and b2m forms the peptide-loading complex with calreticulin, tapasin, TAP, and ERp57
3) a peptide delivered by TAP bind to the class 1 heavy chain forming the mature MHC class I molecule
4) the class I molecule dissociates from the peptide-loading complex, and is exported from the ER
Calnexin
keeps MHC in ER until it is properly folded
Peptide-loading complex
MHC class 1 binds b2m after calnexin and then incorporates with calreticulin, tapasin, TAP, and ERp57
MHC Class 1 Peptide Trimming
1) MHC class 1 is loaded with peptide that is too long at the N terminus (but usually has correct carbody terminus)
2) ERAP removes N-terminal aa to give a peptide of 8-10
3) MHC class 1 molecule moves to Golgi and then plasma membrane
ERAP
endoplasmic reticulum aminopeptidase
Bare Lymphocyte Syndrome
non-functional TAP protein so antigen cannot get into the ER and there is a very poor CD8 responses
Self-Peptides on MHC class I
These can also be presented but T Cell development prevents response
MHC class II Antiger Presentation General
1) macrophage (or dendritic) engulfs and degrades bacterium, producing peptides
2) bacterial peptides bound by MHC class II in vesicles (endosome)
3) bound peptides transported by MHC class II to the cell surface
4) helper T cell recognizes complex of peptide antigen with MHC class II and activates macrophages
Where MHC class II molecules are made
made in the secretory pathway, but they don’t meet antigen peptide until their vesicles from the Golgi fuse with endocytic vesicles
Do MHC Class II get loaded in the ER?
NO but the MHC Class II molecules enter the secretory patheway and ER but don’t get loaded. Work through the invariant chain
MHC class II molecules meeting antigen
1) MHC class 2 molecules are in ER
2) MHC class II alpha and beta chains associate with the invariant chain
3) invariant chain blacks binding of peptides to MHC class II molecules in the ER
4) In vesicles, invariant chain in cleaved, leaving the CLIP fragment
5) CLIP blocks binding of peptides to MHC class II in vesicles
6) HLA-DM facilitates release of CLIP, allowing peptides to bind
CLIP
class II associated invariant chain peptide - cleaved from the invariant chain once the MHC class II moves to an endocytic vesicle from the ER
HLA-DM
exchanges CLIP with a pathogenic peptide
Cross-Presentation of Peptides
exogenous antigens can be presented via MHC class I molecules via cross-presentation
Exogenous antigens
a forgein antigen like in allergy, transplant protein, taken in by breathing or eating etc
When does Cross-presentation happen?
occurs when phagocytic cells engulf and infected and apoptotic cell and generated peptides are transproted to the ER but the mechanism is unknown.
1) phagocyte engulfs infected cell
2) phagolysosome produces antigens that go to the ER
3) present at class 1 but the vesicle also binds somehow
How T Cells recognize the antigen on MHC
TCR makes contact with BOTH peptide and MHC molecule. The third hypervariable region of the TCR alpha and beta chains (most variable) make peptide contact while the first two hypervariable regions contact the MHC molecule
Differential Expression of MHC Class I and Class II Molecules
virtually all cells express MHC class I (intracellular pathogens) but MHC class II are seen on cells of the immune system specialized for uptake, processing, and presentation of antigen (extracellular pathogen)
The protein responsible for transporting intracellular pathogen peptides into the endoplasmic reticulum is:
a. CLIP
b. TAP
c. HLA-DA
d. ERAP
b. TAP
CLIP, which binds to MHC class II molecule is derived from:
a. Calnexin
b. proteasome
c. HLA-DA
d. Invariant Chain
d. Invariant Chain
Tapasin
a bringing protein that binds to both TAP and MHC class I molecules and facilitates the selection of peptides that bind tightly to MHC class I molecules
The T-cell co-receptor CD4 interacts with bound to the surface of .
a. MHC Class II; antigen-presenting cells b. MHC Class I; antigen-presenting cells c. MHC Class I; T cells d. MHC Class II; T cells e. None of the answers given are correct
a. MHC Class II; antigen-presenting cells
The degradation of pathogen proteins into smaller fragments called peptides is a process commonly referred to as:
a. antigen presentation
b. peptide loading
c. antigen processing
d. endocytosis
e. promiscuous processing
c. antigen processing
Which of the following best describes the function of tapasin?
a. Tapasin is a bridging protein that binds to both TAP and MHC class I molecules and facilitates the selection of peptides that bind tightly to MHC class I molecules b. Tapasin is an antagonist of HLA-DM and causes more significant increases in MHC class I than MHC class II on the cell surface c. Tapasin is a lectin that binds to sugar residues on MHC class I molecules, T-cell receptors, and immunoglobulins and retains them in the ER until their subunits have adopted the correct conformation d. Tapasin is a thiol-reductase that protects the disulfide bonds of MHC class I molecules e. Tapasin participates in peptide editing by trimming the amino terminus of peptides to ensure that the fit between peptide and MHC class II molecules is appropriate
a. tapasin is a bridging protein that binds to both TAP and MHC class I molecules and facilitates the selection of peptides that bind tightly to MHC class I molecules
Antigen processing involves the breakdown of protein antigens and the subsequent association of peptide fragments on the surface of antigen-presenting cells with
a. MHC class I or class II molecules b. immunoglobulins c. T-cell receptors d. complement proteins e. CD4
a. MHC class I or class II molecules
Which of the following describes a ligand for an a:b T cell receptor?
a. peptide:MHC complex b. carbohydrate:MHC complex c. lipid:MHC complex d. All of the complexes given are correct e. None of the complexes given are correct
a. peptide:MHC complex
MHC molecules have promiscuous binding specificity. This means that
a. a particular MHC molecule has the potential to bind to different peptides b. when MHC molecules bind to peptides, they are degraded c. peptides bind with low affinity to MHC molecules d. None of the answers given describe promiscuous binding specificity
a. a particular MHC molecule has the potentail to bind to different peptides
Which of the following removes CLIP from MHC class II molecules?
a. HLA-DM b. HLA-DO c. HLA-DP d. HLA-DQ e. HLA-DR
a. HLA-DM
Human MHC
is called human leukocyte antigen complex (HLA) called HLA class I and HLA class II
MHC Diversity Comes From?
Gene families and genetic polymorphism
MHC gene families
multiple similar genes encoding the MHC chains
MHC genetic polymorphisms
presence of multiple alternative forms of a gene in a population
Isotype
product of different genes in MHC class I or II family
Allele
different form of a gene
Allotype
encoded protein from and allele
MHC Class I Isotypes
HLA-A, HLA-B, HLA-C, HLA-E, HLA-G, HLA-F
HLA-A, HLA-B, HLA-C
highly polymorphic, present antigen to CD8 T cells and are ligands for NK cells
HLA-E and KLA-G
oligomorphic, ligands for NK cells
HLA-F
unknown function but intracellular
MHC Class II Isotypes
HLA-DP, HLA-DQ, HLA-DR, HLA-DM, HLA-DO
HLA-DP, HLA-DQ, HLA-DR
highly polymorphic, present antigen to CD4 T Cells
HLA-DM, HLA-DO
oligomorphic, involved in peptide loading of class II
HLA Class II and I Gene Complex
Consists of about 4 million base paris on chromosome 6 with three regions in order Class II Region, Class III Region, Class I Region
Class I Region
HLA class I genes and nonfunctional class I gene fragments
Class II Region
HLA class II genes and nonfunctional class II gene fragments
Class III Region
separates class I and Class II with other genes
HLA Gene complex notation
Remember class II has and alpha and beta chain so genes are A and B (HLA-DMA or HLA-DMB). If there is more than one gene, and number is added to the end (HLA-DQA1 or HLA-DQA2)
Haplotype
combination of HLA alleles - over human history HLA genes have been recombined to thousands of haplotypes - combination of different haplotypes through inheritance means that million of different HLA combinations are represented
HLA-DR Subdivisions
There is one single HLA-DRA gene, but there are 4 different genes encoding the HLA-DR beta chains(DRB1, DRB3, DRB4, DRB5). So DRB1 is present on every chromosomes 6 and can be the only one expressed and there are 3 other types of chromosome 6 that carry either DRB3, DRB4, or DRB5 in addition in DRB1.
HLA class II region genes
almost entirely dedicated to genes involved in antigen processing: HLA alpha and beta chains, TAP, subunits of proteasome that are induced by interferons
Interferons
involved in coordinately regulating genes involved in antigen presentation and processing (HLA class I heavy chains, b2m, TAP, proteasome subunites)
INF-gamma
coordinates expression of HLA class II genes and invariant chain genes through the action of the trascriptional acitvator C2TA
C2TA
MHC class II transactivator
Impaired C2TA
can lead to bare lymphocyte syndrome where class II molecules are not made and CD4 cells cannot function
MHC Polymorphism
highly polymorphic can differ by 1-50 amino acids but substitutions are mainly in domains that bind peptide and interact with T cell receptor but not all contact residues are different
Peptide binding groove variations
determines the type of peptide that can bind but certain positions, most have the same or similar amino acid (anchor residue)
Peptide-binding motif
combinations of anchor residues that bind to a particular MHC isoform
MHC Restriction
antigen-specific T Cell response is restricted by the MHC type. The most diverse aa in MHC molecules is located in the surfaces that the TCR bind. So both the MHC type and antigen have to match the TCR for binding to occur.
MHC Diversity
driven by natural selection from pathogen infections. AA substitutions are concentrated at sites of peptide binding in a nonrandom way. Polymorphisms can provide different peptide-binding specificity
Heterozygote advantage
high degree of polymorphism of HLA isotypes ensures that most of the population are heterozygotes since they can more pathogens
balancing selection
processes that act to maintain a variety of MHC isoforms in a population where successive epidemics make homozygotes die
directional selection
during a specific, epidemic disease exposure, certain MHC isoforms are selected for
Generation of new MHC Alleles
quick rate of pathogen adaptation to MHC molecules, likely suggests rare MHC allels that have not been adapted for are selected for and new variants can form by point mutation, recombination, interallelic conversion
Interallelic Conversion
recombination in which segment of one allele has been replaced by a homologus section of another
HIV/AIDS
MHC heterozygosity has been shown to provide a selective advantage to AIDS progression in people infected with HIV
Autologous
how self-MHC isoforms are described
Allogenic
how foreign MHC isoforms are secribed
Alloreactive T Cells
In every individual, these T cells can respond to peptide and allogeneic MHC molecules from cells of other healthy individuals which is a problem for transpants
HLA Type
need to be similar or identical HLA alleles to avoid alloreaction
Alloantibodies
made during pregnancy from natural alloreaction if the mother’s immune system is stimulated by the HLA molecules n the fetus from the father. Not a danger to fetus but cna be a problem is mom need transpalnt in future.
The term used to describe the expressed protein of a certain gene is:
a. allele
b. allotype
c. haplotype
d. isotype
b. allotype
Foreign MHC molecules are referred to as
a. autologous
b. interallelic
c. allogenic
d. haplotypes
c. allogenic
Six Phases of B-Cell Development
Repertoire assembly (acquiring of functional immunoglobulins), negative selection, positive selection, circulation of mature B cells, B-Cell activation, B-Cell effector functions (stem cells make 60 billion new b cells a day)
B-Cell Development in Bone Marrow
pluripotent hematopoitic stem cells have DC34, give rise to common lymphoid progenitor cell (CD34 and CD10), B-Cell Precursor (CD34, CD10, CD127), pro-b-cells are begining of B cell lineage (CD34, CD10, CD127, CD19)
Pro-B-Cell Stage
rearrangement of the heavy-chains first occurs between D and J gene (early pro-b-cell stage) and then between V and the rearranged DJ (late pro-b-cell stage). Then transcription occurs through the u C-region gene making pre-b-cells
Pre-B-Cell Stages
Large pre-b-cell (not yet rearranging light chain) and small pre-b-cell (rearranging of light chain has begun)
Stromal Cells
stromal cells of the bone marrow provide a microenvironment for b-cell development by making specific contacts with developing B cells and produce growth factors that act on attached b cells (SCF and IL-7)
Nonproductive Rearrangement
when rearrangment of the heavy chain in pro-b-cell is imprecise and ineffecience so the addition of N and P nucleotides can change the reading frame. If this happens from both heavy chain loci then the b cell will die.
Productive Rearrangement
gives rise to function immunoglbulin chain from correct rearrangment of the heavy chain in pro-b-cells. Requires RAG1 and RAG2 which are activated by E2A and EBF trx factors
surrogate light chain
VpreB and gamma5 produced by the b cell to act as a temporary light chain to test the functionality of the pro-b-cell u heavy chain
Pre-B-Cell Receptor
in the ER the u heavy chain assembles with the surrogate light chain and Iga and Igb to make this. must be functional in order to transition to pre-b-cell stage
Allelic Exclusion
ensure only one functional immunoglobulin in made for strong interactions with multivalent antigens. how pre-b-cell receptor prevent more than 1 u chain. once one is made RAG gene trx stops, RAG degrades, chromatin remodles to prevent gene rearragment
Light Chain Rearrangment in Pre-B-Cells
large pre-b-cells divide into small pre-b-cells that don’t make b-cell receptor, RAG reactivate, rearragment of light happens one locus at a time between V and J, 4 loci (2 kappa 2 delta) 85% success, functional IgM shuts down further recombination.
Checkpoints of B Cell Development
make sure functional heavy/light since recombo ineffective.
1) formation of pre-b-cell receptor
2) formation of functional b-cell receptor.
If no pass, apoptosis.
What drives B Cell development?
Protein expression. RAG only active when rearrangement occurs. Tdt expressed during heavy chain rearrangment (why only 50% light chain genes have N nucleotide), Iga and Igb always expressed (important in allelic exclusion and functional IgM)
How does protein expression change for B cell development?
Transcription factors! Required for rearrangement of RAGs, E2A EBF, Pax-5 (binds enhancer regions to begin trascription)
B-Cell Tumors
Because there is lots of cutting, splicing, mutating DNA. Often from translocation of an immunoglobulin gene with a different chromosome
Typical B-Cell Tumor Translocation
between immunoglobulin and proto-oncogene (MYC on chrom 8 and BCL2) Ig on Chrom 14
CD5 Expression on B Cells
only on subset of B cells that arise during embryonic development and don’t go through these 6 phases of b cell development
B Cells with CD5
B-1 cells or called CD5 B Cells (CD5 usually on T cells)
Polyspecificty
allows antibodies produced by B-1 cells to be of lower affinity and thus binds multiple antigens that are typically specific to carbohydrate antigens
Adult B-1
maintain population of B-1 cells through division as no new ones are made in bone marrow
The surrogate light chain is made up of what two proteins?
a. VpreB and lambda5
b. CD34 and CD5
c. E2A and EBF
d. RAG-1 nad RAD-2
a. VpreB and lambda5
What is the main function of pro-b cell development
a. expression of CD5
b. heavy chain rearrangement
c. isotype switching
d. light chain rearrangement
b. heavy chain rearragement
Negative Selection of B Cells
repertoire assembly can make self reactive immunoglobulins that recognize self antigen and immature B cells are programmed to generate negative signals if bind to self antigen resulting in apoptosis or inactivation
Beginning of Negative Selection
begins in bone marrow where multivalent self-antigens present on stromal cells, hematopoiteic cells, and blood plasma macromolecules prevent B cells from leaving the bone marrow
B-Cell Receptor Editing
if immature B cell is multivalent self reactive IgM, IgM expression decreases while RAG continues to allow for further light chain rearrangment. If a new light chain occurs, it can assemble with the old heavy chain to hopefully make new, functional immunoglobulin. Then can leave bone.
Clonal Detection
cell death by apoptosis if new light chains cannot rearrancge with nonfunctional heavy chains to make a good immunoglobulin in B cell
B-Cell Anergy
inactivation of immature b cells with monovalent self-reactive IgM (doesn’t go through editing or apoptosis).
Anergenic B Cells
make IgD and IgM but the IgM cannot assemble on cell surface and the IgD receptors don’t signal activation upon antigen binding. will circulate blood for 1-5 days (normal 40 day half life)
Central Tolerance
Three ways B cells can become self-tolerant - receptor editig, death of multivalent self-reactive B cells by apoptosis, anergy of monovalent self-reactive B cells
Peripheral Tolerance
Because not all self antigen is in bone marrow, b cells can also die by apoptosis or become anergic if they encounter self antigens in peripheral tissues
Autoimmune Response
Caused by B cells that react to self antigens that are inaccessible to B cells (intracellular molecules)
B Cell Maturation General
1) immature B cells produce high levels of IgM and low levels of IgD but that flops when mature
2) maturation requires immature b cells to migrate to secondary lypohid tissues
3) in lymphoid tissue, chemokines are secreted by stromal cells (CCL21) and dendritic cells (CCL19) to attract B cells
4) B cells migrate to primary lymphoid follicle that contains dendritic follicular cells (CXCL13)
5) in primary follicle, maturation of B cells occurs to produce naive B cells (not yet exposed to antigen)
B Cell Differentiation
1) B cell encourters antigen keeps the b cell in the t-cell area of the lymphoid tissue to become activated by CD4 T Cells
2) B cell activation causes proliferation and some plasma cell differentiation (antibodies)
3) other activated b cells move to germinal cells to mature into centrocytes
4) centrocytes can migrate to other lymphoid tissue or marrow to become plasma cell (isotype switched antibodies)
5) come germinal center B cells will develop into memory b cells (isotype switch antibodies)
centrocytes
dividing B cells that have undergone isotype switching and somatic hypermutation)
B Cell Tumor Origin
every cell has an identical rearranged immunoglobulin so they divide from same ancestral cell, but tumors from different patients have different immunoglobulins
B Cell Tumors and Development
Tumors corresponding to all stages of b cell development have been described and their location at defined sites in lymphoid tissue is maintained
follicular center cell lymphoma
grow in follicles of lymph nodes
myeloma
grow in bown marrow
hodgkin’s disease
germinal center b cell origin
The genetif recombination of immunoglobulins that produces a monovalent self-reactiv IgM causes what mechanism to be activated:
a. receptor editing
b. anergy
c. apoptosis
d. clonal deletion
b. anergy
centrocytes are dividing B cells that:
a. immeduately produce soluble IgM and IgD antibodies
b. function as memory cells in a secondary immune response
c. are self-reactive and need to be inactivated through anergy
d. produce antibodies that have matured through isotype switching and somatic hypermutation
d
T Cell Precursor
what a:b and g:d T cells develop from in the thymus
Thymocytes
immature T cells - develop among epithelial cells known as the thymic stroma
Thymus Development
Fully developed before birth and starts to degrade at 1 years old but this nor a thymectomy grossly affects T Cell immunity because repertoire of T cells is long lived and or self-renewing
Thymocyte development
progenitor cells that enter thymus not yet committed, needs interaction with thymic stromal cells to cause division and differentiation. After 1 week prodenitors express CD2 and are committed thymocytes
Double-negative (DN) thymocytes
thymocytes that express CD2 and are committed to becoming T cells, but do not express TCR or a co-receptor
Notch 1
cell-surface receptor on thymocytes that interacts with thransmembrane ligands on thymic epithelial cells and keeps thymocytes on road to T cell
Notch 1 Activity
it is inactive when bound to membrane, binding of the extracellular domain causes cleavage, release of intracellular domain, which acts as trascription factor in nucleus.
T Cell Lineages
either a:b or g:d and happens through complex process where b,g,d all start to rearrange at the same time and there is a competition.
Double-positive (DP) thymocytes
occurs when functional b is made first and incorporated into a pre-t-cell receptor and rearrangment stops so both co-receptors are expressed. Race between g, d, and a begins.
pTalpha
The surrogate chain to test if productive or nonproductive rearrangment of b chain happened.
if g:d t cell rearranges frist
the g:d dimer forms and assembles with CD3 to form a functional receptor and b chain rearrangement stops
productive b chain in T-cell
if b can bind to pTalpha, it complexes with CD3 and zeta to form pre-t-cell-receptor which acts as superdimer)
superdimer
both a receptor and ligand
Pre-T Cell
thymocytes that make functional pre-t-cell receptor that is a superdimer that activates signals to move through checkpoint
rearrangement of alpha chian gene
pre-T-cell receptor stops rearrangement by suppressing RAG, allelic exlusion at the b chain locus, pre-t cell proliferates and expressed CD4 and CD8 makeing DP Thymocytes, large DP proliferate into small DP, rearrangment reactivates to target a, g, d. alpha chain has multiple attmepts.
Delta Locus
situated in the middle of the alpha locus, will be deleted after alpha chain rearrangement thus stopping g:d rearrangment
Gene expression during T Cell Development
First part of a:b development includes CD4, CD8, T-cell receptor. RAGs only expressed during b and a rearrangments.
ZAP-70 and Lck
important signaling molecules that are expressed for most of T cell development
Trascription factors in T cell development
Ikaros and GATA-3 which are expressed through whole development. Th-POK is needed fo rCD4 T Cell development and is activated later.
