Term
| Define polygenic in relation to MHC |
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Definition
| Each class of MHC molecules has several genes |
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Term
| Define polymorphic in relation to MHC |
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Definition
| Each gene has many variants |
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Term
| Why would MHC molecules be polygenic and polymorphic? |
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Definition
| Results in high genetic variability at both the level of individual and species |
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Term
| MHC class 1 molecules present peptides derived from ______ molecules |
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Definition
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Term
| MHC class 2 molecules present peptides generated in ______ |
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Definition
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Term
| Define Antigen Processing |
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Definition
| Generation of antigenic peptides from intact molecules for presentation by MHC |
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Term
| Where are the two intracellular locations that pathogens can reside? |
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Definition
| cytosol or vesicular system/endocytic system |
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Term
| Describe MHC class 1 antigen presentation |
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Definition
1) virus infects cell
2) viral proteins synthesized in cytoplasm
3) peptide fragments of viral proteins bound by MHC class 1 in ER
4) Bound peptides transported by MHC class 1 to cell surface
5) Cytotoxic T cell recognizes complex of viral peptides with MHC class 1 and kills infected cell |
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Term
| Describe the two forms of proteosomes and their function |
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Definition
Constitutive form: found in all cell types
Immunoproteosome form: found in cells that have been stimulated by interferons
degrade cytosolic proteins
composed of 28 protein subunits, shaped like a hollow tube with inner core lined with proeolytic activity |
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Term
| What are the three subunits of the immunoproteosome? What happens with these? |
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Definition
LMP2, LMP7, MECL-1
These subunits displace the corresponding constitutive proteosome subunits following interferon stimulation
Changes specificity of proteolytic activity, increased cleavage of peptides after hydrophobic amino acids
These peptides now have an increased affinity for class 1 |
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Term
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Definition
Induces a proteosome activating complex (PA28) that binds to ends of proteosome
opens up the ends to allow increased rate of peptide generation |
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Term
| Heat Shock proteins related to proteosome |
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Definition
| hsp70, 90, 110 bind proteosome generated peptides and transport to tap complex |
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Term
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Definition
ATP-Binding Cassette proteins.
transport peptides, amino acids, etc across membranes in an ATP-dependent process |
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Term
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Definition
Transporters associated with Antigen Processing 1 and 2
forms a heterodimer with 4 domains
ATP binding domains lie on cytosolic side, hydrophobic domains on ER side
Transports 8-16 aa long peptides |
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Term
| What upregulates TAP genes? |
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Definition
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Term
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Definition
| chaperone protein. binds to a-chain, maintains a partially folded conformation |
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Term
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Definition
| Upon binding of B2-m subunit to the a-chain, calnexin disassociates. |
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Term
| What constitutes the MHC class 1 loading complex? |
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Definition
Calreticulin
Tapasin
ERP57
TAP1 and TAP2 |
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Term
| What happens once the proteosome complex degrades the cytosolic proteins? |
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Definition
| TAP transfers the peptides into ER, then assists in binding the Class 1 molecule. The class 1 heterodimer disassociates from MHC class 1 loading complex, and leaves ER for cell surface |
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Term
| What must happen in order for a class 1 molecule to be transported to cell surface? |
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Definition
| it MUST bind peptide to form a stable structure |
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Term
| What happens if the peptide chunks produced by the proteosome are too large to bind to MHC? |
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Definition
| They are further degrades by ER-specific aminopeptidases (endoplasmic reticulum aminopeptidase associated with antigen processing - ERAAP) |
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Term
| What proteins are crucial for MHC 1 expression? |
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Definition
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Term
| What proteins are super helpful for MHC 1 expression? |
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Definition
| calreticulin, ERp57, tapasin, ERAAP. |
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Term
| Name three viruses that avoid CD8 T-cell detection. How? |
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Definition
HSV - protein that inhibits TAP function
Adenoviruses - protein that prevents mhc1 from leaving ER
cytomegaloviruses - accelerate recycling of class 1 proteins from ER back into cytosol |
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Term
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Definition
| fusion of phagosome with lysosomes that contain anti-microbial compounds |
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Term
| Upon cellular activation, what happens to intracellular vesicles? |
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Definition
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Term
| What is activated at low pH? |
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Definition
| Acid proteases in lysosomes that result in degradation of pathogen proteins into peptides |
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Term
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Definition
| Family of cystein proteases found in lysosomes |
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Term
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Definition
IFNgamma induced lysosomal thiol reductase
Reduces disulfide bonds before they are digested by proteases |
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Term
| How do we protect the MHC class 2 molecules from stealing all the petides from MHC class 1 in the ER? |
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Definition
| Binding is blocked by protein termed MHC Class-2 associated invariant chain. it forms a trimer and non-covalently attaches with 3 class 2 heterodimer complexes |
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Term
| What are the 2 functions of the MHC Class -2 associated invariant chain? |
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Definition
1) to block class 2 peptide-binding site
2) to target the complex to low-pH endosomes for eventual peptide loading |
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Term
| What happens to the invariant chain in an acidic environment? |
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Definition
| It is cleaved into smaller fragments by Cathepsin S |
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Term
| What is left after Cathepsin S cleaves the invariant chain? |
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Definition
| A short li fragment termed CLIP (Class 2-associated invariant chain peptide) bound to peptide-binding groove |
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Term
| What is the function of HLA-DM/H-2M? |
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Definition
Displaces the CLIP peptide.
Similar to MHC2 in the sense of alpha and beta chains, but it is not associated with the surface and there is no peptide-loading groove.
(like a clothespin glued shut) |
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Term
| What increases expression of HLA-DM? |
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Definition
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Term
| What edits peptides in the groove of MHC2 before it is released? |
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Definition
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Term
| What types of cells present MHC class 1? |
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Definition
| T-cells, B-cells, Macrophages, other antigen-presenting cells, neutrophils |
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Term
| What types of cells present MHC class 2? |
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Definition
| B Cells, Other antigen presenting cells, epithelial cells of the thymus, and sorta macrophages |
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Term
| Explain how cross-presentation works |
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Definition
| Infected cells and viral antigens are picked up by host APCs |
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Term
| Phagosome to cytosol pathway |
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Definition
Particulate Ag is internalized into phagosomes
Phagosomes fuse with the ER and acquire Ag-presentation machinery (Tap, tapasin, class 1 molecules, and sec61 translocon)
Some of ther internalized Ag is transferred from the phagosome to the cytosol
Ag is cleaved by proteasomes associated with the phagosome membrane some of the resulting peptides are transferred back into the phagosome by TAP
peptide loaded onto class 1 |
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Term
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Definition
In some situations, the internalized Ag may also be cleaved into peptide by proteases in the phagosome
Tapasin may help load these peptides onto class 1 molecules, which are then transported to the cell surface |
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Term
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Definition
MHC class 1 like molecules encoded outside of MHC loci
Behaves more like class 2 molecules
-not retained in ER, not dependent on TAP
-targeted to vesicles for ligand binding
-binds glycolipids derived from extracellular pathogens/proteins that have been degraded in acidified endosomes/lysozomes |
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Term
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Definition
In the ER, CD! forms a complex with calnexin, calreticulin, Erp57; associates with B2M and endogenous lipids
From the plasma membrane, CD1 recycles to different endocytic compartments where it can acquire self-lipid Ags or microbial Ags
In lysosomes, the formation of CD1-Ag complexes involves saposins that associate with the lysosomal membrane and CD1
Following the acquisition of lipids, CD1 traffics to the plasma membrane; lipid Ag recognized by CD1-restricted T cells |
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Term
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Definition
Chaperones that facilitate contact between lipid Ags and CD1
disintegrate lipid membranes the that the glycolipids are available for loading onto CD1 |
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Term
| MHC class 1 genes include... |
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Definition
| 3 alpha chains in man (HLA-A, B, C) |
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Term
| MHC Class 2 genes include... |
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Definition
3 pairs of alpha and beta chain genes (HLA-DR, DP, DQ)
TAP1 and TAP2: involved with transport of cytosolic peptides into ER for class 1 loading
LMP genes: encode components of the proteosome, upregulated by IFNgamma
tapasin: binds partially folded class 1 molecule with TAP complex in ER |
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Term
| Explain the unique HLA-DP (or DQ or DR) combos |
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Definition
Functions like peas.
P: a1b1xa2b2
F1: a1b1, a2b1, a1b2, a2b2 |
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Term
| What is an MHC haplotype? |
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Definition
| the particular combination of MHC alleles found on one chromosome |
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Term
| How is the expression of MHC alleles co-dominant? |
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Definition
| Heterozygous individuals express 6 different class 1 molecules and 6-12 separate class 2 molecules |
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Term
| Where is the genetic variability of MHC concentrated? |
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Definition
the aminoterminal domains of class 1 and class 2.
Restricted to sites lining the peptide-binding groove (floor and wals of groove) |
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Term
| How does IFN alpha/beta increase class 1-mediated Ag presentation?> |
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Definition
| by upregulating gene expression of class 1 alpha chain, beta2-m, TAP1 and 2, LMP genes, tapasin |
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Term
| How does IFN alpha/beta increase class 2-mediated Ag presentation?> |
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Definition
| Upregulates genes involved in class 2 Ag presentation, including class 2 alpha and beta genes, invariant chain, HLA-DM/H-2M |
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Term
| What activates MHC transcription? |
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Definition
| MHC Class 2 TransActivator (CIITA) |
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Term
| What happens with CIITA deficiency? |
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Definition
MHC Class 2 deficiency
autosomal recessive inheritance
patients present with mild form of severe combined immunodeficiency |
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Term
| TCR-MHC-peptide interaction |
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Definition
TCR binds to MHC-peptide compelx via interaction of complentarity determining regions and both the peptide bound in the groove AND the MHC alpha 1 and alpha2 domains themselves
Specificity of T-cell recognition involves both the peptide and the MHC molecule
Single aa changes in either peptide or MHC can completely inhibit t-cell recognition |
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Term
| What defines t-cell receptor specficity? |
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Definition
| both the MHC molecule and the specific peptide bound to it |
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Term
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Definition
the ability of T-cells to react with allegeneic (non-self) MHC molecules containing non-self peptides
1-10% of T-cells react with MHC alloantigens |
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Term
| Alloreactivity represents a ______ of T-cells |
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Definition
| cross-reactivity. normally specific for foreign peptides presented by self-MHC molecules |
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Term
| What are the two models to explain alloreactivity |
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Definition
1) Peptide-dominant binding
-peptide in non-self MHC interacts strongly with T-cell receptor allowing binding even if the allo-MHC molecule is not a good "fit"
2)MHC dominant binding
-allogeneic MHC molecule provides a good fit for TCR, allowing tight binding in the absence of peptide recognition |
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Term
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Definition
INTACT bacterial or viral proteins that bind to MHC class 2 molecules outside of the peptide-binding groove AND bind the the lateral face of certain VB chain (CDR2 loop) TCR subsets
Forms a bridge between MHC class 2 and the TCR of a CD4 t-cell, results in t-cell activation and differentiation into effector cells
does NOT prime an adaptive immune response that is specific for the pathogen |
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Term
| List some diseases that cause a superantigen response? |
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Definition
| TSS, staphylococcal food poisoning, streptococcal tss, scarley fever, Mycoplasma arthritidis, Clostridium perfringens |
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Term
| Superantigen activation results in: |
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Definition
excessive polyclonal CD4 t-cell activation
massice secretion of CD4 t-cell cytokines
systemic shock
suppression of adaptive immune response |
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Term
| What is humoral immunity essentially? |
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Definition
provides protection to extracelllar spaces in body
activation and differentiation of naive b-cells requires both specific antigen and helper t-cells
helper t-cells are involved in initiating somatic hypermutation and isotype switching |
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Term
| What are the three major mechanisms of humoral immunity? |
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Definition
1. Neutralization: antibodies bind pathogen or toxin and inhibit binding to cell surfaces
2. Opsonization: coat pathogen to allow recognition by Fc receptor-bearing phagocytes
3. Complement activation: antibody bound to pathogen activates complement, results in coating by complement fragments recognized by complement receptors on phagocytes |
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Term
| What are the two important roles that the B-cell receptor serves for b-cell activation? |
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Definition
1. Recognition of specific Ag and signaling into cell upon ligation by Ag
2. BCR ligation/internalization delivers Ag to class 2 peptide pathway |
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Term
| What are the two signals required for b-cell activation? |
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Definition
1. delivered by BCR ligation
2. thymus dependent antigens: delivered by activated CD4 T-cell recognition of MHC class 2 bound peptide; signal strengthened by T-cell CD40L interaction with B=cell CD40
thymus independent antigens: delivered by extensive cross-linking of BCR by antigen OR by ligation of an innate immune receptor |
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Term
| Do thymus independent-1 Ags require T-cell help for B-cell activation? |
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Definition
no, have ability to directly induce b-cell activation, require high concentrations for activity
activate large numbers of B-cells INDEPENDENT of BCR specificity; polyclonal activation producing only IgM; termed B-cell mitogens
poor inducers of affinity maturation or memory B-cells
can stimulate immature and mature B-cells |
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Term
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Definition
Repetitive structures capable of cross-linking BCR
extensive BCR cross-linking overrides need for additional signaling
B-1 B-cells respond to TI-2 Ags
Ab production in response to TI-2 Ag enhanced by DC-derived cytokines
induce IgM and IgG antibodies specific for polysaccharide Ag
little/no somatic hypermutation |
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Term
| What are the three ways that TI 1 and 2 Ags differ? |
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Definition
1. TI-2 Ags do not act as B-cell mitogens, no polyclonal activation
2. TI-2Ags activate mature B-cells, induce anergy in immature B-cells; TI-1 activates both
3. Ti-2 Ags do not absolutely require DC derived cytokines, however these cytokines are required for efficient b-cell proliferation/isotype switching |
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Term
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Definition
T- and B- cells specific for same antigen
Recognition of B-cell class 2 ag-peptide by ACTIVATED CD4+ effector T-cell upregulates CD40L expression on t-cell and induces secretion of class-switching inducing cytokines |
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Term
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Definition
| t-cell dependent antibody responses require activation of B-cells by t-cells that are responding to the same Ag as B-cell |
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