seminar immunity 07 arid 1657

8/14/2019 Seminar Immunity 07 Arid 1657

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CELLLULAR ANDCELLLULAR ANDMOLECULAR BASIS OFMOLECULAR BASIS OF

IMMUNITYIMMUNITY

MUHAMMAD JUNAIDMUHAMMAD JUNAID

07-Arid-165707-Arid-1657


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Structure Of AntibodiesStructure Of Antibodies

Antibodies are proteins produced by B cell andAntibodies are proteins produced by B cell and

plasma cells.plasma cells.

B cell incorporate antibody molecule into theirB cell incorporate antibody molecule into their plasma membrane where they serve as antigen plasma membrane where they serve as antigen

receptor.receptor.

Where as plasma cells secrete these proteins intoWhere as plasma cells secrete these proteins into

blood and other body fluids.blood and other body fluids.

Contd


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Structure Of AntibodiesStructure Of Antibodies

Antibodies are globular proteins called

immunoglobulins.

These are built of two types of chains.A larger heavy chains (50,000-70,000 daltons)

And a smaller light chains (23,000 daltons)

These are linked by disulfide bond.


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Antibody StructureAntibody Structure

Domains comprising a constant region are indicated

by C.

Domains comprising the variable are V.

Each heavy chains contain three C regions (C 1 , C

2, C 3) one V regions and N-terminus of polypeptide.

Each light chains contain one C L regions one V

regions at its N terminus.

The V regions forms the antigen combining site.


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Variation In The AntibodyVariation In The Antibody

Half of each light chains has a variable region V.Half of each light chains has a variable region V.

One quarter of each heavy chain is variable V.One quarter of each heavy chain is variable V.

The remaining three regions are constant .The remaining three regions are constant .

The variable portion of light and heavy chainsThe variable portion of light and heavy chainscontain subregions calledcontain subregions called hypervariable regionshypervariable regions..

Hypervariable regions play a prominent role inHypervariable regions play a prominent role in

forming antigen combining site.forming antigen combining site. Variation in amino acid sequence of these regionsVariation in amino acid sequence of these regions

result in great diversity of antibody specificity.result in great diversity of antibody specificity.

Contd


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Variation In The AntibodyVariation In The Antibody

The combining site has a complementary portionThe combining site has a complementary portionof the antigen which is called epitope.of the antigen which is called epitope.

Because of their close fit ,antibodies and antigenBecause of their close fit ,antibodies and antigen

forms stable complexesforms stable complexes


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DNA Rearrangement Of GenesDNA Rearrangement Of Genes

Encoding B-and T- Cell AntigenEncoding B-and T- Cell Antigen

ReceptorsReceptors Each Ig molecule consist of light and heavyEach Ig molecule consist of light and heavy

chains.chains.

Both have a variable portions V.Both have a variable portions V.

Whose amino sequence varies from one antibodyWhose amino sequence varies from one antibody

to another.to another.

The constant region C remain the same in bothThe constant region C remain the same in both

classes.classes.


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What is the genetic basis for theWhat is the genetic basis for the

synthesis of polypeptide having asynthesis of polypeptide having a

combination of share and uniquecombination of share and unique

amino acid sequences?amino acid sequences?


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One gene one polypeptide hypothesisOne gene one polypeptide hypothesis

In 1965 William Dreyer and J Claude gaveIn 1965 William Dreyer and J Claude gave oneone

gene one polypeptidegene one polypeptide hypothesis.hypothesis.

They proposed that each antibody is encoded byThey proposed that each antibody is encoded bytwo separate genes C gene and V gene. Thattwo separate genes C gene and V gene. That

combine to form one gene.combine to form one gene.

In 1976 Susumu Tonegawa provided evidence inIn 1976 Susumu Tonegawa provided evidence infavour of DNA rearrangementfavour of DNA rearrangement..


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DNA rearrangement lead to theDNA rearrangement lead to the

formation of a functional gene thatformation of a functional gene thatencodes an immunoglobulin chainencodes an immunoglobulin chain


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Mechanism of rearrangementMechanism of rearrangement

The variable region of each immunoglobulin heavy orThe variable region of each immunoglobulin heavy orlight chain is encoded in several pieces known as genelight chain is encoded in several pieces known as gene

segments.segments.

These segments are called variable (V), diversity (D)These segments are called variable (V), diversity (D)

and joining (J) segments.and joining (J) segments.

V, D and J segments are found in Ig heavy chains, butV, D and J segments are found in Ig heavy chains, but

only V and J segments are found in Ig light chain.only V and J segments are found in Ig light chain.

Developing B cell will assemble an immunoglobulinDeveloping B cell will assemble an immunoglobulinvariable region by randomly selecting and combiningvariable region by randomly selecting and combining

one V, one D and one J gene segmentone V, one D and one J gene segment

Contd


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Mechanism of rearrangementMechanism of rearrangement

As there are multiple copies of each type of geneAs there are multiple copies of each type of genesegmentsegment

Different combinations of gene segments can beDifferent combinations of gene segments can be

used to generate each immunoglobulin variableused to generate each immunoglobulin variableregionregion

This process generates a huge number ofThis process generates a huge number of

antibodies, each with differentantibodies, each with differentparatopesparatopes andandthus different antigen specificities.thus different antigen specificities.


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Class switchingClass switching

Once a cell is committed to form a specific antibody it canOnce a cell is committed to form a specific antibody it can

switch the class of Ig it produces. By changing the heavyswitch the class of Ig it produces. By changing the heavychain in the cell.chain in the cell.

This is known as class switch. Occurs without changingThis is known as class switch. Occurs without changing

the combining site of antibody synthesized.the combining site of antibody synthesized. Class switching allows different daughter cells from theClass switching allows different daughter cells from the

same activated B cell to produce antibodies of differensame activated B cell to produce antibodies of different

isotypes.isotypes.

Thus the progeny of a single B cell can produceThus the progeny of a single B cell can produce

antibodies, all specific for the same antigen.antibodies, all specific for the same antigen.

It is initiated by cytokines secreted by T cells. During BIt is initiated by cytokines secreted by T cells. During B

cell interactions.cell interactions.


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Membrane Bound Antigen ReceptorMembrane Bound Antigen Receptor

ComplexesComplexes

The recognition of antigen of B and T cell occursThe recognition of antigen of B and T cell occursat cell surface.at cell surface.

B cell receptor combine epitope.B cell receptor combine epitope.

T cell receptor combine with a fragment ofT cell receptor combine with a fragment ofantigen.antigen.

Both receptor are involved in signalling pathway.Both receptor are involved in signalling pathway.Which activate both the cells.Which activate both the cells.


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Pathway of activation of TCRPathway of activation of TCR

TCR is phosphorylated by src Family ofTCR is phosphorylated by src Family ofLck & FynLck & Fyn

Which recruit zap-70. to TCR.Which recruit zap-70. to TCR.

Map kinase cascade is initiated.Map kinase cascade is initiated.The CD45 protein tyrosine phosphatesThe CD45 protein tyrosine phosphates

activates Lck and Fyn required for TCRactivates Lck and Fyn required for TCRactivation.activation.


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Pathway Of Activation Of BCRPathway Of Activation Of BCR

Reversible tyrosine phosphorylation plays anReversible tyrosine phosphorylation plays animportant role in regulating B cell.important role in regulating B cell.

Antigen binding promotes protein tyrosineAntigen binding promotes protein tyrosinekinase.kinase.

Phosphorylation increases.Phosphorylation increases. Src family PTKs are activated initially and serveSrc family PTKs are activated initially and serve

to phosphorylate CD79a and CD79b therebyto phosphorylate CD79a and CD79b thereby

creating phosphotyrosine motifs.creating phosphotyrosine motifs. BCR complex leads to the recruitment andBCR complex leads to the recruitment and

activation of the PTK Syk, which in turnactivation of the PTK Syk, which in turnpromotes phosphorylation of PLCg, Shc and Vavpromotes phosphorylation of PLCg, Shc and Vav

Contd


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Pathway Of Activation Of BCRPathway Of Activation Of BCR

Tec,btk recruited to p.membrane Plcg activated.Tec,btk recruited to p.membrane Plcg activated.

SLP-65/BLINK recruites effector proteins.SLP-65/BLINK recruites effector proteins.

After BCR activation numerous secondAfter BCR activation numerous second

messenger PPI3 IP 3. DAG activate Pkc.messenger PPI3 IP 3. DAG activate Pkc. IP3 promote Ca ionsIP3 promote Ca ions

Ras, Rap also activated.Map kinase is alsoRas, Rap also activated.Map kinase is also

actavated. Including Erk Jnk and p38.actavated. Including Erk Jnk and p38. Several transcription factor activated whichSeveral transcription factor activated which

initiate gene transcription.initiate gene transcription.


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Major Histocompatibility ComplexMajor Histocompatibility Complex

T cells activated by APC.T cells activated by APC. Small fragment of antigen are held in MHC.Small fragment of antigen are held in MHC.

MHC interacts with TCR.MHC interacts with TCR.

This interaction is further strengthens byThis interaction is further strengthens by

coreceptor CD 4, CD 8.coreceptor CD 4, CD 8.


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Classes of MHCClasses of MHC

Two classes of MHC display antigen whichTwo classes of MHC display antigen which

may be endogenous or exogenous.may be endogenous or exogenous.

Class I endogenous.Class I endogenous.

Class II exogenous.Class II exogenous.


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Inhibition of TCRInhibition of TCR

The phosphorylation of Lck by Csk inhibits T cellThe phosphorylation of Lck by Csk inhibits T cellreceptor signaling and inhibits T cell activation.receptor signaling and inhibits T cell activation.

Csk activity is regulated in T cells by PKA, theCsk activity is regulated in T cells by PKA, the

cAMP-dependent protein kinase activated by thecAMP-dependent protein kinase activated by thesecond messenger cAMP.second messenger cAMP.

The activity of csk depend on CBP.The activity of csk depend on CBP.

T cell receptor complex are localized. CBP alsoT cell receptor complex are localized. CBP alsodirectly activates Csk.directly activates Csk.


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Distinguishing Self from NonselfDistinguishing Self from Nonself

T Cells are recognized by their receptors whichT Cells are recognized by their receptors which

are coded by transcription factors called AIRE.are coded by transcription factors called AIRE.

T Cells whose TCRs have high affinity for bodiesT Cells whose TCRs have high affinity for bodieson protien are destroyed this process ison protien are destroyed this process is negativnegative

selectionselection gradely reduces the chance of attack ongradely reduces the chance of attack on

self.self.


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SummarySummary

Genes are rearranged to form B and T cell andGenes are rearranged to form B and T cell and

antigen receptors.antigen receptors.

V D J undergo recombination to produce manyV D J undergo recombination to produce many

types of antibodies.types of antibodies.

T Cells are activated by MHCs which are on theT Cells are activated by MHCs which are on the

APCs.APCs.

Contd


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SummarySummary

T Cells are activated through different MapT Cells are activated through different Map

Kinase.Kinase.

T Cells are recognized by their own systemT Cells are recognized by their own system

through their receptors.through their receptors.


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Quote:Quote:

Dont screw up the best things in your life justDont screw up the best things in your life just

because you dont know who you really arebecause you dont know who you really are

By: Zig ZaglerBy: Zig Zagler


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ReferencesReferences

www.wiley.com/collegewww.wiley.com/college

www.biocartta.comwww.biocartta.com

www.wikipedia.comwww.wikipedia.com www.immunitysec.comwww.immunitysec.com
http://www.wiley.com/collegehttp://www.wiley.com/collegehttp://www.biocartta.com/http://www.biocartta.com/http://www.wikipedia.com/http://www.wikipedia.com/http://www.immunitysec.com/http://www.immunitysec.com/http://www.immunitysec.com/http://www.wikipedia.com/http://www.biocartta.com/http://www.wiley.com/college


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Thanks for you PatienceThanks for you Patience

Any Questions:Any Questions:

seminar immunity 07 arid 1657

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