Lewin Benjamin (ed.) Genes IX

.!l

c

=o)

gene

whose sequence is different

must have

been

generated

by somatic changes.

One difficulty is to ensure

that every

poten-

tial contributor

in

the

germline

V

gene

segments

actually has been identified. This

problem

is

overcome by the simplicity of the mouse l.

chain

system. A survey of several myelomas

produc-

ing 1"1

chains

showed

that many have the

sequence of the single

germline

gene

segment.

Others,

however, have new

sequences that must have

been

generated

by mutation of the

germline gene

segment.

To determine the frequency

of somatic

mutation in

other cases, we

need

to examine a

large number of cells in which the

same

V gene

segment

is expressed. A

practical procedure

for

identifying such a

group

is to characterize the

immunoglobulins of a series

of cells, all of which

express

an immune response

to a

particular

antigen.

Epitopes used for this

purpose

are small

molecules-haptens-whose

discrete structure

is likely to

provoke

a consistent response, unlike

a large

protein,

different

parts

of which

pro-

voke

different antibodies. A hapten is conju-

gated

with a nonreactive

protein

to

form

the

antigen.

The

cells are obtained by immunizing

mice with the antigen, obtaining the reactive

Iymphocytes, and sometimes

fusing

these

lym-

phocytes

with a myeloma

(immortal

tumor)

cell

to

generate

a hybridoma that

continues

to express the desired antibody

indefinitely.

In one example, l0 out of l9 different cell

lines

producing

antibodies

directed against

the hapten

phosphorylcholine

had the same

Vs seeuence.

This

sequence was the

germline

V

gene

segment

TI5.

one of

four related

Vs

genes.

The other nine expressed

gene

segments

differed

from each

other

and from all four

germline

members of the family. They were

more

closely

related to the Ti5

germline

sequence

than to any of the others, and their

flanking sequences were the same as those

around

TI5. This suggested that

they

arose from

the T15

member

by somatic

mutation.

Fi*tjtI

r:1.:1 I shows that sequence changes

are localized

around the V

gene

segment,

extending in a

region from

-I50

bp downstream

of the

V gene

promoter

for

-1.5

kb. They take

the form of substitutions

of individual nucleotide

pairs.

Usually there are

-3

to

-

I 5

substitutions,

corresponding

to

<10

amino acid changes

in

the

protein.

They are concentrated in the antigen-

binding

site

(thus generating

the

maximum

diversity for

recognizing new

antigens).

Only

some of

the mutations affect the amino

acid

$3{rl,iF.tf,

il;i.il

li Somatjc

mutation

occurs

in the

region

surrounding the V segment

and

extends

over the

joined

VDJ

segments.

sequence, because

others

lie

in third-base

cod-

ing

positions

as well

as

in nontranslated

regions.

The large

proportion

of

ineffectual

mutations

suggests that

somatic

mutation

occurs

more or

less at random

in

a

region

including

the V

gene

segment and

extending

beyond

it.

There is a ten-

dency

for

some

mutations

to

recur on

multiple

occasions. These

may

represent

hotspots

as a

result

of

some intrinsic

preference in the system.

Somatic

mutation

occurs

during

clonal

pro-

liferation, apparently

at a

rate

-

t

g-r

per

bp

per

cell

generation.

Approximately

half of

the

prog-

eny

cells

gain

a

mutation;

as

a result,

cells

expressing

mutated

antibodies

become

a

high

fraction of the

clone.

In many cases,

a single

family

of

V

gene

seg-

ments

is

used

consistently

to

respond to

a

par-

ticular antigen.

Upon

exposure

to

an antigen,

presumably

the

V region

with

highest

intrinsic

affinity

provides

a starting

point.

Somatic

muta-

tion then increases

the

repeiloire.

Random

mutations

have unpredictable

effects

on

pro-

tein function;

some

inactivate

the

protein,

whereas

others

confer

high specificity

for a

par-

ticular

antigen.

The

proportion and

effective-

ness of the

lymphocytes

that

respond

is

increased

by selection among

the

lymphocyte

population

for those

cells bearing

antibodies

in which

muta-

tion has increased

the

affinity

for

the antigen.

Somatic

Mutation

Is Induced

by

Cytidine

Deaminase

and UraciI

Glycosylase

A cytidine

deaminase

is required

for somatjc

mutation as we[[

as

for ctass switching.

U raci t- D

NA

g

lycosytase

activity

i nftuences

the

pattern

of somatic

mutations.

Hypermutation

may be

initiated

by the sequentiaI

action

of these

enzvmes.

23.15

Somatic

Mutation

Is Induced

by

Cytidine

Deaminase

and Uracil

Gtycosylase

59r

Somatic mutation

has many

of the

same

requirements

as

class switching

(see

Sec-

Iion23.l3,

Switching

Occurs by

a Novel Recom-

bination

Reaction:

o

transcription

must

occur in the

target

region

(as

shown

in this

case by the

demand for

the enhancer

that activates

transcription

at each Ig locus;

.

it requires

the enzymes

AID and

UNG

and

r

the

MSH mismatch-repair

system is

involved.

The

way in

which the removal

of the

deam-

inated

base leads to

somatic mutation

is sug-

gested

by the

experiment

summarized in

FiGuftE

23.2?.

When AID

deaminates cytosine,

it

generates

uracil, which

then is removed

from

the DNA

by UNG.

Normally

all

possible

substi-

tutions

occur

at the abasic

site. If

the action of

uracil-DNA

glycosylase

is blocked,

though,

we

see a

different result.

If uracil

is not removed

from DNA,

it

should

pair

with adenine

during

replication.

The

ultimate result

is

to

replace

the

original

C-G

pair

with

a T-A

pair.

Uracil-DNA

glycosylase

can be blocked

by introducing

into

cells the

gene

coding

for a

protein

that inhibits

the enzyme.

(The gene

is a component

of the

bacteriophage

PSB-2, whose

genome

is

unusual

in

containing uracil, so that

the enzyme

needs

to be blocked during a

phage

infection.)

When

the

gene

is introduced

into a lymphocyte

cell

line, there is

a dramatic change

in the

pattern

of mutations,

with almost all

comprising

the

predicted

transition from

C-G to A-T.

The key

event

in

generating

a random

spec-

trum of mutations

is therefore

to create

the aba-

sic site.

The

MSH repair

system is then

recruited

to excise and replace

the stretch

of DNA

con-

taining

the damage. The

simplest

possibility

is

that

if

the replacement is

performed

by an

error-

prone

DNA

polymerase,

mutations

may

be

introduced.

Another

possibility

is that

so many

abasic sites are

created that the

repair systems

are ovenvhelmed.

When replication

occurs, this

could lead to the random

insertion

of

bases

opposite the

abasic sites. We

don't know

yet

what restricts

the action

of this system

to the

target region

for hypermutation.

The difference in

the systems

is at

the end

of the

process,

when double-strand

breaks are

introduced

in

class switching.

but individual

point

mutations

are created

during

somatic

Cytidine

deaminase

creates

a U-G

pair

Uracil DNA-glycosylase

creates

an abasic

site

Normal

mutation

pattern

Replication

inserts

bases

at

random

opposite

the

gap

G

-+

A= 48%

G-->C=39%

G

-+f

=

12o/o

Replication

of

a

U-G

oair causes

G to A transition

+ +

Uracil DNA-

grycosyrase

BLOCKED

G-+A=84%

u+t/= to-lo

A

G

flE*l.JftFj

i3"?f When

the

action of

cytidine deamjnase

(top)

is foltowed

by that of

uraciL DNA-

gtycosytase,

an abasic

site is

created. Reptication

past

this site shoutd

insert

a[[

four

bases

at ran-

dom into

the

daughter

strand

(center).

If the

uraciI

js

not removed

from

the DNA, its reptication

causes

a C-G to T-A

transition.

592

CHAPTER

23 Immune

Diversitv

mutation. We

do not

yet

know

exactly

where

the systems diverge.

One

possibility

is that breaks

are introduced at abasic

sites in

class switching,

but the

sites are erratically repaired

in somatic

mutation. Another possibility

is that breaks

are

introduced

in both

cases, but are repaired

in an

error-Drone manner in

somalic

mutation.

rearranged V11 seeuence

has four to six

con-

verted segments spanning

its

entire

length,

which are

derived

from different

donor

pseudo-

genes.

If all

pseudogenes

participate,

this allows

2.5

x

108

possible

combinations!

The

enzymatic

basis

for copying

pseudo-

gene

sequences

into the expressed

locus depends

on enzymes involved

in recombination

and

is

mechanism

for somatic

hyper-

mutation that

introduces diversity

in

mouse

and

man.

Some

of the

genes

involved

in recom-

bination are required

for the

gene

conversion

process;

for example,

it is

prevented

by dele-

tion of R.4D54.

Deletion of other

recombination

genes (XRCC2,

XRCC3,

andP.1'D5LB)

has another,

very

interesting effect: Somatic

mutation occurs

at the

V

gene

in the expressed

locus. The

fre-

quency

of the somatic

mutation

is

-

I 0x

greater

than the

usual

rate of

gene

conversion.

These results show

that

the absence

of

somatic

mutation in chick

is

not due to a defi-

ciency

in

the enzymatic

systems

that

are respon-

sible in mouse

and

man. The

most likely

explanation for a connection

between

(lack

of

)

recombination and somatic

mutation

is

that

unrepaired breaks at

the locus

trigger the

induc-

tion of

mutations.

The reason

why somatic

mutation occurs

in mouse

and

man but

not in

chick may therefore

lie with

the details

of the

operation

of the repair

system

that operates

on

i1{-;i.iiriIi:i,i.i

Thechickentambdalightl'ocushas25Vpseudogenesupstream

of the sing[e

functionaI

V-J-C

region. Sequences

derived

from the

pseudo-

genes,

however, are

found

jn

active

reananged

V-J-C

genes.

Avian ImmunogLobu[ins

Are Assembled

from

Pseudogenes

r

An

immunogtobulin

gene

in

chicken is

generated

by copying a sequence from

one of 25

pseudogenes

into

the V

gene

at a single active

r.ocus.

The chick immune

system is the

paradigm

for

rabbits,

cows, and

pigs,

which rely

upon using

the diversity that

is

coded in the

genome.

A sim-

ilar mechanism is used

by both the single light

chain

locus

(of

the

l"

tlpe) and the H

chain

locus.

The organization

of the

l,

locus is

drawn

in

:rii:riir::

.,'::

.i

..

It has

only one functional

V

gene

segment, J segment, and

C

gene

segment.

Upstream of the functional

V11

gene

segment

lie 25 Vr

pseudogenes,

organized in

either ori-

entation. They are classified

as

pseudogenes

because either the coding segment is

deleted at

one or both ends, or

proper

signals for recom-

bination are missing,

or both. This assignment

is

confirmed by the fact that

only the

V1y gene

segment recombines with

the J-Cr

gene

segment.

Sequences of active rearranged

V1-J-C1 gene

segments show considerable

diversity, though!

A rearranged

gene

has one or more

positions

at which a cluster of changes has

occurred

in

the sequence. A sequence identical

to the new

sequence

can almost

aiways be found in one of

the

pseudogenes (which

themselves remain

unchanged).

The

exceptional sequences that

are not found in a

pseudogene

always

repre-

sent changes at the

junction

between the orio-

inal sequence and the altered

sequence.

Thus

a

novel mechanism

is employed to

generate

diversity. Sequences from

the

pseudo-

genes,

between

l0

and 120 bp in length, are

substituted

into

the active V11 region by

gene

conversion.

The

unmodified V11 sequence is not

expressed,

even at early times

during the

immune response. A

successful conversion

event

probably

occurs every ten to twenty cell

divisions to every

rearranged

Vtl sequence. At

the end of the immune maturation

period,

a

vrlJ C

Pseudogene

sequence

replaces

corresponding

part

of V11

23.16

Avian

Immunogtobutins

Are

Assembted

from

Pseudogenes593

breaks at the locus. It is more

efficient in chick,

so that the

gene

is repaired

by

gene

conversion

before mutations

can be induced.

l@

B

Cel"L Memory Altows

a Rapid

Secondary

Response

o

The

primary

response

to an antigen is mounted

by

B

cetls that

do

not

survive beyond the response

oeriod.

Memory

B

cetls are

produced

that

have

specificity

for

the

same antigen, but that

are

inactive.

A reexposure

to

antigen triggers the

secondary

response

in which

the

memory

ce[[s are rapidty

activated.

We

are now in

a

position

to summarize

the rela-

tionship

between the

generation

of high-affinity

antibodies

and

the differentiation

of the B cell.

:.r-*ii-:=l i3.l:*

shows that B

cells are derived from

a self-renewing

population

of stem cells in

the

bone marrow.

Maturation

to

give

B

cells depends

upon Ig

gene

rearrangement,

which requires

the

functions

of the SC/D arLd RAG1,2

(and

other)

genes.

If

gene

rearrangement

is

blocked, mature

B

cells are not

produced.

The

antibodies

carried

by the B

cells have specificities

determined

by the

particular

combinations

of V(D)J regions

and any

additional

nucleotides incorporated

during the

lolnng

process.

Exposure

to antigen

triggers

two aspects of

the immune

response. The

primary

immune

response

occurs by

clonal expansion

of B cells

responding

to

the antigen. This

generates

a large

number

of

plasma

cells that

are specific for

the

l#'3il;

ii,Xlli;',il51'l?"T;H,Ti#

lt :

population

of cells concerned

with

the

primary

response

is

a dead

end; these cells

do not live

beyond

the

primary

response

itself .

Provision

for a

secondary

immune

response

is made

through

the

phenomenon

:iJ;::1,ffiTi:';.":1X::#:lililf"11":

antigen.

These

cells do not

trigger

an immune

response

at this time,

although

they may

undergo

isotype

switching

to select

other forms

of Cs region.

They

are stored

as memory

cells,

with appropriate

specificity

and effector response

type,

but are inactive.

They

are activated

if there

is a new

exposure

to the

same antigen.

They

are

preselected

for

the antigen,

and as

a

result

ffI

".:ilff

,,#ilT;:"'"lT:':,

"""T::lT

3

CHAPTER 23

Immune

Diversitv

i*{i{.lFlI

t-t.:+

B ce[[ differentiation

is responsib[e

for

acquired immunity. Pre-B

cetls are converted

to B ce[[s

by Ig

gene

rearrangement.

Initial

exposure to antigen

pro-

vokes

both the

primary

response

and storage

of memory

ce[[s. Subsequent

exposure to antigen

provokes

the

sec-

ondary response

of the

memory

ce[[s.

further

somatic mutation

or isotype

switching

occurs during

the secondary response.

The

pathways

summarized in Figure

23.24

show

the development

of acquired immunity,

that is,

the response to

an antigen.

In addition

to these cells, there is

a separate

set of B

cells,

named

the Ly-1 cells. These

cells

have

gone

through the

process

of

V gene

rearrangement,

and

apparently are

selected for

expression

of a

particular

repertoire

of antibody

specificities.

They

do not undergo

somatic mutation

or the

memory

response. They

may be involved

in

natural immunity,

that is, an intrinsic

ability

to

respond

to

certain antigens.

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pole!pau-evu

80c rcc

is

activated by binding

antigen.

Our

present pic-

ture

of the components

of the

receptor

com-

plex

on a T cell is illustrated

in

FSftljttt

j.:

jj.li;:.

The

important

point

is that

the interaction

of

the

TCR

variable regions

with antigen

causes

the

(

sub-

units

of the CDI complex

to activate

the T

cell

response. The

activation

of CD3

provides

the

means by which

either

crB or

y6

TCR

signals that

it has

recognized an

antigen. This

is compara-

ble to the constitution

of the B

cell receptor, in

which immunoglobulin

associates

with the IgoB

signaling

chains

(see

Figure

2j.26).

A central dilemma

about

T cell function

remains

to be resolved.

Cell-mediated

immunity

requires

two

recognition processes.

Recogni-

tion

of the

foreign

antigen

requires

the ability

to respond to novel

structures.

Recognition

of

the MHC

protein

is

of course

restricted to

one

of those coded by the

genome,

but even so there

are many

different MHC

proteins.

Thus

consid-

erable diversity is required

in both

recognition

reactions. Helper

and killer T

cells rely upon

dif-

ferent classes of MHC

proteins;

however,

they

use the same

pool

of

cr and

B

gene

segments to

assemble their receptors.

Even

allowing for the

introduction of additional

variation

during the

TCR recombination

process,

it is not

clear how

enough different versions

of the T cell receptor

are made available

to accommodate

all these

demands.

V-region

of

TCR

recognizes

antigen

(

chain is efiector

i:ii:,iii:

l:

;;..:;r

The

two chains of the T ce[[ receotor asso-

ciate with the

potypeptides

ofthe CD3 compLex. The vari-

abte

regions

of the

TCR

are exposed on

the ce[[ surface.

The

cytoplasmic

domains

of the

(

chains of CD3

provide

the effector

function.

The Major

Histocom

patibitity

Locus

Codes

for Many Genes

of the

Immune System

r

The MHC locus codes for the ctass

I

and class

II

proteins

as we[[ as for other

proteins

of the

immune

system.

.

Ctass I

proteins

are the transplantation

antigens

that are responsible for distinguishing

"self'from

"nonself'

tissue.

.

An MHC

class I

protein

is active as a

heterodimer

wjth

Fz

microgtobu[in.

.

Class II oroteins are invotved

in interactions

between T ce[ts.

.

An MHC

class

II

protein

is

a

heterodimer of

g

and

B

chains.

The major histocompatibility

locus occupies

a

small segment of a

single chromosome

in the

mouse

(where

it is called

the H2 locus)

and in

man

(called

the HLA

locus). Within

this seg-

ment are many

genes

coding

for functions con-

cerned with the immune

response.

At individual

gene

Ioci whose

products

have been

identified,

many

alleles

have been

found in the

popula-

tion; the locus

is

described

as

highly

polymor-

phic,mearring

that individual

genomes

are likely

to be different

from

one

another.

Genes coding

for certain other functions

also are

located in

this

region.

Histocompatibility

antigens

are classified

into three types by

their immunological

prop-

erties. In addition, other

proteins

found on lym-

phocytes

and

macrophages

have a

important

in

the

function of

cells of the

immune system:

MHC class

I

proteins are the transplan-

tation antigens.

They are

present

on every

cell

of

the mammal.

As their

name suggests,

these

proteins

are

responsible

for the

rejection

of foreign tissue, which

is

recognized as such

by virtue of

its

particular array of

transplanta-

tion antigens.

In the

immune system,

their

pres-

ence on target

cells

is required

for the

cell-mediated

response.

The types of class

I

pro-

teins are defined

serologically

(by

their anti-

genic properties).

The

murine class

I

genes

code

for the H2-I( and

H2-DlL

proteins. Each mouse

strain has one of several

possible

alleles

for each

of these

functions. The

human

class I functions

include

the classical

transplantation

antigens,

HLA-A. B. and C.

23.20 The Major Histocompatibitity

Locus Codes

for

Many

Genes

of the

Immune System

599

NIHC

class

II

proteins

are

found

on the

surfaces of both B

lymphocytes

and

T lympho-

cytes, as well as on macrophages. These

pro-

teins

are

involved in

communications between

cells that are necessary to execute the immune

response; in

particular,

they are required for

helper T

cell

function.

The murine class II

func-

tions

are defined

genetically

as I-A and I-E. The

human

class II region

(also

called HLA-D) is

arranged into four

subregions, DR, DQ,

DZIDO,

and DP.

The

complement

proteins

are coded by a

genetic

locus

that

is also known

as the S

region;

S stands for

serum,

indicating

that the

proteins

are components

of

the

serum.

Their role is

to

interact

with antibody-antigen complexes to

cause

the lysis of cells in the classical

pathway

of the humoral response.

The

Qa

and

Tla loci

proteins

are found on

murine hematopoietic

cells. They are known

as

differentiation antigens, because

each

is found

only on a

particular

subset of the blood cells,

presumably

structurally

related to the class I H2

proteins,

and like

them are

polymorphic.

We can now relate

the types of

proteins

to

the

organization of the

genes

that code

for

them.

The

MHC region

was originally defined by

genetics

in

the mouse, where the classical H2

region

occupies 0.3 map units. Together with

the adjacent

region where mutations

affecting

immune function

are also found,

this corre-

sponds to a region

of

-2000

kb of DNA. The

MHC region has

been completely

sequenced

in

several mammals,

as well as in

some birds and

fish. By

comparing these

sequences, we find

that the organization has been

generally

conserved.

The

gene

organization

in mouse

and man

is

summarized

in

il{iti't!:

ii;-,:.1.

The

genomic

regions

where the class

I

and class II

genes

are

Iocated mark the original boundaries of the locus

(going

in the

direction

from telomere

to cen-

tromere;

right to left as shown in

the figure).

The

genes

in the region that separates the

class

I and

class

II

genes

code for a variety

of func-

tions; this

is

called the class

III region.

Defining

the ends of the

locus

varies with the species,

and the region beyond the class I

genes

on the

telomeric side

is

called the extended class I

region. Similarly, the region

beyond the class II

genes

on the centromeric side is

called the

extended class II region. The major

difference

between

mouse and human is

that the extended

class II region contains some class I

(H2-I()

genes

in the mouse.

There

are several

hundred

genes

in

the

MHC regions of mammals, but it is

possible

for

MHC functions to be

provided

by far fewer

genes,

as

in

the case of the chicken, where the

MHC region is 92 I(b and has only nine

genes.

As in comparisons of

other

gene

families, we

find

differences in the exact numbers

of

genes

devoted to each function. The

MHC locus shows

extensive variation between individuals,

and

as a

result

the

number

of

genes

may

be differ-

ent

in

different individuals. As a

general

rule,

however, a mouse

genome

has fewer

active H2

genes

than a

human

genome.

The

class II

genes

are unique to mammals

(except

for one sub-

group),

and as a rule, birds and

fish have

differ-

ent

genes

in their

place.

There

are

-8

functional

i':i.l:.i!il-

il.il.i,:;

The MHC region

extends for >2 Mb. MHC

proteins

of classes

I

and II are

coded bV

two

separate regions. The

class III region is

defined as the segment

between them. The extended

regions

describe

segments that

are syntenic on either

end of the ctuster. The major

difference

between mouse

and human is

the

presence

of H2

class

I

genes

in the

extended

region

on

the [eft.

The

murine

[ocus

is

[ocated

on chromosome 1.7, and the human

locus is located

on chromosome

6.

CHAPTER 23

Immune

Diversitv

Lewin Benjamin (ed.) Genes IX

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