I2: Adaptive Immunity

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antigen

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reacts with an antibody or T cell

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antigens react by

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antigenic determinants or epitopes
most are macromolecules or are capable of binding to them

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immunogen

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ability to induce an immune response

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the larger the protein and the greater the complexity =

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larger the immunogenic character

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hapten

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reacts with antibodies but do not induce their production
lack immunogenicity
have low MW

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how are anti-hapten antibodies produced

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hapten-carrier complexes/conjugates

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an example fo anti-hapten antibodies

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conjugate vaccines

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features of antigens that react Ab or BCR

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require native confromation
surface exposed/charged epitopes

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features of antigens that react with T cells

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must be succeptible to antigen processing and presentation
usually proteins
convert to short peptides by APC
conformation is less important and do not need to be surface exposed

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most Igs migrate as

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gammaglobulins on electrophoresis

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antibody functions

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serve as antigen receptors on B cells
antigen clearance and opsonophagocytosis
provide specificity to allergy
activate complement by the classical pathway

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J chain

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polypeptide that links the dimers of IgA together and the pentamers of IgM

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secretory component

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immune portion of receptor
protects the immunoglobin from enzyme
facilitates the IgA sticking to epithelia

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IgA function

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found in mucosal areas- gut, respiratory tract, urogenital tract
prevents colonization by pathogens
found in saliva, tears, breast milk

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IgD function

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antigen receptor on B cells that have not been exposed to antigens
activates basophils and mast cells

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IgG function

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PRovides the majority of antibody-based immunity against invading pathogens
only antibody capable of crossing placenta

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IgM location

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Expressed on the surface of B cells

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IgM function

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eliminates pathogens in the early stages of B cell mediated immunity before there is sufficient IgG

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natural antibody

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antibody that is present at birth
induced by carb. antigens of microbial flora
low titer and affinity

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isohemagglutinin

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develop naturally
IgM
Form as a child
reactive of cells of human- agglutinate

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idiotype

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markers associated with the variable regions
distinguish the combining sites of different Abs

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allotypes

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inherited markers, single amino acid substitutions, distinguish different individuals

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classical complement pathway is activated by

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IgM or IgG Ab binding to Ag, C1q binding to 2 adj. Fc regions and C1qr2s2 assembled and activated

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monoclonal gammopathy

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abundance of monoclonal antibodies produced
non-malignant

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myeloma proteins

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monoclonal antibody fragment

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Bence-Jones proteins

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often seen in human disease
excess light chain synthesis
dimeric
precipitate on heating

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hybridoma technology

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monospecificity for Ag of interest
produce antibodies

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how to produce antibodies in hybridoma technolog

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immunize a mouse with desired Ag
Recover immune splenic B cells
Fuse B cells with an immortal myeloma cell ine
Screen the cell hybrids and grow in vitro
return the hybridoma cells to the mouse for high level Ab production

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T cell precursor migrates to the

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thymus

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TCR-B genes are

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rearranged

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the first molecule that is expressed is

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pre-TCR

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Once pre-TCR is expressed

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there is positive selection

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the next step is

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TCR-alpha gene rearrangement and expression of TCR

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After TCR alpha expression

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positive and negative selection

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once alpha and beta TCR segments are expressed

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CD4/CD8 lineage is committed

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Double negative thymocytes

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Pre-TCR

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double positive thymocytes

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CD4 and CD8 is expressed and positive and negative selection occur

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Single positive thymocytes

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either CD4 or CD8 expressed

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positive selection triggers

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cell becomes permissive for TCR-alpha chain locus rearrangement
expression of CD4 and CD8
proliferation
stops additional TCR beta locus arrangements

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Only thymocytes that ______ can be positively selected

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can bind MHC-peptide complexes

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cells that fail to bind MHC-peptide complexes

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under apoptosis

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if the CD4+8+ recognizes MHC class I then it is____
If it recognizes MHC class II then it is ____

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CD8+
CD4+

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Different individuals express

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different MHC

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mature T cells bear receptors that are

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restricted only to the self MHC of the individual host

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Three outcomes of DP stage of development

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TCR can bind MHC-peptide in thymus strongly
TCR doesnt bind MHC peptide cmoplexes
TCR binds with weak affinity

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three receptor-mediated signals that induce optimal activation of T cells by antigens

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TCR activation
Co-receptor activation
Cytokine-mediated activation

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cytokine-mediated activation is usually

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autocrine signaling

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CD4 binds

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MHC class II

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CD8 binds

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MHC class I

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CD28 binds

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B7 family members

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macrophages method of Ag uptake

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phagocytosis

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macrophages MHC ii expression is

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inducible

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B7 coreceptor in macrophages is

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inducible

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Macrophages activates____ t cells

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effector and memory T cells

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B cells take up antigens by ____ and their MHC ii expression is ____

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BCR-mediated phagocytosis
constitutive

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B cells B7 coreceptor are

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inducible

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B cells activate ____ T cells

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naive, effector and memory

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Dendritic uptake antigens by _____ and MHCii expression is ____

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pinocytosis
constitutive

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dendritic cells affect _____ t cells

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naive, effector, memory

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regulatory T cells function to

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inhibit immune responses

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reg. T cells express

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CD25 and FoxP3

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Reg T cells secrete____ which______

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IL-10 and TGF-beta which inhibits lymphocytes and macrophage activation

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reg t cells maintain

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peripheral tolerance

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cytotoxic T cells express

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CD3

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cytokines produced by cytotoxic T cells

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IFN-gamma

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CTL kill by

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perforin/granzyme, fas/fas ligand or TNF-mediated mechanisms

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NKT cells bear

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NK cell markers

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NK cells are specific for

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glycolipids + CD1

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NKT cells express

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invarient TCRa chain

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NKT cells kill by

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perforin/granzyme, fas/fas ligand, TNF-mediated mechanisms

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Th1 cells release what cytokines

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IFN gamma and TNF alpha

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Th1 cells promote

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lylmphocyte growth

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cells affected by Th1 cells

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macrophages, Tc cells
cell-mediated

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Th2 cells release what cytokines

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IL-4, IL-5, IL-13

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Th2 cells promote

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lymphocyte growth

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Th2 affects

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B cells- humoral immunity

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NK cells are not

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T cells

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NK cells kill how

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rapidly without proliferation

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NK cell kill by

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perforin/granzyme, Fas/Fasligand or TNF-mediated mechanisms

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NK cells recognize

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targets that lack MHC class I they recognize "missing self"

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Cytokines produced by NK cells

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IFN gamma

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NK cells are regulated by

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activating and inhibitory receptors

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activating receptors recognize

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a variety of ligands on target cells

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inhibitory receptors recognize

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non-polymorphic residues on MHC class I

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the ____ is dominant over ___

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inhibitory over active

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Loss of MHC I on a target cell releases

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inhibitory signal and permits NK cell activation

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IL-17 produced by and causes

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Th17 cells that causes intestine inflammation

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in B cells, ________ are the first chains to undergo rearrangement

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IgH chains

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after IgH rearrangement, ____ is expressed

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pre-BCR

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Pre-BCR undergoes_____

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positive selection

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after pre-BCRs have been positively selected, _____ occurs

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IgL chain gene rearrangement and expression of the BCR

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Immature B cells

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exit from bone marrow

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maturation of B cells occur in

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the periphery

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in the beginning of B cell expression ____ is expressed

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mIgM and mIgD co-expression

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after mIgM and mIgD co-expression ____occurs

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positive and negative selection

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once the B cells are in the periphery they

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are antigen dependent and before they are antigen independent

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B cells eventually mature into

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plasma cells or memory cells

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Ig undergo

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class switching, V region hypermutation and selection, antibody affinity maturation

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negative selection

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deletes autoreactive cells or induces BCR editing

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BCR editing process

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autospecific B cell undergoes a k/l locus rearrangement until they are positively selected or DNA runs out

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most immature B cells

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die

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B cell-Th cell contact

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TCR-MHC II

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co-receptors of B cell- Th cell contact

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B7, CD40

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Th cell derived cytokines that help activate B cells

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Il-2,4,5,6

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the introduction of ______ increases antibody affinity

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point mutations into V regions of Ab genes

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cells undergoing somatic hypermutation are selected under ______

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conditions of decreasing Ag concentrations because affinity is greater- more will bind stronger

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increased affinity =
decreased affinity =

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positive selection
negative selection

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CR2 co-receptor recognizes

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C3D-antigen complexes

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CR2 receptor has ____ activity

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associated Src kinase

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Factor I

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cleaves and inactivates C3b and C4b to iC3b, iC4b
also cleaves iC3b to form C3d which activates CR2

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NF-kB is

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transcription factor regulated by localization

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NF-kB is bound to

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inhibitor, IkB

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NF-kB nuclear translocation occurs because

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IkB is phosphorylated and degraded

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NF-AT is a

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transcription factor regulated by localization

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____ causes NF-AT to be dephosphorylated

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calcineurin

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dephosphorylated NF-AT can then

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translocate to the nucleus

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IL-2 causes___ in b cells

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b cell growth and higher IL-4R on B cells

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IL-4 causes ____ in B cells

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switching from IgM to IgG and IgE

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IL-5 causes___ in b cells

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switching to IgA

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IL-6 causes

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differentiation into plasma cells

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TGF-B1 causes ___ in b cells

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switching to IgA

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IL-13 causes ______ in b cells

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switching to IgE

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T cell independent antigen example

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polysaccharide with identical repeating determinants

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T cell independent antigens _____

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do not induce class switching

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Some T independent antigens can bind

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additional receptors (LPS binds TLR4)

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T-cell independent antigens have ___

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little somatic hypermutation and no memory

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HiB PS vaccine is an ____

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T-independent vaccine of capsular polysaccharide- low affinity antibody and poor memory

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HiB DT vaccine

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T-dependent vaccine of PS covalently linked to DT higher affinity Ab and memory B cells

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mucosal antibody responses

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external secretions of GI, polmonary, GU, salivary, mammary

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structure of secretory antibodies

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Dimeric IgA + J + Secretory Component

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Dimeric IgA is processed by

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epithelial cells to make secretory IgA

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epithelial cells have a poly Ig receptor that binds

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IgM and IgA

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specific examples of superantigens

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staphylococcus
streptococcus
mycoplasma
epstein barr virus
rabies virus

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ITAM phosphorylated by

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Lck

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Lck phosphorylates

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ITAM

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ZAP-70

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recruited by ITAM that's phosphorylated and acts as a protein tyrosine kinase

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PLCgamma

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cleaves into DAG and IP3

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PKC

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activated by DAG and phosphorylates IkK which normally inhibits NF-kB

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NF-kB

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activates IL-2, IFN-gamma, TNFa production

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NF-kB is a

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transcription factor

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Calcineurin

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dephosphorylates/activates NF-AT

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NF-AT

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activates IL-2, IL-4, IFN-gamma, TNFa production

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NF-AT is a

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transcription factor

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MAP kinase activates

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AP-1

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AP-1

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activates production of IL-2

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cyclosporine

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inhibits calcineurin and therefore inactivates T cells

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Th1 cells produce

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IFNgamma and TNF alpha

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Th1 cells promote

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cell-mediated immunity: macrophages, increase in MHC class II production and increase phagocytosis and killing

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Th2 cells produce

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IL-4,5,13 which are cytokines that produce antibodies

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toxic shock syndrome results from

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polyclonal activation of T cells by a superantigen
massive cytokine release which activates macrophages and endothelial cells to produce inflammatory mediators- shock!