W
tdk^r^rl
; i
stream of a mammal,they
ncttF
Z , [
f can an organism store enough generic iqf-prmariqn to
y :
produced by the immune s tehs of mammals rr
#" F
g tt
tt g
, questions have become clear.
COMPONENTS OF I'HE IMMUNE SYSTEM
Three different types of white blood cells play central
roles in the immune response in vertebrares. These
cells are (l) B lymp4ocyrei',(c4lled B cells because
they are produced in bone mirrow), (2) T l1tryppa1.
qttes (called T cells because rhey are produced in the
tlrp:rus gland), and (3) mdcropba&es. Arttiltotlics ore
syrttllesiged lry B lyntlthocltes andare either secreted
or rEifffi membrane-bound on_the surface of the B
cell depending on the condirions, During the bumoral
immune respolLrg these antibodies bind to free anti-
gens in the circulatory syrtem and agglutinate them.
1'lre resulting antibody--a:atigen comlttexes arc tben
i:f;:';ff;!,x:{:iw{e,,,1, !';?,;,,,,,;l ;
responsg, The T cells synthesize antisen receDtors thar
ietffie antigens on iellsurfaces aia Effift lffi*f
of the antigen-conaining cells by the activated T cells
(Fig. 16.1, right). Ditrerent T lyrnphocvres perform this
function in slightly differEpt ways. Hou,wer, in gen-
eral, the attack of the T cell on the anrigercarrying cell
requires both the speciftc T cetl receptor and one or
more blstocotnpatibility antlgm rccep tors,the mech-
anisms by which antibodies, T cell ieceptors, and
histocompatibility antigeg rceptors are produced are
described in the following sections of this chapter,
l. I
VAST REPERTOIRE OF ANTIBODIES
T of cells. By what mechanism could this occur, and hon
Scanning elmron micrograph of human lmmunoddlciency vlrus panlclcs
(the causadve agent of AIDS) anacklng a helper T lymphoqte (thoo by
Le,'rnae liilsson, Copwight 0, Bcchringer I.rgelheim Internnional GmbH.)
infinile uarie1t 6f qlllibodies that can bc s.),tttltesi:cr;
,iyo,lespgnse to antige,Ts tbat tbe ctninral l.rrr.t rro;
,l,1ryff h.
'ln'cuidil*rl1 encountered How Can an Organism have
prepareci to synthesize an anribody designed to bind
very specifically to a particular antigen wirhout ever
having made contact with the antigeni Moreover, how
code for he amino acid se{ue"nces of a*Jiftffiffd^un-
limited variery of antibodies? These and related ques-
tions about the immune response had puzzled genet-
)
icists for several decades. Vithin the iast iew 1'ears,
however, the main features of the answers to these
We do not know how many difterent antibodies a
mouse or a human can produce, but we do know thar
the number is very large, almost ceftainly in the mil-
lions. This preseltts a paradox. The complete hunmn
genome (i.e,, one of each of the 23 pairs of humrn
chromosomes) contains about 3 x iOe nucleotidr:-
pairs. If all of this DNA were in rhe form of uninrer-
rupted coding sequences ofgenes each 1000 nuclei;-
tide-pairs long (of course, we know that much of it is
not), the genome woulid contain a maxinrum of about
3 million genes, Since we know rhat rnanv of these
genes code for various RNA molecules, enn,ntes. and
structural proteins, and we know drat many of the.se
gene.s contain long noncoding introns, how can \\,e
account for the genetic informatitrn needed to code for
the plethora ol different anribodies?
Hpotheses: Gcnetic tdo}a,'
1rm15
olAntibody Diversifl' ( kqc.$'+r"' ..,c.q*nr )
,
.,
last ifdhpts to explain the genetic basis of anribodv
diversity can be roughly grouped into three different
hypotheses.
t. The "germ tine" tttpothes,r ro,.alhllf;illT) .,n7,.,
ldte gtrtt line gme for each antibod.l'. (This agreed
with our arrly knowledge about protein sl,nthesis, bur
presented the paradox of not enough DNA) i rc[ ur\q(
i
2. The "somglic mr44tion" l4tpotbesis srated rhat there is
t"0t$ 8ne JPa fdfF* linegenes 5pscifoing each major
class of antibodtes-and tha'r6e a a,#ff)\Wr,,rfr,rc,t t,t
a high frequotqt of sontdtic mutatlon-mutation oc-
curqffijg"the antibody-producing somaric cells or in
cell lineagii' leading ro antibody-producing cells. (There
was no precedent for a high frequency of mutation
oc:urring in only cenain genes and in only cenain qpes
could it be regulated?)
3. Thd'ntin,igrir" pgg4tsissured that *," Oiffi\!c,^'
Senerated by $e slii{fipggi tnany !nt6ll s(,.{,,?(',7/, . l'r
afcwgenesitttoailittQitttdeoJpossibiiLol]tl)ilill
tlons. The shuffling would occur by recombinarion y,
processes in somatic cclls. (This required oully norel [i
mechanisms lcr rearranging segnlenr cf DNA.) l
449

450'
We now know that the minigene hypo*,esis ex-
plains a great deal of the observed diversity, However,
we also know that somatic mutation contributes addi-
donal diversity. Finally, we know that one segmer-lt (the
M amino acid sequence varies among antibodies specific
s
B ce
: ie: T ce
I
antlg6n
/ receptor
Phagocytosis of
an(igen.antibody
complexes
by macrophages
I:igure 16.1 Schematic diagram showing the maior com-
ponenu of *re immune response in venebrates. A foreign
iubsance such as rhe coat prctein of avirus acu as an antigen
to trigger the rymthesis of large amoun$ of antibodies that
react specifical\, with the antigen and remove it from the
circulaioq'svsrem. Two qpes of immune response occur. (1)
B lyrnphocltes synthesize and secrete antibodics that conr-
plex *;ith free antigens in the bloc,dstreanr; rhese complexes
are then ingesrdd and destroyec, hy macrophages. (2) T
li'mphoqtes synthesize antigen receptors th4t remain bound
CI I^JTTER 16 GINF,TIC CONTROI, OT TI{E IMMLINI] PTSPONSI;
"constant" region; see the following discussion) of
each antibodychain is specified by a "gene" or "gene
segment" that is present in the genome in only a few
copies. Thus, all duee hypotheses were correct in
ceftamre5-p-eds. qnue CnwlLdb
Structure 0f Aniibodies
Antibodies belong to the class of proteins alled lm-
munoglobulins. Each antibody is a tetramer com'
posed of four polypeptides, two identical ligbt,cbains
and two ldentical beat4; 66o1*, joined by disullide
bonds (Fig. 16.2). The light chains are about 220 amino
acids long, and the hearry chains are about UM50
amino acids krng. Every chain, heary and light, has an
amino-terminal aariable regiort, within which the
for different antigens, arid a carbory-l-termtnal con.
stantregion,within which the amino acid sequence is
the same for a[[antibodies.df a given immunoelobulin
(lg) class, Ieiff&ft{tf.h{&;ntinding spicifi city.
The vuiable regions of all antibody chains are about
hiSoCOmpaub ity 110 amino acids long.
an gen re"ptOr
of proteins iarry OUL parricular rutlu'
out piilu{-uru func'
Regions OI
XeglOnS PrOlemS Inat
that Carry 1
Each antibody hx two an. I
tions are c:lled domalns-dom.abtc
tiom.hindino
bFttJ cllpr
0or ,catteach pfof I Chii I
which
"
f&med by thi variabl. ,.gion, of one light cHri, \ -l
one heavy chain (Fig. 16.3). In addition, the consunt /.
regions sf the two heavy chains interact to form a third I
domain,alledtheeffectorfunctiondomain,wlttchis)
rerponribl. for the propeiinteractfin of the antibody,
with other components of the immune sJntem.
There are five classes of antibodies: IgM, IgD, IgG,
IgE, and IgA. The blass to which an antibody belongs,.
and thus the function that it carries out, is determined
by the stpaure of is heavy chain constant region (i.e.,
the structure of its effector fuqgjgn {gq{Ug). For
S
example,IgD antibodies usually rfm?rin 56und to the
of the cells ln which they are synthesized,
surfaces
: :
chains of 33&3 ,
1:
*'
\r
,,\
tothesurfaceoftheTcells.Theseand8enreceptorsadin.
concert with histocompatibiliry andgen receptors ro recog-
nize and destroy cells that czrry the antigens. Thus, the B
cells carry out a humoral immune response, and the T cells
carry out a cellular intmune response. The vast diversiry of
both antibodies and T cell recepiors is produced by genome
rearrangements that alie placeduring the differentiation of
B and T lymphocyres from stem cells. The histocompadbility
antigens are encoded by a large cluster ofgenes in the major
:
h istocompatibiliry complex QWHC).
 451

AN IBO DA7ESIWI GENOtt REARRANG ENrS fB DIFFE ON

Thus, when we examine the structure of antibod-
ies, we see that their diversity resides almost entirel1'
within the variable regions of the molecules. If these
polypeptides were synthesized from colinear nucleo-
tide-pair sequences of genes, one gene per polrpep-
tide chain, the genome would have to contain a vast
array of genes with highiy variable sequences at one

'Constant

:l:.

W ttI
ittt

,I
H


,l
q , ,
ence laPyOf

IPtti




:

reglolls,

n attP

i
ANTIBODY D RSIT l GENOME
RE GEA4ENTS DURING
BL IPHOCY E DIFFERENTLiT10N

t
I
1 lrlI:
# #
:9 .

antibodieS may have the same antigen binding speci rs ,7 G S r r rog r/90 /77
'C ri
/,,

nciv,as determllled byttevariabl reglonsOfttc four 'g 7

7 ` `
s 9 ? ,77'4 47 ( (

chains,but different immunological functions, de

r/9


0/,
'
7/9o`4)
,7
R(1` ( /

tcrmined by tte consttnt reglons of the m/o lleaw `" 7/7 r/J` t Each B lympllo
chains. q te produces only a single type ofantibody, at is,all
.

Figure l(rrJ gpx6s.filling rnodel of antlbody srru(ure
showing the three funaional domains of immunoglobulins.
The naro heavy chains are .shown in whire and blue, respec.
tively. The rwo light drains are shown in orange. The olive
colored componen$ are the associated carboirydrate moi-
will lary depending on the
eties; their location and structure
inrmunoglobulin (lg) class, The strucure shosrn is fcr a
human igG rnolecule. (After E. W. Silvenon, M. A. Navia, artd
D. Ii. Davics, Proc. lt'utl. Acad. Sci. U.SA 74: >14G->11+,
197i,)
 452 C4 R16 GENETIC CON tOL OF THEIMMUNE ESPONSE

the antibodies produced by a given B lymphocyte have
the same antigen-binding specifi ciry.
Each ariibody chain is synthesized using informa-
tion srored in several different "genes" of "gene seg-
ments." (Some genedcists call these DNA seqiter:ces
"genes," and others prefei to call them "gene seg-
ments." \\/e will call them gene segmenm in the follow.
ing discussion.) Note thar the rrtassical concepr of one
gene-one pollpepdde is not adequllte, at leasc in i$
simplest form, to explain gerre-antibodv relationships.
gene-segment cluster and the C* gene segment, and
rhe C*-proxirrral/* segments, if any, remain berween
the fused V-I* segment and the C* segment in the
differentiated B lymphocytes (Fig. 16,4b). This entire
D M sequ enc e (L ;V J *-noncoding-C*) is ranscribed
(Fig. 16,4c) and the noncoding sequences are re-
moved during RNA processing (Figs. 15.4c and @, just
like the noncoding sequences or introns of any otlrer
eukarl'otic gene.

Lambda Light Chains

Iirrppa f-iglrt Chrins ll^"tl-I'
lAmhda lighr chain genes are also assembled from
Synthcs ofthekappalightchainiscontrolledbythrecr
sb!"ffiie segrnents during B lymphocyte development,

ItIB; TI The major difference is tJiat each /; gene segment
comes with its own C1 lene segment, that is, ttre
Pi: l 1
genome rearrangements i'equired for lambda chain
, slmthes is join I;-V1 segmeilts to^-q segments. Mice
1have only folr/^{ gene segments, whereas humans
have six. This correlates with the hct that only 5
1 i 71Fe t

percent of the antibodies of mice are of the lambda

s , 17-20 arnino adds long,

rr
rype, whereas 40 percent <lf the antibodie.s of humans

for the transport of thO antibOdy
which is cssential
have lambda light chains.

tteF: : tl
nlembran ,alld thus is not part ofthe rlnal antibody.
Heaqr Chains
The arrangement oftte kappa chm gene segmen6
The genetic information coding for antibody heavy
chains is organized into Ls-Vr, J n, and Cs gene seg-
ments analogous to those for kappa light chains; but
tbere is one additional geile seg?nefltt called D for
diversiry, fuat codes for 2-1J amino acids of tbe
uariable region. The variable region of the heavy
chain is thus encoded in three separate gene segments
that must be joined during ts tymphocyte develop-

ment. In addition, there are from one to four C, gene
segments for each Ig class.
In the mouse, there are a toal of eigbt C, gme

segments, all funoional, arranged on the chromosome

trtettts an.d tbe C* gme segment. in the sequence C6p, Cp,'Cqj, Crrr, Cor*, Corro,

In genn line cells, the five/* segments $ sepa-r. CH,, Cno (Flg. 16,5a). Con, Cm, Cx, and C1,o code for

rated from the V* segment$ by a long (we don't yet i the heavy chain constant regions of IgM, IgD, IgE, and

Igli respectively. Four gene segrnents, Cprj, Cq1,

know how long) noncoding sequence and from the C. \

segment by an approximately 2000-nucleotide-pair- { Csr2s, And Csr2o, code for IgG heary chain constant
Iong noncoding sequence, During tbe deuelopm(Ntt , regions.
ttj'ct B ly'rtltl:oc1tte, tbe Farticular kilppa light chliin I : In humans, there are 9 or 10 functional C, gene .l
gene tbat will be expressed in tbat aell is assembled \ Segments: C11o, Cp6, Cnr.,, Cr.rr, Cisrj, Cay, Curt, I

ft'ottt one L**v* segrnent, one J* segnrcnt, and the \ probably Cs,2, Cpo1, at-d Cyu2. The human C, gene I

sitt.qle C* stgfient b.y a process o.f somatic recombi- \ cluster also contains two nonfunctional "genes," com- |
,tittiun (r*igs. 16,4a and b). Thi.s proce.ss joins any one \ monly called pseurlrigenes, with very similar struc- \
of the approximatell,300L*-y segmens witil aoy one \ tures. Pseudogenes are panizrl duplicates of structural I
of the five/* segmen6, {tit}the delerion of all inter- I genes that have incorporated suflicient changes that I

vening DNA (Fig. 16,4b).lr yields a fused tr./. gene I they are not biologlcally active and usually are not \
segment coding for the entire \ariable region of the I transcribed. Pseudogenes are turning out to be quite L
kappa chain. The noncoding sequence between theJ* J common in eukaryotes. J

l
i
i

l
 IBODY
DrVERSITr GENOME ttLttRttGEMEN DURING B L PHOCY DlFFERENTIATION
"



1

/A

W/
J

:

(b) DNA of mature I ly;rnphocyte: --U
-

(c) Primary transcript:

//

(d) Mature mRNA: , Poly A

n
)tnJa
(c) Primary translation productr

t a

(t) Mature kappa light chain:

.),i- Amlno acid no 1 98 108 214
:-_>'
. i.

. Variable Constant
-region region

Figure 16.4 Thegenetic conrrol ofhuman antibody kappa involved. (After P. Leder, Scr Atner. 246(5):10/-11i, 1982.)
light chains See thc icxt for' x descriptiol'r of tile l)roccsses

(a) Germ line DNA:

: v

(b) lmmature B lymphocyte DNAr
l

(c) Mature B lymphocytc producing IgG,

i,f,"r,
rwiti:\l rp

(d) Mature B lymphccyte iroducing lgE:

(e) Mature I tymphocyte prooucing lgA,

Figure 16.5 1\e genetic contl'ol ol mouse antil)ody hedq, rcglol15 ofibur closcly related FOrms oFJgG.Scc thc tcx[rl)r
chains. C/1., Cn, Crro aod Cilo encode the hcaly chain a descHplon oFthc proccsseS in olved( ter lNl l Da ls
constanr rebions of lgili, lgD, IgE, and IgA, respectively, Crrrr, S i Kinl,and L.Hood,6 22:1-2,1980)
Cr.r,, Crrra and Crr1zo encode thc heavy chain constant

u
?uQ Q I dtT


454 CHN R16( ENETIC CON 1ltOL OF TliE IMMUNE PONSE

In nrt;u.se .germ line cclls. tl',crrc lr:c cL)();ti t,(i0

L.,y-\:r, .qerte seg?rieilts, something like lu-5(t D gene
se!ilic.nts, 4 J^ gme {;egme?tts, arrd 8 C1, gene seg.
tiiatrts, arrlitgccl on tite chrolnosc,nle in the i:rer:eding
order (Fig1. 16.k). Dtu'ing rhe developmenr of l)
ivnrphoote trorn a stcrn ceil (a rnitorically aaiivc
nratic cell frorrr rvhich other ryDes of celis "stcrn" or
arise bv cell clivision end differenrintiot')), sornatic re.
conrbinarion joins one 1,1-Vs gene segmcnt $'ith one
D gene .segmer)t and oneJ,, gene segntcnr, delcting the
$!'o ilrten'ening sequences of DirrA, to form one cou-
rinurlus DNA scquence (y'HDi!) thar codes for the
r:ntirc hear,y chain variablc rcgion (Figs. 16.5a ancl b).
i-.iass Ss'itcirirrg
At the time that antibody synthesis begins in the dcvel- ;
oping B l1'mphoote, all the 6r gene segmenm are stilli
present, separated from the newly formed LT.VHDJHi
ulated to differentiate inrc a mature B lymphocyte.
ments are deleted (Figs. 16,5c-e). The class of antibod-
ies produced after class switching is determined by
AYTJ BOD{ DI\/I.II SITY: ALTERNA'{'E
PATfI\fi/A1'S OIr' TRANSCRIPI SPUCING
I Another rype of clas.s switching during B lvmphoq,te
so- clilferentiation occurs at the level of RNA processtng
{ l"splicing'). Cernin marure B lvrnphocytes produce
i" both IgM and IgD nntihodies. Ir should be emphasized,
hr.rwever, that tirese antibodies differ only in their
eifector function domains; tirey have identical antigen-
binding domains, specilied by the same V./. (or Vr/^)
and V,DJ,, fused gene segments. In ttrese cells, a
primary transcript that extends through both the Cr*
zrnd 6'r,6 gene segments is syrrthesized. During process-
ing, the VrDJ,r transcript sequence may be spliced to
either the Cr* sequence or the Cr6 sequence, such,
*rat both rypes of heary chaln are synthesized in the
same cell (Fig. 16.5).
A further complexiry cbserved in antibody synthe-
sis is the sequ entl.al prodruction of membrane-bound
and secrcted fornts oJ' a giuen anttbody. The first
antibodies to appear in developing B lymphocytes are
membrane-bound IgM moJecules. Subsequently, these
celis switch to the production of a secreted form of
IgM. These nvo forms of IgM differ only in the Q-
terminal portions of rheir heavy chains. The heavy
I chain of the membrane-br:und form is 21 amino acids
" lcng.1 than that of the secreted fcrm, Themembrane.
bourttl beatl cbai:t hu a 41-amino-acid-long by.
dropbobic siriuence atthe C terminus that is probabty
responsible for anchoring.it to the cell surface. This
hydrophobic sequence is ieplaced by a 2)-amino-
acid-long ltydropbilic sequencc inthe secteted form

:
'

.i l1/ l
165
= ) OntrOns)iuSt hkc those of many other euka7 dc

(a)DNAl





lranSCrlpt on

O mmars/1.n l_

/

Possible alternate
(c) I\,,lessengei RNAs: mcdes ol processing

m

TranJa n
lTra
lgM hvy chOh3 igD h w chans

ffttli
l

alternate modes oFsphcing the heaw chain transcHpt.

 SIGNtt SEQUENCES GOVERN GENOME GEMEN"
5S

(a)DNA:

OM :

{}{}{} }
//

M SplClng

mRN
_

bn

Me
md


Transcription

)1
% ll
dng b





1 M
g

mRNA _

Transtltion
t
I

irf i'.'.U.JnlJ
Flgure.16.7 Gen-eticcontrcl uf themembrane-boundand light chains, (Airer p. Lecler, Sci Amct..246(5):102-1li
secreted forms of IgM. Only the lreary chain genes
gene-producrs are shown since both forms have idenrjcal
and tbS:.)

genes (Chaprer L3) pp. 35G359).'the C, gene seg-

ments contain four to six exons and three to five
introns (Fig. 16.7). In membrane-bound anribodies,
the heavy_ chain constant iegions are'produced by
splicing all six exons rogeiiler (Figs. 16,7a and &), The
last rqvo exons code for the hydrophobic. tails of the
membrane-bound heavy chains, During synthesis of
the membrane-bound form, the fifth C, exon is spliced
to a site 20 codons from the end of the fourthr exon
(Fig.16,7b), thus changing the amino acid sequence of
this pordon of the heavy chain constant region. In
secreted antibodies, the heary chain constant regions
are therefore rhe product of the first four exons (Fig,
16.76)`
The use of aiternate pathwap of transc-ription and
1
RIIIA processing to synthesize membrane-bound and i
secreted forms has been firmly established for the IgM \
class of antibodies. Recent evidence suggesrs that sim-
) segments have identical signalsequences located ad-
iiar alternate pathways of transcriptton iid splicing are
I
responsible for the production of rhe membrane- \
bound and secreted forms of the other classes of im-
J gene segments.pikewise, D and Cgene segmenr have
munoglobulins as well.
SIGNAL SEQUENCES GOWttRN GENO IE
ARRANGEMENTS
( IJow are dte genome rearrangemenrs rhat occur dur-
ing B lymphocyte development regulated? Wlut con-
trols the somatic recombination evenLs such that a lr
'gene segn'tent is joined to a segment and not to
/
another V segment or directly to a C segment? Several
long segments of chromosomal DNA carrying clusrers
of Vgene segmenis,, gene segmens, and/ gene seg-
ments of both m:ce and humans have now been si-
quenced, and the resulting nucleodde-pair sequences
sugge.st the presence of speciftc V-J, V-D, and D-J
folging signals. The same signal sequenccs. are found
XBfftEfrflfo all V gene segm-=enm, Similarly,' all / gene
jacent to their, coding sequences; however, their
signal sequenc{ is different from that adjacent to V
their own adjacfnt signal sequences.
\ __\
$sr

__


=




56 C11 P ER16 GEN

IC CONTROl OF THE IMi`LINE RESl)ONSE

08 me


_
_

) 0:G
C:G
A:T
A:T
nonamer A:T
T T
ArT
9:rr
12nucleotide A:T 22 nucleotide
Spa,ec
u:
(tt) Hypothetical T: A
"stem-loop" U: C
intermediate hbptamer 4 : T
with known Ui G
heptameric

and nonarietic
Ar T

signal
t


__
III

1:

sequenCeSr
1: r
U:U

T:A
utu
heptamer T : A
C;G
A: T
-t-,^f
\--1 -
-ispacer I iA
rznllclcotloe
G:c
-/
22nucleotide
sPacer
' r,e
AA
nonamer T : A
T:A
T:A
. G;C
Gic
/))\
\/1P
t

(c) B lymphocltc 0NA: -#&EI-+-ffiu+--

' Joined V.2Jp

l

Ftgrn.e.{6.,9 Signal sequences and rheir proposecl role in
vJ* ioining. The germ line.and B lyrn.:ho&e bNA arrange-
ments shown in (a) and (c), r'especihelf, as well as ihe
The signal sequences conrrolling V-J, V-D, and "preceding" (to the left as drawn in Figs , 1,6.4 andl,t
Dy' ioining concain 7-base-pair (heptamer) and 9-base- the/* gene segments. These signal sequences have
pair (nonamer)-long seguences separated by spacers potential to form "stem and loop" structures as
of differenr, but specific lengths, Eor f"-7. joining, the

l
spacer in rhe V* stgnal sequence is 12 nucleotidepairs
long, whereas that in *Le /-
signal sequence is 22
nucleotide-pairs long. The heptamer and nonamer contalns a 12 base palr spacer and the otter contains
sequences located "after" (to the right as drawn in Figs. Z?-base-pair spacer. This requirement would
16.4 and
_16.8) the V*
gene segmerlrs are complemen- edly be enforced by the specific prorein(s) rr
ury (n'ith the exception of one base-pair) to those he pttng process.Ve shitt s=nd
 ANITIBODY DlVTRSIT V 31.E JOINING SHES AND SOMATIC MUTA ONS
R

He: Jl .p
appear to control Vs-D and D-Js joining, whereas
somewhat different signal sequences mediate class P" 1

switching (see P. Leder, S'ci Arner, 246(5): 102-tt5, 5' CCTCCCACAGTG CACTGTCCTCC m 3.

1982). 3' GGAGGGTGTCA C GTGACACCACC-5'

4
5

ANTIBODY DIVEP"SITYI VARI,ABLE .JOINING

SITES AND SOMATIC NTUTATIONS
(b)

() GiC
T:A
A comparison of the diversity of amino acid sequences G:C
A:T
present in antibody molecules with that prediaed C:G
from the sequences of gene segments that encode A:T
these antibodies revealed rhat rhere i.s nrore variation

'

lt`
CIG=G
C C T C C

J
T-6 G 3.

_-7
,in amino acid sequences at the
[y' juncrions rhan is

61
vum l

predicted by the nucleotide sequences. Subsequeut

studies slrowed that mttcb of this attditional-diuersity
ucould
4 5' CCl:1:191 ttnngo huiirqcrv'
be explained b),aariatton tn ytteffi#ite_i1 GTCC-3..K`
\ recombination rluing tbe Y7J jointng euenk. An S
example of the use of alternate sites of joinin! of I,. (d) 1 s,-ccrrcc-3, V Cktto
Q
gi/
andl* gene segments'in the mouse is illustrated in Fig. !-1J

Pro Trp
16.9. During the joining of gene segments V*n, and.l5,
recombinaticn has been shown to occur between four 2 s',- CCTcGG-3'
Y\_1J
adfacent nucleotide po.sitions at rhe iurrction sites. As Pro Arg
shown in Fig. 16.9d, these recornbinalion evenrs pro-
3 5',-CCTCCG-3'
duce four drfferent nucie,ctide scquences that encode .-rJ.-r-

three distinct amino acids at position 96 in the mc)use Pro Pro

kappa light chain. Since amino icid 96 occurs in a 4 s',-CCTCCC-3', ,

region of the antibody chain that is invr;lved in antigen
binding, alternate 7j joining evenrs of this type un-
doubtedly contribute significantly to rhe grear diversiry
of antibody specificity that is observed in vertebrares.
Similar alternate joining events have been docu-
mented for V1-[ anCVol-D-{rjoining reactions, Thus,
tbe rce of altenutte sltes of recomltibmtion during
tbe joining euents rhatare involved in the assembly of
mature antibody gnes ln'ouides an additional mecb-
anism for gcticiett\ng a,,firbocllt diueriqt.
_De;pite-the vasr arlay of antibody qliversiry pro-
duced by (1) the joining of large families of V, D, and|
gene segrnents and (2) the use of alternate positions of
recombination during the joining reactions, consider-
able dau demonstrate that still another mechanism
must be involved in the geoeratiqn of antibody diver-
sity. This has been CItablished by comparing (1) the
nucleoride-pair sequences ofexpressed genes with the
sequences of germ line gene segmenrs and (2) the
acnral amino acid sequencCI of antibody chains with
the amino acid sequences prediaed from the nucleo-
tide sequences of thg genes, For exampie, when the
actual amino acid sequences of different mouse tr,
chains were compared with the predicted amino acid
sequences (based on the nucleotide-pair sequences of
L, gene segments) of L, light chains, di-fferences were
found in tne variable regions away from the junction
sitgs, Similar observations have been made in .studies
q-
'# r.\-
Pro
Amin0 acid number 95
Pro
96
t:igure ,t6.9 Diversitv at rhe V-I* iuncrion produced bv
ltriation in the exact posirion of tire joining reaction. (a)
Sequences ol V*n, and/*, at the sites that will form the
junction. The adjacent hepunucleotide signal sequences rhar
are beiieved to plav a central role in bringing the V- and/*
gene segmen[s into juxtaposition are also shonn. (b) Putariue
role of the hepranucleotide signal sequences olV*., aodJ *,
in tire recombinational ioining process (see Fig. 16.8 frlr a
more complete diagram of this event). (c) Four positions of
joining that have been docuntented for the mouse V*0, and
, /*, gene segments, (d) the producu of the four akernare
' joining events shown in (c) are listed along wirh the amino
acids that these sequences predict for amino acid residues
number 95 and 96 in the resulting kappa light chain. (Besed
on the results of E. E. Max, J. G, Seidman, and P. Leder, Arcc
NatL Acad. Sci. U.SA 76:3450-3454,1979.)
of heavy chain variable regions. In essentially all cases,
qh.e.ghaqgps have resulted from singie u.,.or16g.pair
trbYtffifi8$. Such substitutions riay represent 1-2
percent of the nucleotide-pairs of the gene segmenr
encoding the variable regions of antibodies. These

'
45s ,tt{l'rER 16 GENETI. coN'r*oL .!'THE l^.{MUr.rE *.ES',NSE
,V ,2

nucleodde-pair substiturion, ,r. ,r.#,Icl occur ,,f;.". segnrenrs, tf rhere are 300 )tngenesegmenrs,2,
ro
bv sonic' mechanisn ol scntitiir; tttLtttttirLti rhx is iJ o gene iegnrents, and 6 Js gene'iigments in human
resricted to the DM sequences encoding the variable f1 germ Iine iells, 45,000 drffeient heiw chain variable
regions of antibodv chains. Because rhese change.s in 3 regions coultl be a.ssembled. Using 'rl-rese esrimlres,
thevariablesegmentsof antibodvgenesoccurarsuclrJ' 67,500,000 differenr antigen-binding sltes could be
atrigh frequeno', the process bv which they occur is produced using just kappl lighr chains. I-ambda light
often called suttiltic bypetmtttatirtn.The mechanism chains produce anothei ievel of diversiry.
bv n'hich somadc hypermuution occurs is unlinown, Clearly, these anribody gene-segment fusions pro
Somatic hlpermutation of regions of antibody viCe for a vast amount of antibody diversiry. We now
genes that encode antigen-binding sites may be of
know, however, rhar further diversity is generated in
great value to the organism. 'ffithour this mechanism rwo additional ways: (1) somatic mutation and (2)
fbrgeneradngandbodydiversity,therangeof available variabiliry in rhe sites ar wfuch V-J, V-D, aod D-J
andbody specificity would be fixed ln terms of rhe
joining evenrs occur. In toral, rhe possible range of
sequences present in the genome at binh and the
antlbody diversiry seems almost limitless.
combinadons that could be produced by the various
levels of gene segment joining reacrions, Viruses and
other pathogens are consrantly evolving and produc-
ing new varianr with new antigenic determinanm. To REGUI"A,TION OF TR{.ISCRIPTION:
provide an adequate defense against the changing A TISSUE-SPECIFIC ENTIANCER
antigenic composition of these viruses and other com-
ponenE of the environrnent, the immune systeln must It has been known for several years that germ line
also be capable of rapidly responding ro rhese antibody genes are not transcribed or are transcribed
changes. What beuer wav to provide rhis safeguard at very low levels. Yet, in antibody-producing B lym-
dran ro endow antibody genes with dreir own mecha- phogmes, 10 to 20 percent of the mRl{ar molecules are
nism for rapid adaptation ro new antigens that might antibody gene transcripts. Vhat, then, is responsible
evolr,e in the future-somatic hrpermutatiorr? for the activatiori of transcriprion of antibody genes.
that undergo l'earraugentents and become active? In
the case ofrhe heavy chain genes, the answer appears
to be thar the rearangerlnnt process brings tbe pro-
I I 0\\I ll,{t,"t' COIViBINATIONS? moters ktcatec[ u\stream of Ln-Yr, gene segrnents
inlo tbe ,runge of in/luence oJ' a strong enbancer
One can leadii,v see that a large anounr of diversiti, cany elernent locate.d in the ir:tron beween the /s gene
be generated by the ioining of andbodygene segmenrs \ segn')enm and the Cn*gene segmenr (Fig. 16.10), Each
as iust described. For example, consider rhe number of f Ly-Vn gene segment conrains aR upstream promoter,
different kappa lighr chains posslble in humans: 30C I I'k-rwever, prior to the genomic rearrangement events
1/* gene segn']ents x 5"I* segmcrrrs =1500 fused V._/,. ) rhat lead ro heaw chain synthesis, rhis enhancer is over
gene segmenm, The healy chain variable region pro. 100,000 nucleotide-pairs away ffom the closest Irr-V,
vides even greaier diversiry because of the nlultiple D ' piornoter (Fig. 16.1C, rop). P,-esumably, this enhancer

grll. rvqir\u\or'

9oudu
Promoter Enhancer rt

+ < 2,OOO nuclotlde-palrs +
;.: ti,g t t t' t I 6. I (/ Pos irion of the dssue-specilic enhancer in the
/ segmenr-proximal intron of the heavy chain gene cluster of
the rnouse relative to the position of the promoter ln germ
line DNA (top) and after alenomic rearrangement leadilng ro
hc'ary chain slnrhesis (bonom). Prior ro rhi rearangenrcnr,
rlre enhancer is over 100,000 nucleotide-pairs fr-om tlre
 l;,;
t.

459
ALLELIC EXCLUSION

PoPulstion of B lynlPhocytes
cannot activate transcriptio!1 front promoters that are each Dloduclng s dlfferent sntlbody
located that far away, However, reafrangement events
occurring during B'cell differentiailon (see Fig. 16'5)
move the promoter of the closestIs-It gene-segment
to within less than 2000 nucleotide'pairs from the
enhancer (Fig. 16,10, bottom), The enhancer can now
,@",61'@-=
activate transiription from the promoter located up-
stream from the LrV, gene segmenl.The enhancer
=#=
".#. _#
irutolued in tbe actiuation of heatty cbain'syntbesis
is tksue specific; it acti\"ates transcription ory in
lirnphocyes and t',as no effect in cells derived from
other tissues. Presumably, the acdvation process re-
quires the presence of a transcriptional'activating fac-
Anligen
tor that is synthesized in llT nphoqtes' but not in other I

qpes of cells.
A similar enhancer element has been found in the
intron bemeen the light chain/* gene segment cluster
{ii -.-_-__#-'
oJ
and the C^ coding sequence. Thus, it seems iikely that
the movement oI aniibody gene prornoters into the
range of influence of tissue^specific enhancers may be
a gJneral mechanism of activation of aniibody genes I stirrr"tron or
during the differentiation of B lymphocytes. I cell dlvlslon

CLONtt SELECTION ,
Uo to this point, we have avoided the question of how

-#.
-\ ,.1 T '\.,*l
an organism initiates the qnthesis of antibodies spe- A
cific t5 antigens ttrat it has not previously encountered'

This is nicely explained by the clonal se'lection theory'
Recall that alt tbe antiboclies ptodu'ced bjt a single B
tyntpb o cy te ltaue tbe same antigcn' birttling Specific'
i4,,^out itillerent calls in a poputation of B lympho-
cltes will have undergone differmr: gaxom1. rear'
iangements learlirtg lo tbc prodrtction of antihodics
uirt ailluent-sperT|iritint Thus, the population of B
lymphocyes in i numan or a mcuse willbe producing
irery large vaniery of antibodies. The clonal selection
theory states that the bindi:tg of a particular for.eign
antigen to an antihocllt on tbe surfctce o/ a B lympho'
afie-stimrtlates tbat cett to diuide, producing large
riumbers of this particular B lymphocyte (a "clone" of
identical cells; aria tnus hrge amounts of the particular
-the,
antibody thai recognizes foreign antigen (Fig'
16.11),
xA -#-
Pooulation or 'clone' of B lymphocytes all producing
lhe same antibody speclfic to the stimulatlng antigen
Flcure I6,Jl Sclrematic diagmm of the role of clonal
selection in the immune rcsponse. Genomic f?arrange-
mens, the use of altcrnate loining sites, ancl somatlc nlpcr-
,nut tion all contribute to rhe developtnent of a population
,ir i"*oiio.vtii that colleaively prirduce a rast rarien' of
Jif.rJni'*ti6odies (ahhough &ih cell produces. only a
ii*f . n r. of -dbodi). whe-n a panicular antibody binds tois
,"'1n,iL!n,tit. ceil broducing'tirat panicular antibodi'
iiir"lii.Ji"
-o-"prtrtM aivide. efter a seiics of iell divisions,
a clonal
of S celG is produced, with all cells producing
th<i same antibody.

genome rean'(tnguneflt of liSht cbaitr coding. sa'

ALLELIC EXCLUSION \ gen ont c rect'1'a ttq? t t c t t i
E.tenccs antl one productiue
I

Consider one final point al-rout dre genetic control of
antibody sprthesis, Each B lymphocite makes only one
type of aniiUody, \flhy? Mammalian cells are diploid;
tir"u ..rv t*o iets of genetic information coding for
each of the antibody c6ainc, But only one productiue
if hrnrry clsain ioding seqttenL:es occttr in tttclt l;
nntobintclThis phenomenon is called allelic e't'
itiion6"*rs. one of the "alleles" ls excltulctl ft'onr
bcing expresserl.How? \flhy? At present, we s.till don't
tno*. Cteuty, there must be some type of a feedback

460
mechanism rhat arrests the recombination process(es)
involved in drese antibody gene reaffangemelt'us once
a productive rearrangement has occuned and the cell
has suned to synthesize a functional antibody, The
simplest mechanism would involve inhibition of tltis
process by the mature antibody itself. Howeuer, fur-
ther work wili be required to establish the mechanism
by which alielic exclusion occurs.
1' CELL R.ECEPTOR VARIABILITY
T lymphocytes mediate the cellular immune response
(see Fig, 16,1). The T cells recognize antigens on the
surface of cells and kill the cells carrying these anti-
gens. Like the antibodies produced by B lymphocytes,
T cells can recognize and destroy cells carrying
amazingvariety of antigens. Thus, the T cell response
also exhibits a phenomenal degree of specificity, How
is this specificity produced? The answer is thatT cells
pt'odltce membrane-bound receplors tbat *re uery
';iittilu.r to lbe antiboclies produced byB lymphocyes,
Moreover, tbe diuersity ofT cellreceptorspecficity is
lrorluced by gmome rearrangentents analosolts lo
riLt.,stt irutoluecl in antiboctlt plodu.:tion (See the pre-
a chain
Vari3ble region
Constirrrt regiOn
Cytoplasm
Variabte region
I'lsure L6.12 Diasraflis showins (a) the strucnrre of a T
ceTl receptor adt$SEsln *re cel in'embrane and (b) the
regions ofthe a and p receptor proteins that are encoded by
t?ft,. -
i,i;
tt "
F ER
C 16 GENttIC CONFROL OF THE lMMUNE ttSPONSE
ceding sections of this chapter). But how do T lympho-
cytes avoid interacting witlt free antigens to avoid
duplicating the function oi B cells in the immune
response? As it turns out, T cells must simuluneously
recognize both tire offending antigen on the cell sur-
face and another protein that,occurs only aaached to
cell surfaces. This second cell-surface prorein that the
T cell must recognize is the product of one of many
genes in rhe maior histocompatibility complex
(uac) The MHC locus (see the following section)
encodes a complex group of proteins that are present
on all the cells-in tire body of a human (or a mouse).
Thus, T cells are able to recognize and ,any cell
produdng 4 gen 411g9n , ?
of a viru-s) in any tissue of the body. The turteraction
the T cell receptor with the two rypes of cell-surface
antigens (the offending antigen and the histocompat!
an bility antigen) is illustrated in Fig. 16.1.
' Tbe T celt receptott are composed of two poly'
peptide cbains, a und p, eacb encoded b! l-y, D, J,
aia C gene segrnents ittst like cntiboC,T cbains. Itrc
q- and B-po\peptides, Jike antibody chains, cont in
variable regicus that form the antigen'binding sites
and constant regions that anchor the receptors on the
cell surface (Fig,15.l?4), The rariable regions of the T
cell receptcrs ire encoded by multiple L-V, D, andJ
P chaln
NHc
Variablo reEtioo
Constailt region
' Constant rogion
the Z-V, D, J, and C gene segmenu, respectively, (After M. K
Davis, Y. Chien, N. R J, Giscoigne, and S. M. He&ick
Immu.rnl, Reu, 8: 235-258,,:1984.)
t OR HIST()COMMTIBILiW COMttEX
61

(a) Germ-lirre:

(b) Rearranged functional P {hain gt,ne;

ments for both kappa light chains and lrearl'antibodv
chains. l-lowever, there are more/ gene segntetlts irt
drc T cell receptor gene clusters. For example, there
are 72 lrrnctional J gene segmenls for B receptor
polypepticles (fig. 16'13). Moreover, we still do not
tnow wheiher oi not tlre rariable segmenls of T ccll
receptor gettes underSo son)atic h1'permuution lrt

any case, it is clear rhatT ccll receplorc c.tltihit Q ,lt'{'((

annunt of diuarsiil, and that tltis diuersit)'is Sertet'"

Hi

: a.ted b.1t gen() trxe rearran Setnents dtu'i ttg'[ l1'n'1' 6"'
c-t,tc tlifierentiation it't a manner analogous to thosc
iiruol,,ed in the producr,ion of antibody dit'ersin' ill B
[)'nrphocytes.
As was mentioned earlier, there are several differ-
ent rypes of T t)'mphot)-tes and they plai'different roies
in thi cellular immune response, For an excellettt
Ciscussion of tite different rlPes of T cells and their
lmtt resp:fi functions, the reader is referred to Chapter 24, "Intntu-

fthc T:clrcceptofgclcclustcls niq,," of.Molecular Cell Biologt byJ. Darnell, H' Lodish,
and D. Baltimore.

MAJ OR HISTOCOMPATIBILITY COMPLEX

The immune response in mammals is a very contplex

variable regions are encoded byollyabOut30 Vgene
segments,whereas ttere are about 300 y gene seg
process involving a large number of different mllcro-
nrolccule.s antl clifferent ccll t1pes. Our dlscussion ttr
this point has lreen restricted to the genetic control of
the iynthesis of antibody chains and T cell receptor
protein.s. Many of the other compollents o[ the inr'
mune response, such as the trarcplar*atiott ntlliScrts
that are largely responsible for the rejection of foreign
tissues in iransplant operations, are controlled b,r' 2
muldgene complex called the major bistoconqati'
bitity cornplex (MHC).In humans, theil{HC proteins
 (-riAl/niR 1(r GllNlillc coNi'i{ol, 0F Tl'lli lMMLlNn RIiSPONSB
462

are errcodecl by the HLA (forlluman Ietrkocye rtnti-
gen complex) locus on chrontc.,some 6; in the mouse,
in" muC locus is designirredrfl'2 (ffistocompatibility
locus 2) an<J is on chromosome 17. In both mice and
frurrni, rhe tllHC locus is yery large (>2 x 106 nucleo
dde-pairs) and col'ltains a laqe rtumber o-i genes
Moreover, there is a t'ery large nuntber of distinct
alleles for many of these genes such that rhe probabil-
in, of anv rwo individuais being identical for all the
,titlc genes is e>cremely small. The MHC genes are
said tJ be ttigbly potyiorphic because of the large
number of alleles of individual genes that are usually
segregating in a given population. , --
" ine uac genes encode three different classes of
oroteins that aie involved in different aspecs of the
i**un. response. The structure of the human '4r'IlC
cells of an organism and permit T lyn,phocyes to
disdnguish "self" from "foreign." The M'HC clztss I
protei-ns are the antigens that usually are responsible
ior the refection of foreign tissues in tissue and organ
in Fig. 16.1,-these antigens
transplants. As illustrated
play ikey role in the recognition and destruction of
telis carrying foreign andgens by cytotoxic T lympho-
qtes. A single f cell receptor is believed to recognize
both the foreign antigen and the class I histocompati-
bility antigen during the cytotoxic T ceil immune re-
sponse.
that
The MHC class II genes encode polypeptides
are located pimaily on tbe surfaces of B lympho'
II proteins provide
qttes and rhacropbages, Ir4HC ciass
a soecial vpe of T lymphocye called the 'T helper
celi" with capaclryfoi self-recognition and facilitate
r.h'e

(l//A) locus and the relative locations of genes that communication'berween the different q'pes of cells
encode the different classes of histocompatibiliry anti- involved in the immune response, Finally, the MHC
gens are shown in Fig. i5.14. Theclass I genes encode clcss III gmes cofip|etnent Proteins that
interact with complexes and induce
ihe trcotsplafltatiofl a.ntlSel?s mentioned. The class I
proteins exist as gtycoproteins anchored as integral cell lysis.
The MHC cl`SS class ll antigens are auchorec
membrane proteins with the antiSenic determinans
in the cell have structures very similal
exposed on the outside ofcells. lhey are present on all

locus;

:! :: T cusm

Tf',
One gene:

I +
I
\*----Y----------
+
lntrace uiar
Domain of Signal Enracellular
region Transmembrane region
antigen encoded: Peptide
domain

\\,.rwruul \fl\lmnfir\ -+ lm&uttd \u:

{b it\\'r \,\r\t -1 S'eetPfrlr
p\onht^,'
(r\\u\ui \\ro\\un\ -) ?\$0ucsd
h 5 T tt\\t af\hgtn
 SUMMARY
to the strucrures of T cell rcceprors (see Fig. 16.12).
However, the diversiry of MHC antigens is much less
than that ofantibodies and T cell receptors, and, so far
as is known, no genomic rearrangement is involveci in
SUMMARY
The immune system of verebrate animals protects
them from invasion by pathogenic microorganisms
and other foreign substances, The immune response is
very complex, It involves three different tlpes of white
blood cells: (1) B t1,tnlthocltas that procltricc antibod.
ics, (2) 'l' l-yttt/tl.tot'.1,l(,.r Ihat proc[l cc 'l rall t\'(.(f )l()rs
and use them to seek out and cleslrol, cclls cctnltitlg
foreign antigens , and (3) n ncropbct.qes that carry out
, ltba?oc.l'!osis rtl rttt tittotl.l,*tttli,qctt c'oliTrl1,.r'1,.s,
ruscs, [.lactcria, and so on, ht trclclition, T ccll rcc<tgni-
tion of cells that are producing foreign antilens re-
quires tlre pre.sence of specific tti:;tocotnltutibiI it.1,
antigens encoded by the mcjrn' bi:;tot:otttpatittiIit1t
complex (the Hl"{ locts in l-rumans).
A remarkable feature of the immune response is
rhe seemingly limitless uariety o! antibodies anti T
cell receptor proteins tbat can be g,nS11t.tirt,, ',,
response to antigens tbrtt tbe anintal |tas not preti.
ottsly encountered. We now understand how this
phenomenal diversity of anribody specificiry and T cell
receptor specificiry is produced. Thegenetic inforna.
tion coding fctr antibod.y cltains is stoired hz seueral
sets of gene segntetzls, and the segnrents are put
together in the appropriate sequences by gcnome
realTangements tbctt occur during tbe deueloltment
of tbe antibody.producing cells (tlt,z I1 lympho.
c1te.sJ.'The same mechanism is used to generare vari-
abiliry in the antigen specificiry of T cell receptors. The
germ line DNA contains rhe genes encoding T cell
receptor proteins stored in the form of sets of gene
segmenB that are assemblcd into functional genes
during the differentiation of T lymphoq,tes from srem
cells.
Antibodies are compo.sed of trtto lillltt choitrs
(either kappa or lambcla) and truo lteeuy cl.tuirts.
Each antibody chain contains a utrriable region tbat
forns thc an lige n.hiuclirtg.silc ancl a crntslunt n:giort
that atrcbors tbe antibody to tbc cell surfacc in the
case of membrane-bound antibodies. The uariable
rc'gions of antibocties are encoded by eitber two
(ligbt cbains) or thrce (hcaa.y cbuitrs) gcne scg,nents
that are prcscut in the gczrr lirtLt DNtl itt rttrtltiltle
copies. The constant regions ol antibodies are en-
coded by lene segments that are present in the ge-
nome in only one or a few copies pe r cell. Kappa llgbt
cbain genes are assorubled by genomic rcdn.ange-
ments ibat occu.r during B cell ttiflererfiiation lrom
463
the genetic control of MHC antigen diversin,, Insread,
the observed diversiry r,lsults from the presence of a
large number of highly polymorphic MHC genes,
about 300 L*-Y * gene segments, 5 J* gene segrrc/r/.$,
and onc C,* gene scgnxenl, Fttttclional heat:.l, c'ltain
genes are sirnilarj assembled lrom oltorrt 30() l.tr
Y,, gene segruents, l0 D gette segnrc,tts,.1
.lr, 11cttt,
s('Sntents, and I C,, &ene segmcntr The r.sc o.[ rtltcr.
rtrrlc silt,s ol' gt'ttt, .\'(,.(/,/(,/,/ .joittittg cluring thcr l.ic-
nomic rearrangement events and sotttul ic lt.l,1tct'tttrr.
tcrtiott within the variable region genc segntents
y . contribute to rhe production of additional antiboclr,
cl ivcrsity.
Antibodies are ol five dift'erent immunoglobtrlin
classes: tgrl4, tgD. tgG, IgE, and /gA. The class oi
",.,l'15rrdy is cleternrined by its bcat,.f cboitr ''ott.tiiitii
rcgion, which in tr.rrn is determined by the C .tcrrc
selntent that was expressecl during is synthesis, C/,i.;.'
switching occurs q,hen a B lymphocyte stops s,virdte-
siz.ing one class of anribody and begins s)nrhesiziug
another class of antibody with rhc samc antigeu spec.
ificitr,. Class switching involves the expression of the
saure variable region gene segtxcnts but a diiterent
healy chain constant region gene segmFnt. d-lriss
su'itc:hittp tttrxl riftetr occt!rs by lirtbti(.gcnotnic
reorrongefiruefs sirnilar to.those that resulrtd in the
, synthesis of the original antibody chains. Horvever.
class switcltirtg can alsct occur bJ, allatnale paftents
of transcript splic i t tk.
Germ line anticody genes are transcribed at a ven-
low rates or not at all. The productive rearrangemenr
of antibody gene scgmenrs during B cell ciifferenria-
tion apparently actiuates transcriptiott of tbe atsetn.
blerl gene lry bringing tbe promoter hcotcd ttl)-
slreatrtJ)rttn tlte L-Y gette segtilenl ittttt ll.ta rltt?1, t).t
irfluence of a tisxrc-specific cnbancer located in the
intron bcnveen thg/ segmi:nt..clu.ster and tlie C gene
segnrent. \\
Clonal selectioz nicely explaihp the production of
large numbers of B lymphocytes all ,synthesizing the
same antibody with specificiry for bidnd_a panicular
andgen present in the circulatory .system of an aninial.
Only one productive light chain genomic rearrange-
ment and one productive heavy chain genonric rear-
rattgerncnt cln occur in a given l) lynrphoqre. This i.s
known x allelic et;clusion and, clearly, must be con-
trolled by some type of feedback mechanism. How-
ever, the rnolecular basts of allelic exclusion remains
unknown.
Tbe class I an.tigens produced b), tbc ntaior


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