5. AgRc Genetic

7/23/2019 5. AgRc Genetic

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Immunoglobulin Genetics



Immunoglobulin GeneticsHistory

• Same C region could associate with many V regions

– IgG Ab with different specificities

• Same V region could associate with many C regions

– Same idiotype on IgG and IgM Ab

• V and C regions coded for by separate genes



ight Chain Gene !amiliesGerm line gene organi"ation

J 1 C 1

E

J 2 C 2

E

J 3 C 3

E

J 4 C 4

EP

L V1

P

L Vn

P

L V2

Lambda light chain genes; n=30

P

L V 1

P

L V n

P

L V 2 J

2 J

3 J

5 C

E

J

1 J

4

Kappa light chain genes; n=300



ight Chain Gene !amiliesGene rearrangement and e#pression

L V 1 L V

nL V

2 J

2 J

3 J

5 C

J

1 J

4

DNAP PP E

P P E

L V 1 L J

5 C

V 2 J

4

DNA

DNA Rearrangement

V CJ

V C

Protein

Transport to ER

Protein

TranslationCL V J

E

L V CJ

RNA

Transcription

Primary transcript

CL V JRNA Processing

RNAmRNA



Hea$y Chain Gene !amilyGerm line gene organi"ation

Introns separate exons coding for H chain domains

Heav chain genes; Vn=1000! "n=1#

P

L V1

P

L Vn

P

L V2 D2 D3D1 Dn

C

C

C 3 C

C 2C 1 C 4 C 1 C

2

J2 J3 J5J1 J4

E

C1 C2 C3 C4



Hea$y Chain Gene !amilyGene rearrangement and e#pression

P

L V1

P

L Vn

P

L V2 D2 D3D1 Dn C

C J2 J3 J5J1 J4

E

DJ rearrangement

P

L Vn

P

L V1

P

L V2D2

D1 C

C J5

J4

EDNA

VDJ rearrangement

D2 C

C J5

J4

EP

L V1

P

LV2

DNA

Transcription

D2 C

C J5

J4

E

LV2

RNAPrimary transcript



Hea$y Chain Gene !amilyGene rearrangement and e#pression

EPrimary transcript

E

J4D2V2 C

C

J5L C

C

J5L D2 J4V2

RNA Processing

An

mRNA !or C

C

L DJV C

L DJV

An

mRNA !or C

Translation

C

"ea#y c"ain

C

L DJV C

L DJV

C

"ea#y c"ain

Transport to ER

C

"ea#y c"ain

V C

C

DJV C

DJV

C

"ea#y c"ain

V C



Class Switching

• %&A

rearrangement

– Antigendependent

– Switch site

– Same V%'

– (H cyto)ines

L

3 2

1 4 1 2

P

L V DJ

$ $ $ $ $ $ $ $

P

L

$

1 2

$ $

Primary Transcript %g&or %gD

Primary Transcript%gE

RNA

DNA

DNA

DNA Rearrangement

L

V DJ

V DJV DJ





Mechanism of %&A

*earrangements

• *ecombination

signal se+uences

,*SS- – &onmer

– Heptamer

– . or / turn signals

$ %ag&1 and %ag&2

L V

2

J C

1

Lam'(a lig"t c"ains

L V

1

J C

2

)appa lig"t c"ains

ea#y c"ains

L V

2

J C

211

D

eptamer

CACA*T*

*T*TCAC

Nonamer

ACAAAAACC

T*TTTTT**

23 'p

23 'p

T+o t,rn

R$$

2

Nonamer

**TTTTT*T

CCAAAAACA

eptamer

CACT*T*

*T*ACAC

12 'p

12 'p

-ne t,rn

R$$1





0rder of Ig Gene 1#pression

.

/

ea#y c"ain gene

VDJ recom'ination

Pro(,cti#e rearrangement 0

es

No

Transcri'etranslate

1st

2n(

or

Apoptosis

Progenitor cell

Pre cell

ea#y c"ain

Paternal&aternal




.

/

Lig"t c"ain gene

VJ recom'ination

Pro(,cti#e rearrangement 0

es

No

Transcri'etranslate

Lig"t c"ain

4 t"

Apoptosis

1st /

2n( /3r( /

4t" /

or

Pre cell

&at,re cell

.




1#plains2

• 3hy an indi$idual 4 cell only produces

one )ind of Ig with one )ind of hea$y and

one )ind of light chain

• 3hy an indi$idual 4 cell only ma)es

antibodies of one specificity

• 3hy there is allelic e#clusion



0rigin of Antibody %i$ersityHistory

• %efinition – %i$ersity ,repitoire- is the total

of all the Ab specificities that an organism

is capable of e#pressing

• (heories

– Germ line theory

– Somatic mutation theory



0rigin of Antibody %i$ersityCurrent concepts

• Multiple V genes

$ V&' and V&"&' (oining

$ ')nctional diversit

$ * region insertions

+ ,mino acid

se-)ences notencoded in the germ

line

D region

T **C CC

Pro Trp

C C C C C C

V gene

T **

D region

C C C C C C

V gene

T **

C **C CC

Pro Arg

C C C C C C

V gene

T **

D region

C *CC CC

Pro Pro



/./,,/.

/./,,/./ .

rea "*,

/d/ adds n)cleotides

Ligate

* region insertion Intron

'"

'

'

'

"

"

"

.eneration of * region insertions



0rigin of Antibody %i$ersityCurrent concepts

• Multiple V genes

$ V&' and V&"&' (oining

$ ')nctional diversit

$ * region insertions

$ omatic m)tation

$ ombinatorial association



Generation of %i$ersity

B cell receptor(Immunoglobulin)

Heavy Light

V gene segments 1000 300

D gene segments 15

! gene segments " "

# region insertion $$

!unctional %iversity $$$ $

&omatic mutation $ $

V ' D ' !

1000 ' 15 ' "

V ' !

300 ' "otal ' 10

" 1*+ ' 10

3

,ombinatorial association -*+ ' 10-

$ ,g independent process $ lonal selection



( Cell Antigen *eceptor

• Heterodimer of an and a chain

• Gene structure and e#pression of the chain is

analogous to the immunoglobulin light chain

• Gene structure and e#pression of the chain isanalogous to the immunoglobulin hea$y chain

• &o somatic mutation in ( cells







(he germline organi"ation of the

human (5cell receptor 6 and 7 loci



( cell receptor 6 and 75chain gene

rearrangement and e#pression



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5. AgRc Genetic