Role of B Cells and Antibodies in AcquiredImmunity against Mycobacterium tuberculosis
Jacqueline M. Achkar1, John Chan1,2, and Arturo Casadevall1,2
1Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 104612Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461
Correspondence: [email protected]
Accumulating evidence has documented a role for B cells and antibodies (Abs) in theimmunity against Mycobacterium tuberculosis (Mtb). Passive transfer studies with monoclo-nal antibodies (mAbs) against mycobacterial antigens have shown protection against thetubercle bacillus. B cells and Abs are believed to contribute to an enhanced immune re-sponse against Mtb by modulating various immunological components in the infected hostincluding the T-cell compartment. Nevertheless, the extent and contribution of B cells andAbs to protection against Mtb remains uncertain. In this article we summarize the mostrelevant findings supporting the role of B cells and Abs in the defense against Mtb anddiscuss the potential mechanisms of protection.
Approximately one-third of the world’spopulation is infected with M. tuberculosis
(Mtb). It is generally thought that the majorityof this population harbors latent bacilli, ofwhich only �10% develop the disease activetuberculosis (TB) during their lifetime. The in-terplay of immunological components resultingin contained and stable latent Mtb infection(LTBI) is incompletely understood. Cell-medi-ated immunity (CMI) plays a key role in thedefense against Mtb (Lewinsohn et al. 2011; Ot-tenhoff 2012; Ottenhoff and Kaufmann 2012),but increasing evidence suggests that CMI isnot the sole defense mechanism against the tu-bercle bacillus. In humans, an intact CMI doesnot consistently protect against disease, and inMtb-infected nonhuman primates, cell-mediat-ed responses do not significantly correlate with
the outcome of infection (Lin et al. 2009). Fur-thermore, not all individuals with LTBI andimpaired CMI develop TB. Current and newlydeveloped TB vaccines targeting CMI have lim-ited efficacy in humans, and vaccine-inducedcell-mediated responses often lack significantcorrelation with efficacy (Colditz et al. 1994;Fletcher et al. 2013; Tameris et al. 2013). Thesefindings support a role for additional immunecomponents in the protection against Mtb be-yond that contributed by CMI.
The strong evidence for CMI as the maindefense mechanism against TB has historicallyset up a false dichotomy that posited no rolefor humoral immunity (Maglione and Chan2009; Achkar and Casadevall 2013). The generalbelief that, because of their extracellular loca-tion, antibodies (Abs) are not involved in the
Editors: Stefan H.E. Kaufmann, Eric J. Rubin, and Alimuddin Zumla
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protection against intracellular pathogens fur-ther limits an open view for the role of B cellsand Ab-mediated immunity against Mtb. How-ever, this view has been largely discredited andabandoned based on abundant evidence frommany systems (reviewed in Casadevall 2003).We note that although immunoglobulins area major product of B cells, these lymphocytescan contribute to the host immune response toMtb via Ab-independent mechanisms (Bosioet al. 2000; Maglione et al. 2007; Maglioneand Chan 2009; Russo and Mariano 2010; Al-meida et al. 2011; Zhang et al. 2012). WhereasAb-independent B-cell effects are largely accept-ed by the field, the historical controversy revolv-ing around the role for B cells and the humoralimmune response in the defense against Mtbtypically relates solely to that of Abs. Therefore,in this review, we refer to B cells and Abs asdistinct immunological elements simply tostay within the currently operating intellectualframework in the Mtb field.
Abs have many mechanisms by which theycan modify the outcome of bacterial intracel-lular pathogenesis, ranging from opsonizationto signaling through Fc receptors (FcRs) (re-viewed in Casadevall 1998, 2003; Nimmerjahnand Ravetch 2008). Furthermore, just as for oth-er facultative intracellular pathogens, there isplenty of evidence for an extracellular phase ofMtb during which it can be directly targeted byAbs (Smith et al. 2000; Casadevall 2003; Grosset2003; Karakousis et al. 2004; Kim et al. 2010;Ahmad et al. 2011; Hoff et al. 2011; Driver etal. 2012). Importantly, Abs have been shown toplay an important role in the defense againstother intracellular pathogens such as Salmonel-la, Chlamydia, Cryptococcus, and Histoplasmaspp. (reviewed in Casadevall 2003), and forsome of these pathogens such as Salmonella, vac-cines protecting through Ab-mediated immuni-ty have ultimately been developed and licensed(Collins 1974).
A classic example for a paradigm shift froman exclusive CMI-centric view toward accep-tance of an important role for Ab-mediated im-munity occurred in the field of mycology, inwhich B cells and Abs were also once consideredto have no protective role. As in TB, it was not
possible to establish a consisted protective rolefor humoral immunity with polyclonal seraagainst fungi such as Candida albicans andCryptococcus neoformans (reviewed in Casa-devall 1995). However, the implementation ofhybridoma technology produced immunoglob-ulins that revealed the existence of protectivemonoclonal antibodies (mAbs) and challengedthis dogma (reviewed in Casadevall 1995; Casa-devall and Pirofski 2012a). Also like Mtb, manyof the medically relevant fungi such as C. neo-formans and Histoplasma capsulatum are facul-tative intracellular pathogens, and the controlof infection with these fungi requires vigorousgranuloma formation indicative of CMI. Thebreakthrough in medical mycology came fromthe work of Francoise Dromer and colleagueswho identified a protective Ab against C. neofor-mans, a finding that suggested the notion thathumoral immunity could mediate protection ifthe right Ab response was elicited (Dromer et al.1987). Two decades later humoral immunityhad been shown to be protective against numer-ous fungi (reviewed in Casadevall and Pirofski2012a), and two vaccines against C. albicans arecurrently in clinical trials, both of which are be-lieved to mediate protection by eliciting a pro-tective Ab response (reviewed in Cassone andCasadevall 2012). Parallel developments appearto be occurring in the TB field. In the followingsections we discuss the complexity of humoralimmunity in TB, the evidence for a role of Absand B cells in the protection against TB, and thepotential mechanisms for Ab-mediated immu-nity. Based on the discussed findings we posit arole for B cells and Abs in the protection againstTB and suggest that an effective immunityagainst Mtb includes a humoral component.
COMPLEXITY OF THE HUMORAL IMMUNERESPONSES AGAINST Mtb
TB serological studies provide abundant datathat Mtb induces a humoral immune responseto a wide variety of mycobacterial antigens(Ags) in humans and animals. Although hu-mans and nonhuman primates show consider-able heterogeneity in Ab responses against Mtb(Lyashchenko et al. 1998; Ireton et al. 2010;
J.M. Achkar et al.
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Kunnath-Velayudhan et al. 2010, 2012), Abresponses in other animal species such as ele-phants or deer are more homogeneous (Lyash-chenko et al. 2008, 2012). Animal and humanserum transfer studies have provided inconsis-tent and sometimes contradictory data regard-ing a role of Abs in the protection against TB(reviewed in Glatman-Freedman and Casade-vall 1998). Several observations suggest expla-nations for these inconsistent results. Just asin other diseases such as fungal infections inwhich the Ab response is complex and involvesboth protective and nonprotective Abs (re-viewed in Casadevall and Pirofski 2012a), inter-study inconsistencies might have been due to thevariability typically found in polyclonal prepa-rations. Nonprotective or even disease-enhanc-ing Abs can also negatively or positively influ-ence the efficacy of protective Abs when these actin combinations (Nussbaum et al. 1996; Chowet al. 2013), further highlighting the difficultywhen evaluating polyclonal preparations. Thediscovery that fungal Ags targeted by protectivemAbs do not always elicit an Ab response dur-ing a natural infection (Nosanchuk et al. 2003),could be another explanation for negative re-sults when transferring immune sera from vac-cine studies. On the other hand, little is knownabout the role and complexity of protective Absin Mtb infection models that mimic human in-fection by developing both natural LTBI andTB without modification of immunity. Andlast, Ab responses against Mtb can be species-specific (Lyashchenko et al. 2007, 2008), andthus the transfer of Ab preparations obtainedfrom a species different than the one studiedwould also result in considerable variability.
EVIDENCE FOR A ROLE OF HUMORALIMMUNITY IN THE PROTECTIONAGAINST TB
The efficacy of Ab-mediated immunity againsta microbe can be established by the three gen-eral approaches as proposed by Casadevall(2004): (1) Establish that passive administrationof a microbe-specific Ab modifies the course ofinfection to the benefit of the host; (2) ascertainthat the presence of microbe-specific Abs in a
host is associated with decreased susceptibilityto infection and disease; and (3) establish thatincreased susceptibility to disease exists in hostswith deficits in humoral immunity and/or Bcell function. For TB evidence for all three cri-teria has now been documented (Table 1).
Passive transfer studies with Abs against my-cobacterial Ags. Evidence that passive Ab trans-fer can improve the outcome of experimentalmycobacterial infection in mice was document-ed by eight independent groups for mAbsagainst mycobacterial Ags (Teitelbaum et al.1998; Pethe et al. 2001; Chambers et al. 2004;Hamasur et al. 2004; Williams et al. 2004; Buc-cheri et al. 2009; Lopez et al. 2009; Balu et al.2011) and three recent studies with polyclonalIgG or serum within the same species (mice) orfrom humans to mice (Roy et al. 2005; Guiradoet al. 2006; Olivares et al. 2006) (Table 2). Stud-ies that have probed the role of protective mAbshave used a variety of parameters to assess theirefficacy including prolongation in survival time(Teitelbaum et al. 1998; Chambers et al. 2004;Hamasur et al. 2004), reduced dissemination(Pethe et al. 2001), reduced tissue pathology(Chambers et al. 2004; Lopez et al. 2009; Baluet al. 2011), and reduced mycobacterial burdenas measured by colony forming units (CFU)(Hamasur et al. 2004; Williams et al. 2004; Buc-cheri et al. 2009; Lopez et al. 2009; Balu et al.2011). Of note, one study also compared theeffect of mAb with IFN-g and the combinationof both (Balu et al. 2011). Although a significantreduction of lung CFU was seen with the com-bination of mAb and IFN-g, and a borderlineeffect for mAb alone, no significant CFU reduc-tion was seen with IFN-g alone, pointing to-ward a potentially important interplay betweenAb and cytokine in the protection against TB.Recent passive Ab transfer studies in mice usinghomologous or heterologous (human) serahave also shown protection against experimen-tal infection (Roy et al. 2005; Guirado et al.2006; Olivares et al. 2006). However, none ofthese monoclonal or polyclonal Ab transferstudies include a comparison to the efficacy ofBCG (Bacille Calmette–Guerin) vaccination inmice. When viewed from this context we notethat whereas vaccination with BCG often induc-
B Cells and Antibodies in TB
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Table 1. Evidence of antibody-mediated protection against Mycobacterium tuberculosis infection
Criterion Evidence References
Passive Ab transferstudies
Eight independent groups have shownprotection and/or modification of thecourse of mycobacterial infection in micewith passive transfer of mAbs tomycobacterial antigens (Table 2).
Three independent groups have recentlyshown protection in mice with passivetransfer of immune polyclonal sera.
Teitelbaum et al. 1998; Pethe et al. 2001;Chambers et al. 2004; Hamasur et al.2004; Williams et al. 2004; Buccheriet al. 2009; Lopez et al. 2009; Baluet al. 2011
Roy et al. 2005; Guirado et al. 2006;Olivares et al. 2006
High Ab titer associatedwith reducedsusceptibility
AM-containing conjugate vaccine elicitsAb response that reduces susceptibilityto infection.
BCG as well as Mtb antigen-containingconjugate and DNA/RNA vaccines elicitcellular and humoral immune responsesand improve outcome of infection.
Hamasur et al. 2003; Glatman-Freedman et al. 2004
Huygen et al. 1996; Hamasur et al. 2003;Glatman-Freedman et al. 2004; Xueet al. 2004; de Valliere et al. 2005; Giriet al. 2006; Grover et al. 2006; Teixeiraet al. 2006; Chang-hong et al. 2008;Kohama et al. 2008; Palma et al. 2008;Niu et al. 2011
Increased susceptibilityin hosts with Abdeficits
Peak of childhood TB is temporallycorrelated with nadir in maternal Ab.
Lack of Abs against certain mycobacterialantigens is associated with TBdissemination in children and adults.
Lack of early humoral immune response inMtb-infected nonhuman primatespredicts high likelihood for reactivationdisease.
B-cell-deficient mice are more susceptibleto TB.
Polymeric IgR-deficient mice loosemycobacterial antigen-specific IgAresponse in saliva and are moresusceptible to respiratory BCG infection.
IgA deficiency increases susceptibility tomycobacterial infection in mice.
Beyazova et al. 1995; Cruz and Starke2007; Donald et al. 2010
Sada et al. 1990; Costello et al. 1992;Boggian et al. 1996; Gupta et al. 1997;Dayal et al. 2008
Kunnath-Velayudhan et al. 2012
Vordermeier et al. 1996; Maglione et al.2007, 2008
Tjarnlund et al. 2006
Rodriguez et al. 2005; Buccheri et al.2007
Other Existence of mycobactericidal AbsFcR-mediated phagocytosis promotes
phagolysosomal fusion.FcR-mediated phagocytosis increases
macrophage Ca2þ signaling andintracellular killing.
Higher FcyRIA expression in (i) subjectswith TB compared with LTBI, and (ii)subjects before compared with afterantituberculous treatment.
IgG bound to BCG enhances oxygen releasein phagosomes and antimycobacterialactivity of alveolar macrophages.
Conti et al. 1998Armstrong and Hart 1975
Malik et al. 2000
Sutherland et al. 2013; Cliff et al. 2013
Suga et al. 1996
Data in table modified with permission from Achkar and Casadevall 2013.
mAb, monoclonal Ab; AM, arabinomannan; BCG, Bacillus Calmette–Guerin; Mtb, M. tuberculosis; TB, tuberculosis; FcR,
Fc receptor; LTBI, latent Mtb infection.
J.M. Achkar et al.
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Table
2.Pa
ssiv
etr
ansf
erst
udie
sw
ith
monocl
onal
antibodie
ssh
ow
ing
pro
tect
ive
effe
cts
agai
nst
exper
imen
talm
ycobac
teri
alin
fect
ion
mA
b(i
soty
pe)
Targ
etan
tige
n
(typ
e)M
odel
Org
anis
m/
antige
n
chal
lenge
(route
)
mA
bad
min
istr
atio
n
(tim
ing
toin
fect
ion)
Chan
ge
inC
FUB
iolo
gica
lef
fect
Quan
tita
tive
effe
ctR
efer
ence
9d8
(IgG
3)A
M(c
apsu
lar
po
lysa
cch
arid
e)
Mo
use
(BA
LB
/c
and
C57
BL/
6)
Mtb
(ae
and
i.t.
)i.
t.(s
imu
ltan
eou
s/
pre
incu
bat
edm
Ab
wit
hM
tb)
$L
un
gs,
sple
en
and
live
r
Pro
lon
ged
surv
ival
and
enh
ance
d
con
tain
men
to
f
Mtb
wit
hin
gran
ulo
ma
cen
ters
30%
–60
%o
fm
Ab
-tre
ated
mic
esu
rviv
ed.
75d
(33%
for
.22
0d
)vs
.
dea
thin
con
tro
lm
ice
wit
hin
30d
(p
,0.
01)
Teit
elb
aum
etal
.
1998
4057
(IgG
3)H
BH
A(s
urf
ace-
exp
ose
dp
rote
in)
Mo
use
(BA
LB
/c)
BC
G(i
.n.)
i.n
.(s
imu
ltan
eou
s/
pre
incu
bat
edm
Ab
wit
hB
CG
)
$L
un
gs
� Sple
en
Red
uct
ion
of
dis
ease
dis
sem
inat
ion
Red
uce
dsp
leen
colo
niz
atio
n
by�
3lo
g(10
)C
FU
s3
wk
po
stin
fect
ion
inm
Ab
-
trea
ted
mic
eco
mp
ared
wit
hco
ntr
ols
(p
valu
en
ot
stat
ed)
Pet
he
etal
.
2001
TB
A61
(IgA
)16
-kD
aa
-cry
stal
lin
(in
trac
ellu
lar
and
cell
wal
lp
rote
in)
Mo
use
(BA
LB
/c)
Mtb
(ae
and
i.n
.)i.
n.
(3h
bef
ore
and
3o
r
6d
afte
r)
�L
un
gsC
FU
red
uct
ion
in
earl
yd
isea
se
Red
uce
dlu
ng
colo
niz
atio
nb
y
�1
log(
10)
CF
U9
d
po
stin
fect
ion
inm
Ab
-
trea
ted
mic
eco
mp
ared
wit
hco
ntr
ols
(p
,0.
01)
Wil
liam
s
etal
.
2004
SMIT
H14
(IgG
1)
AM
po
rtio
no
fL
AM
(cel
lw
all
glyc
oli
pid
)
Mo
use
(BA
LB
/c)
Mtb
(i.v
.)i.
v.(s
imu
ltan
eou
s/
pre
incu
bat
edm
Ab
wit
hM
tbo
r1
hp
rio
r)
�L
un
gs
�L
iver
� Sple
en
CF
Ure
du
ctio
nan
d
pro
lon
ged
surv
ival
Red
uce
dlu
ng,
live
r,an
d
sple
enco
lon
izat
ion
by
�1
–2
log(
10)
CF
U14
d
po
stin
fect
ion
inm
Ab
-
trea
ted
mic
e1
hb
efo
re
infe
ctio
nco
mp
ared
wit
h
con
tro
ls(
p,
0.05
lun
gs
and
p,
0.01
live
ran
d
sple
en)
and
surv
ival
of
7–
8/10
(75%
)m
Ab
-
trea
ted
mic
eve
rsu
s4/
10
(40%
)co
ntr
ols
at70
d
(p
,0.
01)
Ham
asu
r
etal
.
2004
Con
tin
ued
B Cells and Antibodies in TB
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Table
2.
Continued
mA
b(i
soty
pe)
Targ
etan
tige
n
(typ
e)M
odel
Org
anis
m/
antige
n
chal
lenge
(route
)
mA
bad
min
istr
atio
n
(tim
ing
toin
fect
ion)
Chan
ge
inC
FUB
iolo
gica
lef
fect
Quan
tita
tive
effe
ctR
efer
ence
MB
S43
(IgG
2b)
MP
B83
(cel
lw
all
and
CF
pro
tein
)
Mo
use
(BA
LB
/c)
Myc
obac
teri
um
bovi
s(i
.v.)
i.n
.(s
imu
ltan
eou
s/p
re-
incu
bat
edm
Ab
wit
h
M.
bovi
s)
$L
un
gs
$ Sple
en
$ Liv
er
Red
uce
dlu
ng
pat
ho
logy
and
pro
lon
ged
surv
ival
Twic
eth
ees
tim
ated
amo
un
t
of
no
rmal
lun
gti
ssu
ein
mA
b-t
reat
edm
ice
com
par
edw
ith
con
tro
ls
(p
,0.
05)
and
8/8
(100
%)
of
mA
b-t
reat
ed
mic
esu
rviv
ed.
38d
(en
d
of
exp
erim
ent)
vers
us
0/8
(0%
)o
fco
ntr
ol
mic
e
(dea
thw
ith
in30
–34
d)
(p,
0.00
5)
Ch
amb
ers
etal
.
2004
TB
A61
(IgA
)an
d
TB
A84
(IgA
)
16kD
aa
-cry
stal
lin
(in
trac
ellu
lar
and
cell
wal
lp
rote
in)
and
38-k
Da
Pst
S-
1(C
Fp
rote
in)
Mo
use
(BA
LB
/c)
Mtb
(i.t
.)i.
t.(m
Ab
give
n30
min
bef
ore
infe
ctio
n)
�L
un
gs
(on
ly
for
TB
A61
)
Red
uce
dlu
ng
pat
ho
logy
(on
ly
for
TB
A61
)
Red
uce
dlu
ng
colo
niz
atio
n
by�
200�
103
CF
U21
d
po
stin
fect
ion
inm
Ab
TB
A61
-tre
ated
mic
e
com
par
edw
ith
con
tro
ls
and
TB
A84
-tre
ated
mic
e
(p
,0.
05)
and
red
uce
d
per
ibro
nch
ial
infl
amm
atio
nin
TB
A61
-
trea
ted
mic
eco
mp
ared
wit
hco
ntr
ols
21d
po
st-
infe
ctio
n(p
,0.
05)
Lo
pez
etal
.
2009
Con
tin
ued
J.M. Achkar et al.
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Table
2.
Continued
mA
b(i
soty
pe)
Targ
etan
tige
n
(typ
e)M
odel
Org
anis
m/
antige
n
chal
lenge
(route
)
mA
bad
min
istr
atio
n
(tim
ing
toin
fect
ion)
Chan
ge
inC
FUB
iolo
gica
lef
fect
Quan
tita
tive
effe
ctR
efer
ence
TB
A61
(IgA
)16
-kD
aa
-cry
stal
lin
(in
trac
ellu
lar
and
cell
wal
lp
rote
in)
Mo
use
(BA
LB
/c,
C57
BL/
6,
C3H
/HeJ
)
Mtb
(i.v
.)i.
n.
and
i.v.
give
nat
3,5,
or
7w
kas
CIT
wit
h
INF-g
,p
oly
clo
nal
Ab
agai
nst
IL-4
,an
d
mA
bT
BA
61in
mic
e
trea
ted
for
4w
kw
ith
INH
/R
�L
un
gsin
CIT
-
trea
ted
mic
e
Pre
ven
tio
no
fT
B
rela
pse
inm
ice
trea
ted
wit
hC
IT
toge
ther
wit
h�
gran
ulo
ma
form
atio
nan
d�
cyto
-an
d
chem
oki
ne
leve
ls
Red
uce
dlu
ng
colo
niz
atio
n
by�
3–
4lo
g(10
)C
FU
8w
kp
ost
infe
ctio
nin
CIT
-
trea
ted
mic
eco
mp
ared
wit
hco
ntr
ols
;str
on
gest
pro
tect
ion
wh
enC
ITgi
ven
5w
kp
ost
infe
ctio
n
(p¼
0.00
1)
Bu
cch
eri
etal
.
2009
2E9
(IgA
1)16
-kD
aa
-cry
stal
lin
(in
trac
ellu
lar
and
cell
wal
lp
rote
in)
Mo
use
(CD
89tg
)M
tb(i
.n.)
i.n
.w
ith
and
wit
ho
ut
INF-g
(2h
pri
or
and
1o
r21
dp
ost
)
�L
un
gs
� Sple
en
Red
uce
dlu
ng
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B Cells and Antibodies in TB
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es variable reduction in CFU at 30 d of infection(Keyser et al. 2011), the effects of passive mAbvaried from being less than, comparable, andgreater than described for BCG vaccines (re-viewed in Achkar and Casadevall 2013). Addi-tional transfer studies with more standardizeddesigns, and ideally an additional BCG-vacci-nated control group, are needed to allow forbetter comparison of the effects of Ab-basedprotection against Mtb.
Association of the presence of Abs against Mtbwith decreased susceptibility to infection and dis-ease. Mice immunized with conjugate vaccines,containing arabinomannan (AM), a mycobac-terial capsular, and cell wall polysaccharide, de-velop high IgG titers against AM and are moreTB-resistant than control mice (Hamasur et al.2003; Glatman-Freedman et al. 2004. Whencomparing one of these AM conjugate vaccinesto BCG comparable efficacy was demonstrated(Hamasur et al. 2003), providing additional ev-idence for the potential of certain Abs to protectagainst Mtb. Furthermore, it is noteworthy thatBCG and other mycobacterial Ag-based vac-cines including DNAvaccine elicit both humor-al and cellular responses (reviewed in Achkarand Casadevall 2013). In contrast to most TBvaccine studies, de Valliere et al. (2005) investi-gated the role of Abs induced after BCG vac-cination. They showed that BCG-induced Absenhance effects of both the innate and cell-me-diated immune responses against mycobacteria.Thus, although protection of TB vaccines is of-ten attributed only to the cellular response, onecannot rule out that the humoral response alsocontributed to host defense.
Association of increased susceptibility to dis-ease with deficits in humoral immunity and B-cellfunction. The peak of vulnerability to TB in earlychildhood coincides with a nadir in Ab (Beya-zova et al. 1995; Fairchok et al. 1995; Cruz andStarke 2007; Donald et al. 2010). This asso-ciation is supported by a study showing thatthe lack of Abs against the mycobacterial cellwall glycolipid lipoarabinomannan (LAM) cor-relates significantly with disseminated TB inage-matched children (Costello et al. 1992).Also of note is that patients with HIV-associatedTB, which tends to progress faster and frequent-
ly disseminates, also have lower Ab titers againstLAM or AM (Boggian et al. 1996; Yu et al. 2012),although this association warrants further in-vestigation. A role of Ab in protection is alsosupported by serological studies finding lowerAb levels in children and adults with the occur-rence of disseminated and extrapulmonary TB(Sada et al. 1990; Gupta et al. 1997; Dayal et al.2008; Ziegenbalg et al. 2013). These findingssuggest that Abs against certain Ags could re-duce the risk of TB dissemination in humans.Such a hypothesis is supported by studies inanimal models. For example, the mycobacterialsurface protein heparin-binding hemagglutininadhesin (HBHA) promotes Mtb disseminationin mice, whereas passive transfer with a mAbagainst HBHA reduces extrapulmonary dissem-ination (Pethe et al. 2001) (Table 2). Further-more, our group has recently shown that anAM-conjugate vaccine prevented Mtb dissemi-nation in mice, an effect that was not observedwith BCG vaccination (R Prados-Rosales, un-publ.).
Perhaps the closest to a state of pure B-cell-related deficiency in humans is the clinical en-tity of hypogamaglobulinemia (Bruton 1952;Good and Zak 1956; Conley et al. 2009). Al-though clinical studies have reported TB inpersons with immunoglobulin (Ig) deficiency,these patients typically present with infectionscaused by bacteria commonly associated withhuman diseases such as Streptococcus pneumo-nia (Good and Zak 1956; Conley et al. 2009).On diagnosis of hypogammaglobulinemia, sus-tained periodic IVIG therapy is required forpreventing infection-associated mortality (Bru-ton 1952; Good and Zak 1956). Such therapiescan obscure the potential significance of Abdeficiency in the defense against Mtb. Patientsnot receiving this standard Ig therapy will likelysuccumb to “endogenous” colonizing patho-gens and not Mtb. Therapy with Rituximab,which depletes CD20þ B cells and has beenused widely in the treatment of B-cell malignan-cies and autoimmune diseases (Czuczman andGregory 2010; Townsend et al. 2010), has notbeen associated with increased susceptibility toMtb. In contrast, it has been amply showed thatanti-TNF therapies enhances the risk for devel-
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oping reactivation TB (Keane et al. 2001). Ofnote, however, is that studies including individ-uals receiving Rituximab have not revealed anincreased risk for infection to bacterial patho-gens (reviewed in Rubbert-Roth 2012; Ruder-man 2012; Schoels et al. 2012; Isaacs 2013) in-cluding those that are known colonizers of thehost, and which defense has been shown to behighly B-cell-dependent (Bruton 1952; Goodand Zak 1956). Hence, the absence of increasedsusceptibility to TB with these therapies cannotbe used to argue against a role for Ab-mediatedimmunity. The mechanisms underlying thisobservation are likely multifactorial and remainto be determined. It is conceivable that theycould be due to specific pharmacokinetic prop-erty of Rituximab or the inability of this mo-noclonal antibody to deplete the long-livedCD20 – plasma cells.
In animal models, IgA-deficient mice aremore susceptible to BCG infection than wild-type controls (Rodriguez et al. 2005). PolymericIgR-deficient mice vaccinated with the myco-bacterial protein PstS-1 had lower PstS-1-specif-ic IgA levels in their saliva and were moresusceptible to BCG infection than vaccinatedwild-type mice (Tjarnlund et al. 2006), andIgA administration in the setting of interleu-kin-4 (IL-4) and interferon-g (IFN-g) adminis-tration conferred protection against Mtb in mice(Buccheri et al. 2007). Furthermore, mice lack-ing the y-chain of an activating receptor for theFc portion of Abs (FcyR) are more susceptible toMtb infection and advanced pulmonary diseasethan wild-type mice (Maglione et al. 2008).
Studies with B-cell-deficient mice mostlysupport the role of B cells in TB immunity butsome have also provided inconsistent results.Two of four published studies report that B-cell-deficient mice are more susceptible to ex-perimental infection (Vordermeier et al. 1996;Maglione et al. 2007). A different study chal-lenging with Mtb after isoniazid therapy foundno difference between B-cell-deficient and wild-type mice (Johnson et al. 1997). One studyfound that the pulmonary histopathology wasmore pronounced in B-cell-knockout com-pared with wild-type mice after low-dose Mtbinfection (Bosio et al. 2000). Of note is that
humans with pulmonary TB were also foundto have lower percentages of peripheral bloodB cells compared with asymptomatic individu-als with and without presumed Mtb infection(Corominas et al. 2004; Hernandez et al. 2010).These findings, together with the observationthat an infected host mounts a robust Ab re-sponse against Mtb, provide strong support forthe notion that B cells actively participate in theimmune response to Mtb.
INFLUENCE OF B CELLS ONOTHER IMMUNE CELLS IN MtbINFECTION
There is ample evidence that T cells and macro-phages play a critical role in the defense againstMtb infection and disease. However, B cells, justas T cells, interact with various immune cells,thus contributing to the defense mechanisms.We note that the extent of cellular interactionsrenders it challenging to quantify the amount ofprotection contributed by a single specific im-mune cell population. Studies involving variousanimal TB models have provided compellingevidence that T-cell deficiency produces strongsusceptibility phenotypes (Flynn and Chan2001; Cooper 2009; Ernst 2012). A recent reportshowing that T cells play a central role in coor-dinating the antimycobacterial effects of a vari-ety of immune cells during the innate phase ofthe host response further underscores the sig-nificance of this lymphocyte population indefense against Mtb (Yao et al. 2014). The im-portance of T cells in defense against the tuber-cle bacillus is further supported by enhancedsusceptibility of humans defective in T-cell-ac-tivating elements as a result of mutation in thereceptors of IFN-g and IL-12 (Abel and Casa-nova 2000; Casanova and Abel 2002; Fortinet al. 2007). It is curious that in these naturallyoccurring human models, the genotypes aremostly associated with infection with relativelyweakly virulent mycobacteria such as environ-mental bacilli and BCG. This observation couldbe due to the higher probability of exposure toenvironmental mycobacteria than to Mtb, andthat BCG-osis is the result of direct inoculationof the vaccine during immunization.
B Cells and Antibodies in TB
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Although macrophages play an importantrole in initiating IL-12/IFN-g-related anti-mycobacterial functions, it was reported thatnonselective depletion of this immune cell in amurine TB model resulted in enhanced protec-tion against pulmonary TB, whereas selectiveablation of activated macrophages increasedsusceptibility (Leemans et al. 2001, 2005). Inaddition, although it was shown that mutationsat or near the Scl11a1 (Nramp1) locus, a genethat confers macrophage resistance to mycobac-teria, resulted in susceptibility to Mtb in certainhuman populations (Fortin et al. 2007), thisallele appears to play no role in the control ofthe tubercle bacillus in mice (North et al. 1999).These results suggest that valid testing of thesignificance of specific immunological factorsin defense against Mtb may require an appro-priate host, adding yet another layer of com-plexity to studies aimed at deciphering protec-tive antituberculous response.
B cells, in addition to being a rich source ofAbs, can modulate the immune response by vir-tue of their ability to present Ags and produce awide variety of cytokines. These modulatingfunctions play important roles in affecting thedevelopment of immune cells including T cells,neutrophils, macrophages, and dendritic cells(reviewed in Maglione and Chan 2009; Koza-kiewicz et al. 2013b). B-cell-deficient mice aremore susceptible to Mtb infection, and this de-ficiency results in enhanced lung immunopa-thology and increased pulmonary neutrophilinfiltration and IL-10 production (Maglioneet al. 2007). The importance of B cells in theregulation of neutrophil influx at the site of in-fection is supported by another study showingan abnormally rapid neutrophil migration in B-cell-deficient mice, and demonstrating the ca-pacity of B cells to down-regulate neutrophilmotility (Kondratieva et al. 2010). The capacityof B cells to down-regulate neutrophil motilityappears critical for the effectiveness of BCG vac-cination in mice (Kondratieva et al. 2010). TheB-cell-deficient phenotypes are reversible byadoptive transfer of B cells from infected wild-type (WT) C57BL/6 mice, establishing B-cellspecificity. Reversal of these lung phenotypesis associated with the presence of Ig in serum
of recipient mice without a requirement for pul-monary homing of transferred cells (Maglioneet al. 2007). These observations suggest that therescue effect of transferred B cells is at least par-tially caused by Ab-mediated immune regula-tion and indicate that humoral immunity playsa significant role in the defense against Mtb.This notion is further supported by our recentobservations that tissue neutrophilia in B-cell-deficient mice can be reversed by administrationof sera from tuberculous mice (Kozakiewiczet al. 2013a).
A role for B cells regulating T cells in immuneresponses to Mtb is supported by our findingthat in chronic infection, CD4 T-cell prolifera-tion and IFN-g production in B-cell-deficientmice are significantly different than that inWTs (Maglione and Chan 2009). Mice defi-cient for the inhibitory FcgRIIB (FcyRIIB – / –)are more resistant to Mtb compared with WTcontrols (Maglione et al. 2008). These findingscorrelated with enhanced pulmonary Th1responses, evidenced by increased IFN-g-pro-ducing CD4þ T cells, and suggests that Abs canregulate CD4 Th1 response in acute TB throughengagement of FcR by Ab-Ag complexes. Fur-thermore, in mice and humans, features ofgerminal center B cells suggest that they are im-munologically active (Ulrichs et al. 2004; Ma-glione et al. 2007). We and others have shownthat B cells are a conspicuous cellular compo-nent in lung granuloma of humans, nonhumanprimates, and mice with TB (Gonzalez-Juarreroet al. 2001; Ulrichs et al. 2004; Tsai et al. 2006;Flynn 2010). It has recently been shown in bothhuman and mouse models that B-cell nodules intuberculous lung tissues are populated withCXCR5þ T cells (Slight et al. 2013). This T-cellpopulation, which is directed to infected lungsvia expression of CXCR5, plays a role in the con-trol of Mtb by promoting macrophage activationand lymphoid nodule formation (Slight et al.2013).
Accumulating experimental evidence has re-vealed the significance of the interaction be-tween B and T lymphocytes in the germinal cen-ter in an immune response, including thatdeveloped against microbial pathogens (Vi-nuesa et al. 2005; Ma et al. 2012). The clinical
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relevance of this interaction was shown recentlyin the qualitative and quantitative analysis ofthe germinal center reaction in HIV (humanimmunodeficiency virus) models (Vinuesa2012; Cubas et al. 2013; Locci et al. 2013; Pillai2013; Schmitt and Ueno 2013). The results ofthese studies revealed that the nature of the B-cell humoral immunity in response to antigens,particularly as it related to the generation ofbroadly neutralizing antibodies, was highly de-pendent on the T follicular helper cells, whosedevelopment occurs in the germinal center (Vi-nuesa 2012; Cubas et al. 2013; Locci et al. 2013;Pillai 2013; Schmitt and Ueno 2013). Indeed,abnormalities of the B-cell and humoral im-mune response in individuals infected withHIV have been documented (Moir and Fauci2009). Thus, it remains possible that the aber-rant B-cell compartment of the host immuneresponse contributes to the susceptibility ofHIV-infected individuals to the tubercle bacil-lus. Similarly, because of this B:T interaction, itis not straightforward to determine the relativecontribution of these two lymphocyte popu-lations in the defense against Mtb. It is possi-ble that B cells and humoral immunity couldaccount, at least in part, for the enhanced sus-ceptibility to Mtb in individuals afflicted withT-cell-deficient states other than that associatedwith HIV infection. Together, these observa-tions indicate that protective mechanismsagainst the tubercle bacillus are complex andmost certainly involve redundancy, renderingquantification of the relative contribution tothe overall host resistance to Mtb by specificimmunological factors difficult. This difficultyis further compounded by the highly interactivenature of immune cells.
MECHANISMS OF Ab-MEDIATEDPROTECTION AGAINST Mtb
Mycobacteria are potentially susceptible tomechanisms of Ab-mediated immunity irre-spective of whether they are in their intracellularor extracellular phase (Fig. 1). Internalizationof Mtb through FcgR after Ab opsonization hasbeen reported to trigger phagolysosomal fusion(Armstrong and Hart 1975) and promote intra-
cellular killing in a mechanism that increasesCa2þ signaling (Malik et al. 2000). Alveolarmacrophages ingesting BCG opsonized withIgG manifested an enhanced oxidative burst, aphenomenon that could translate into increasedmicrobicidal activity (Suga et al. 1996). Stim-ulation of surface receptors can affect the fate ofinternalized microbes. In this regard, killing ofthe intracellular parasite Toxoplasma gondii isenhanced by stimulation of Fc1RII-CD23 re-ceptors by immune complexes (Vouldoukis etal. 2011), and there is evidence that activation ofthe same receptor enhances activity against my-cobacteria (Mossalayi et al. 2009). Ab couldalso help host defense by potentiating the effectof cell-mediated immunity. In this regard, thereis some evidence that Abs to BCG antigens canpotentiate both adaptive and innate cell-medi-ated immune responses against mycobacteria(de Valliere et al. 2005). Additional evidencecomes from the observation that sera from in-dividuals who were exposed to TB and hadhigh, but not low IgG to tuberculin blockedproliferation of PBMCs when stimulated withtuberculin (Encinales et al. 2010). For otherpathogens, such as Chlamydia spp., specificAb can enhance cell-mediated responses by al-tering cytokine responses and promoting Agpresentation through enhanced uptake andprocessing (Igietseme et al. 2004), and similarmechanism could apply to mycobacteria. In ad-dition, there is also clear evidence for an extra-cellular phase of Mtb during which it can bedirectly targeted by Abs (Smith et al. 2000; Ca-sadevall 2003; Grosset 2003; Karakousis et al.2004; Kim et al. 2010; Ahmad et al. 2011; Hoffet al. 2011; Driver et al. 2012).
Engagement of distinct FcyRs can diver-gently affect the susceptibility for TB, suggestingthat targeting FcyRs can be a means to enhanceTB immunity (Maglione et al. 2008). In contrastto the inhibitory FcyRIIB– / – strain, mice lack-ing the y-chain of activating FcyRs are moresusceptible to Mtb infection with exacerbatedimmunopathology and increased productionof the anti-inflammatory cytokine IL-10 (Ma-glione et al. 2008). Because different isotypesand IgG subclasses engage different types ofFcyR, the class of the Ab response is likely to
B Cells and Antibodies in TB
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be important in resistance. This is consistentwith the well-established data that Ag-Ab inter-actions with FcR can modulate the immuneresponse, which has been exploited in the treat-ment of a variety of diseases, most notably neo-plastic and autoimmune disorders (Kalergisand Ravetch 2002; Rafiq et al. 2002; Clynes2005; Dhodapkar et al. 2005). In fact, a recentmultisite human gene expression study foundthat expression of FcyRIA was significantly andconsistently higher in subjects with TB com-pared with those with LTBI, regardless of HIVcoinfection (Sutherland et al. 2013). These find-ings were consistent with another study showinga significant reduction in FcyRIA expression inTB cases after antituberculous treatment whencompared with pretreatment expression (Cliffet al. 2013). FcyRIA is predominantly expressed
by monocytes and macrophages, is induced byIFN-g, promotes Ab-dependent cytotoxicity,mediates the clearance of immune complexes,and may have been responsible for the control ofMtb after Ab-mediated phagocytosis observedin earlier studies (Armstrong and Hart 1971).Overall, these study results of FcyRs in bothhumans and animals further support a protec-tive role of the humoral immune componentagainst Mtb.
Other functions of Ab could also contributeto protection against mycobacteria. For exam-ple, specific Ab forms Ag-Ab complexes that canthen be cleared by the reticuloendothelial sys-tem. Evidence for the potential of this mecha-nism comes from the observation that Ab canpromote the clearance of mycobacterial Ags thatcan impair host immunity through their immu-
Opsonization
Variable regions
Constantregions
Heavychain
Lightchain
Generation of Ca2+
and oxidants
Antibody enhancement ofcell-mediated immunity
Reduced damage to host frominflammatory response
Mycobacterium
Complement activation
ImmunomodulationC1
Antigen clearance
Direct antimycobacterialactivity
Figure 1. Illustration of the various reported mechanisms of antibody-mediated protection against Mycobacte-rium tuberculosis such as opsonization (Armstrong and Hart 1975), increase of macrophage Ca2þ signaling(Malik et al. 2000), and release of oxidants (Suga et al. 1996; Mossalayi et al. 2009) enhancing intracellularkilling, other mechanisms enhancing cell-mediated immunity (de Valliere et al. 2005; Encinales et al. 2010),clearance of immunomodulatory mycobacterial antigens (Glatman-Freedman et al. 2000), direct antimycobac-terial activity (Conti et al. 1998), and activation of complement (Hetland et al. 1998; Carroll et al. 2009;Manivannan et al. 2012).
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nomodulatory properties (Glatman-Freedmanet al. 2000). For both fungi and bacteria specificAbs binding to surface components have beenshown to modulate gene expression (McClel-land et al. 2010; Yano et al. 2011). In the caseof the bacterium Streptococcus pneumonia ag-glutinating non-opsonic Abs trigger bacterialdeath through quorum sensing-related mecha-nisms (Yano et al. 2011). Abs mimicking fungalkiller toxin have been reported to be microbici-dal to Mtb (Conti et al. 1998). Although suchAbs would not be expected to occur in an im-mune response to Mtb infection, the fact thatsome Abs can directly kill mycobacteria pro-vides a precedent for notion that some Abs onthe mycobacterial surface could trigger similareffects.
Abs are known to be powerful modulatorsof the inflammatory response. Given that theoutcome of mycobacterial infection is highlydependent on the tissue inflammatory re-sponse, it is likely that Ab responses couldhave beneficial or deleterious effects dependingon their ability to influence inflammation. Theinflammatory properties of Abs are complexand depend on their effect on microbial inocu-lum and their effector functions of the constantregion (isotype). In general, IgMs are thoughtto be pro-inflammatory through their highcomplement-activating capacity (Ciurana etal. 2004), whereas IgG can be pro- or anti-in-flammatory depending on the complement-ac-tivating capacity and type of FcR receptor en-gaged (Lux et al. 2010; Ballow 2011). Severalstudies have established that specific Abs to my-cobacteria can modulate complement activa-tion. The binding of complement to BCG canbe enhanced by Ab with IgG . IgM (Carroll etal. 2009). Among patients with TB, the ability ofAb to trigger complement activation on BCGcorrelated with IgG2 but not IgM (Hetland etal. 1998). Human IgG has also been shown topromote complement activation on Mtb, whichwas associated with increased phagocytosis bymacrophages (Manivannan et al. 2012).
It is possible to conceptualize how Abs withpro- and anti-inflammatory properties couldinfluence the outcome of infection by consider-ing these properties in the context of the dam-
age-response framework. This framework pos-its that damage is maximal at the extremes of theimmune response, with disease occurring whendamage reaches a threshold to affect homeosta-sis (Casadevall and Pirofski 2003). In the caseof TB, caseous necrosis and miliary disease rep-resents extremes of too much and too little in-flammatory response, respectively (Casadevalland Pirofski 2003; Achkar and Jenny-Avital2011). Hence, pro- and anti-inflammatory Abscould mediate beneficial or deleterious effectsdepending on where the host is on the curve ofdamage versus immune response. The need forthe right balance of inflammatory response tocontrol Mtb infection is further supported by arecent study showing that although the proin-flammatory cytokine tumor necrosis factor(TNF) is critical in the host defense againstTB, its excess leads to enhanced disease in zebra-fish and humans (Roca and Ramakrishnan2013). Taking the importance of the right bal-ance of the combined immune responses to Mtbinto consideration, Abs that are proinflamma-tory could help hosts that respond with too littleinflammation, whereas those that are anti-inflammatory could help hosts with exuberantinflammatory responses that result in tissuedestructions (Fig. 2). Studies assessing thepro- and anti-inflammatory properties of Absagainst Mtb are warranted to further elucidatethe potential value of such Abs in disease statesat opposite ends of the immune competencyspectrum.
CHARACTERISTICS OF PROTECTIVEAbs AGAINST Mtb
The Ab parameters that contribute to protec-tion include amount, specificity, affinity, andisotype. For Mtb, very few mAbs have been char-acterized in detail and consequently the diffi-culty to identify trends in the characteristics ofprotective Abs to Mtb. However, it is possible todiscern some themes. Protective Abs to Mtb rec-ognize at least four different antigens. The mu-rine isotypes IgM, IgG1, IgG3, and IgA haveeach been shown to protect against TB (Table2). The finding that an IgG3 to AM lost protec-tive efficacy when converted to IgG2a provides
B Cells and Antibodies in TB
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support for the notion that the constant regiontype has an important role in the activity of theAb against Mtb. (Schwebach 2002). An addi-tional example of this phenomenon is the ob-servation an IgA against the 16-kDa a-cristallinwas active against Mtb, whereas an IgG1 mAb tothe same epitope had no protective efficacy(Williams et al. 2004). Intranasal administra-tion of an IgA1 combined with IFN-g signifi-cantly ameliorated lung H37Rv infection inmice transgenic for human CD89m but not inCD89-negative littermate controls, providingevidence that IgA-mediated protection requiredCD89 (Balu et al. 2011). The fact that IgA canprotect against pulmonary Mtb infection is im-
portant given the role of this isotype in mucosalimmunity. Evidence that the amount of Ab iscritical for protection comes from the observa-tion of prozone-like effects in passive experi-ments in mice (Schwebach 2002).
PERSPECTIVE ON IMPACT OF Abs AT THEVARIOUS Mtb INFECTION STATES
Based on the known functions of Abs and theresults of various studies we envision that Ab-mediated immunity can serve a protective roleagainst Mtb at various states of infection. Earlyin infection Abs could enhance host defenses bypromoting phagocytosis through FcR, a process
Active TB
A
B
Active TB
LTBI
LTBI
Host response
Host response
Disease threshold
Disease threshold
Dam
age
Dam
age
Figure 2. Interpretation of the potential function of pro- and anti-inflammatory antibodies against Mtb in thecontext of the damage–response framework. (A) Potential effects of a proinflammatory antibody with enhancedinflammation leading, on the one hand, to the improvement from disseminated/miliary TB in an immuno-compromised host (left) to localized granuloma formation and, on the other hand, to progression fromgranuloma to caseous necrosis in the more immunocompetent host (right). (B) Potential effects of an anti-inflammatory antibody leading to worsening TB dissemination in the immunocompromised host who hasalready reduced inflammation (left), but improved containment of local disease from caseous necrosis togranuloma formation in the more immunocompetent host with a strong inflammatory response (right).LTBI, latent TB infection. (Figure reproduced with permission from Achkar and Casadevall 2013.)
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that is known to increase intracellular killing andrapid uptake and processing of mycobacterialAgs. Similarly, Abs could activate complement,a process that would further promote phagocy-tosis and cellular recruitment to the site of in-fection. Given that mycobacterial polysaccha-rides and lipopolysaccharides are powerfulimmunomodulators that can interfere with thedevelopment of effective immune response, thepresence of Ab to these Ags could contribute tohost defense by promoting their clearance. Abscan function as pro- and anti-inflammatorymolecules depending on their ability to acti-vate FcR, and this effect could be beneficial byheightening an effective inflammatory responseor down-modulating runaway granuloma for-mation, which has the capacity to destroy tis-sues. We anticipate that Ab could have differentroles depending on the immunological state ofthe host. For example, the proinflammatory ef-fects of Ab-mediated immunity may help pro-tect immunologically naıve hosts during initialinfection. In this regards, naturally occurringAb, in particular IgM, is critical for defenseagainst many infectious diseases (Casadevalland Pirofski 2012b) and could have an im-portant role in protection against Mtb by pro-moting an early inflammatory response. In con-trast, IgG elicited by vaccines would be expectedto function primarily through FcR engagement.At this time the relative importance of thesemechanisms is unknown, and it is possible thatthey differ from host to host. However, given thatAbs have the capacity to modulate practically allaspects of the interaction between Mtb and itshost, there is a high likelihood that this arm ofthe adaptive immune response can make a ma-jor contribution to host defense. Hence, there isa need for additional studies of Ab function andits potential role on both defense against andpathogenesis of mycobacterial infections.
PERSPECTIVE FOR A ROLE OF Abs IN TBVACCINE EFFICACY AND TB TREATMENT
Vaccines based solely on induction of T cellshave not been successful to date. One possibleexplanation is that immunity requires a layereddefense including a multipronged approach to
obtain effective protection by a TB vaccine. Inmice, as discussed above, B cells and Ig areimportant components of anti-TB immunity ca-pable of modulating various aspects of host re-sponse against Mtb (Maglione and Chan 2009;Achkar and Casadevall 2013; Kozakiewicz et al.2013b). In view of these observations, it wouldbe prudent to explore the possibility that B cellsor Abs may play a role in engendering protec-tion during vaccination against Mtb, regardlessof the importance of humoral immunity in op-timal control of a natural tuberculous infectionin humans. Indeed, BCG has been shown to beineffective in engendering protection in B-cell-deficient CBA/xid mice against Mtb challenge(Kondratieva et al. 2010) and BCG immuniza-tion in B-cell-deficient mMT mice elicits a CD4Th1 response that is inferior to that in the wildtypes (Kozakiewicz et al. 2013a). Understandingthe B-cell and humoral immunity during Mtbinfection and immunization and harnessingsuch responses might lead to strategies and pro-tocols required for the development of a muchneeded effective TB vaccine.
The ideal role of vaccine-induced neutral-izing Abs would be the prevention of both in-fection in naıve individuals and progressionto disease in Mtb-infected individuals. Wheth-er this is an achievable goal, and to what ex-tent humoral immunity with specific isotypeswould be required, is unclear with the currentstate of knowledge. Given the heterogeneity ofhuman hosts and their humoral immune re-sponse, as well as the complexity of TB patho-genesis, it is possible that a cocktail of inducedAbs against various targets and with variousfunctions would provide higher protective effi-cacy than a single type of Ab. One of the likelymost promising targets would include the Mtbcapsular polysaccharide AM, as our group hasrecently shown that immunization with a con-jugate vaccine containing this antigen protectsmice better against Mtb infection than immu-nization with BCG.
An additional promising role of Abs wouldlie in their use as adjunctive treatment ofTB, especially in the setting of drug resistance.Such treatment could potentially shorten treat-ment duration and improve cure rates. Ab ther-
B Cells and Antibodies in TB
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apy against TB would likely have to be based onmAbs given the unpredictable heterogeneity ofpolyclonal serum preparations. Ab-based ther-apies have revolutionized the treatment of cer-tain malignancies and autoimmune diseases(reviewed in Chan and Carter 2010; Weineret al. 2010), and two mAbs have been approvedfor the treatment of infectious diseases (re-viewed in Casadevall et al. 2004; Saylor et al.2009). Furthermore, recent data, generated byour group and others, provide evidence that acombination of mAbs against different epitopescan enhance protective effects against infectiouspathogens (Chow et al. 2013; Pohl et al. 2013).Thus, just as for vaccines, Ab-based therapyagainst TB will also be likely most effective iftargeting multiple epitopes and/or antigens.Furthermore, for a beneficial impact on thedisease, pro- versus anti-inflammatory mAbsmight have to be selected taking the level ofhost inflammatory response to TB into account(Fig. 2). To move the field of therapeutic Absahead, various mAbs will need to be generated,characterized, optimized, and tested individu-ally and in combination in vitro before beingevaluated for their protection against experi-mental TB in animal models.
SUMMARY
When taking into account the older data (Glat-man-Freedman and Casadevall 1998; Glatman-Freedman 2006), the fact that for other faculta-tive intracellular pathogens such as fungi andSalmonella spp. Ab-mediated immunity hasbeen shown to be important, the complexity ofAb responses to mycobacteria and more recentstudies (Table 1), it is difficult to avoid the con-clusion that humoral immunity has an impor-tant role in the protection against TB. Whenweighing the evidence, positive studies aremuch more significant than negative studiesgiven that protective and nonprotective Absexist and that the Ab response to Mtb is hetero-geneous. In fact, the most straightforward in-terpretation of negative studies is that theparticular serum or vaccine used in that studydid not result in Ab-mediated protection. Incontrast to negative studies, positive studies pro-
vide direct evidence for the ability of Ab-medi-ated immunity to contribute to the host defenseagainst TB. Consequently, we interpret the avail-able data to indicate that TB vaccines that induceAb-mediated immunity as well as Ab-basedtherapy could result in enhanced protection.We note that the protective mechanisms againstthe tubercle bacillus are complex and highly in-teractive, rendering quantification of the relativecontribution of B cells and Abs to the overallhost resistance to Mtb difficult at this time.However, what is certain is that the TB field can-not go forward ignoring the contribution of Ab-mediated immunity if progress is going to bemade in understanding the basis of host resis-tance and the design of future vaccines.
ACKNOWLEDGMENTS
This work was supported by funds from theNational Institutes of Health (NIH)/Nation-al Institute of Allergy and Infectious Dis-eases (NIAID) (AI-067665 and AI-105684 toJ.M.A., AI063537 and AI094745 to J.C., andAI-033774, AI-052733, and AI-033142 to A.C.),the National Heart, Lung, and Blood Institute(NHLBI) (HL-059842 to A.C.), the Center forAIDS Research (CFAR) at the Albert EinsteinCollege of Medicine (AI-51519 to J.M.A.), theAeras TB vaccine foundation (J.M.A. and A.C.),and the Food and Drug Administration (FDA)(1U18 FD004012/01 to J.M.A.). A.C. is also therecipient of a Bill & Melinda Gates Grand Chal-lenge award and TB Vaccine Accelerator Pro-gram award. We thank Anke Ziegenbalg for hergraphic assistance with the figures.
REFERENCES
Abel L, Casanova JL. 2000. Genetic predisposition to clinicaltuberculosis: Bridging the gap between simple and com-plex inheritance. Am J Hum Genet 67: 274–277.
Achkar JM, Jenny-Avital ER. 2011. Incipient and subclinicaltuberculosis: Defining early disease states in the con-text of host immune response. J Infect Dis 204 (Suppl):S1179–S1186.
Achkar JM, Casadevall A. 2013. Antibody-mediated immu-nity against tuberculosis: Implications for vaccine devel-opment. Cell Host Microbe 13: 250–262.
Ahmad Z, Fraig MM, Bisson GP, Nuermberger EL, GrossetJH, Karakousis PC. 2011. Dose-dependent activity of
J.M. Achkar et al.
16 Cite this article as Cold Spring Harb Perspect Med 2015;5:a018432
ww
w.p
ersp
ecti
vesi
nm
edic
ine.
org
Press on November 13, 2020 - Published by Cold Spring Harbor Laboratoryhttp://perspectivesinmedicine.cshlp.org/Downloaded from
pyrazinamide in animal models of intracellular andextracellular tuberculosis infections. Antimicrob AgentsChemother 55: 1527–1532.
Almeida LP, Trombone AP, Lorenzi JC, Rocha CD, MalardoT, Fontoura IC, Gembre AF, Silva RL, Silva CL, CasteloAP, et al. 2011. B cells can modulate the CD8 memoryT cell after DNAvaccination against experimental tuber-culosis. Genet Vaccines Ther 9: 5.
Armstrong JA, Hart PD. 1971. Response of cultured macro-phages to Mycobacterium tuberculosis, with observationson fusion of lysosomes with phagosomes. J Exp Med 134:713–740.
Armstrong JA, Hart PD. 1975. Phagosome-lysosome interac-tions in culturedmacrophages infected withvirulent tuber-cle bacilli. Reversal of the usual nonfusion pattern andobservations on bacterial survival. J Exp Med 142: 1–16.
Ballow M. 2011. The IgG molecule as a biological immuneresponse modifier: Mechanisms of action of intravenousimmune serum globulin in autoimmune and inflamma-tory disorders. J Allergy Clin Immunol 127: 315–323;quiz 324-315.
Balu S, Reljic R, Lewis MJ, Pleass RJ, McIntosh R, van Koo-ten C, van Egmond M, Challacombe S, Woof JM, Ivanyi J.2011. A novel human IgA monoclonal antibody protectsagainst tuberculosis. J Immunol 186: 3113–3119.
Beyazova U, Rota S, Cevheroglu C, Karsligil T. 1995. Hu-moral immune response in infants after BCG vaccina-tion. Tuber Lung Dis 76: 248–253.
Boggian K, Fierz W, Vernazza PL. 1996. Infrequent detectionof lipoarabinomannan antibodies in human immunode-ficiency virus–associated mycobacterial disease. SwissHIV cohort study. J Clin Microbiol 34: 1854–1855.
Bosio CM, Gardner D, Elkins KL. 2000. Infection of B cell-deficient mice with CDC 1551, a clinical isolate ofMycobacterium tuberculosis: Delay in dissemination anddevelopment of lung pathology. J Immunol 164: 6417–6425.
Bruton OC. 1952. Agammaglobulinemia. Pediatrics 9: 722–728.
Buccheri S, Reljic R, Caccamo N, Ivanyi J, Singh M, SalernoA, Dieli F. 2007. IL-4 depletion enhances host resistanceand passive IgA protection against tuberculosis infectionin BALB/c mice. Eur J Immunol 37: 729–737.
Buccheri S, Reljic R, Caccamo N, Meraviglia S, Ivanyi J,Salerno A, Dieli F. 2009. Prevention of the post-chemo-therapy relapse of tuberculous infection by combinedimmunotherapy. Tuberculosis (Edinb) 89: 91–94.
Carroll MV, Lack N, Sim E, Krarup A, Sim RB. 2009. Mul-tiple routes of complement activation by Mycobacteriumbovis BCG. Mol Immunol 46: 3367–3378.
Casadevall A. 1995. Antibody immunity and invasive fungalinfections. Infect Immun 63: 4211–4218.
Casadevall A. 1998. Antibody-mediated protection againstintracellular pathogens. Trends Microbiol 6: 102–107.
Casadevall A. 2003. Antibody-mediated immunity againstintracellular pathogens: Two-dimensional thinking comesfull circle. Infect Immun 71: 4225–4228.
Casadevall A. 2004. The methodology for determining theefficacy of antibody-mediated immunity. J ImmunolMethods 291: 1–10.
Casadevall A, Pirofski LA. 2003. The damage–responseframework of microbial pathogenesis. Nat Rev Microbiol1: 17–24.
Casadevall A, Pirofski LA. 2012a. Immunoglobulins in de-fense, pathogenesis, and therapy of fungal diseases. CellHost Microbe 11: 447–456.
Casadevall A, Pirofski LA. 2012b. A new synthesis for anti-body-mediated immunity. Nat Immunol 13: 21–28.
Casadevall A, Dadachova E, Pirofski LA. 2004. Passive anti-body therapy for infectious diseases. Nat Rev Microbiol 2:695–703.
Casanova JL, Abel L. 2002. Genetic dissection of immunityto mycobacteria: The human model. Annu Rev Immunol20: 581–620.
Cassone A, Casadevall A. 2012. Recent progress in vaccinesagainst fungal diseases. Curr Opin Microbiol 15: 427–433.
Chambers MA, Gavier-Widen D, Hewinson RG. 2004. An-tibody bound to the surface antigen MPB83 of Mycobac-terium bovis enhances survival against high dose and lowdose challenge. FEMS Immunol Med Microbiol 41:93–100.
Chan AC, Carter PJ. 2010. Therapeutic antibodies forautoimmunity and inflammation. Nat Rev Immunol 10:301–316.
Chang-hong S, Xiao-wu W, Hai Z, Ting-fen Z, Li-Mei W,Zhi-kai X. 2008. Immune responses and protective effi-cacy of the gene vaccine expressing Ag85B and ESAT6fusion protein from Mycobacterium tuberculosis. DNACell Biol 27: 199–207.
Chow SK, Smith C, MacCarthy T, Pohl MA, Bergman A,Casadevall A. 2013. Disease enhacing antibodies improvethe efficacy of bacterial toxin-neutralizing antibodies.Cell Host Microbe 13: 417–428.
Ciurana CL, Zwart B, van Mierlo G, Hack CE. 2004. Com-plement activation by necrotic cells in normal plasmaenvironment compares to that by late apoptotic cellsand involves predominantly IgM. Eur J Immunol 34:2609–2619.
Cliff JM, Lee JS, Constantinou N, Cho JE, Clark TG,Ronacher K, King EC, Lukey PT, Duncan K, Van HeldenPD, et al. 2013. Distinct phases of blood gene expressionpattern through tuberculosis treatment reflect modula-tion of the humoral immune response. J Infect Dis 207:18–29.
Clynes R. 2005. Immune complexes as therapy for autoim-munity. J Clin Invest 115: 25–27.
Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E,Fineberg HV, Mosteller F. 1994. Efficacy of BCG vaccinein the prevention of tuberculosis. Meta-analysis of thepublished literature. JAMA 271: 698–702.
Collins FM. 1974. Vaccines and cell-mediated immunity.Bacteriol Rev 38: 371–402.
Conley ME, Dobbs AK, Farmer DM, Kilic S, Paris K, Gri-goriadou S, Coustan-Smith E, Howard V, Campana D.2009. Primary B cell immunodeficiencies: Comparisonsand contrasts. Annu Rev Immunol 27: 199–227.
Conti S, Fanti F, Magliani W, Gerloni M, Bertolotti D, SalatiA, Cassone A, Polonelli L. 1998. Mycobactericidal activityof human natural, monoclonal, and recombinant yeastkiller toxin-like antibodies. J Infect Dis 177: 807–811.
B Cells and Antibodies in TB
Cite this article as Cold Spring Harb Perspect Med 2015;5:a018432 17
ww
w.p
ersp
ecti
vesi
nm
edic
ine.
org
Press on November 13, 2020 - Published by Cold Spring Harbor Laboratoryhttp://perspectivesinmedicine.cshlp.org/Downloaded from
Cooper AM. 2009. Cell-mediated immune responses in tu-berculosis. Annu Rev Immunol 27: 393–422.
Corominas M, Cardona V, Gonzalez L, Cayla JA, Rufi G,Mestre M, Buendia E. 2004. B-lymphocytes and co-stim-ulatory molecules in Mycobacterium tuberculosis infec-tion. Int J Tuberc Lung Dis 8: 98–105.
Costello AM, Kumar A, Narayan V, Akbar MS, Ahmed S,Abou-Zeid C, Rook GA, Stanford J, Moreno C. 1992.Does antibody to mycobacterial antigens, including lip-oarabinomannan, limit dissemination in childhood tu-berculosis? Trans R Soc Trop Med Hyg 86: 686–692.
Cruz AT, Starke JR. 2007. Clinical manifestations of tuber-culosis in children. Paediatr Respir Rev 8: 107–117.
Cubas RA, Mudd JC, Savoye AL, Perreau M, van Greve-nynghe J, Metcalf T, Connick E, Meditz A, Freeman GJ,Abesada-Terk G Jr., et al. 2013. Inadequate T follicular cellhelp impairs B cell immunity during HIV infection. NatMed 19: 494–499.
Czuczman MS, Gregory SA. 2010. The future of CD20monoclonal antibody therapy in B-cell malignancies.Leuk Lymphoma 51: 983–994.
Dayal R, Singh A, Katoch VM, Joshi B, Chauhan DS, Singh P,Kumar G, Sharma VD. 2008. Serological diagnosis oftuberculosis. Indian J Pediatr 75: 1219–1221.
de Valliere S, Abate G, Blazevic A, Heuertz RM, Hoft DF.2005. Enhancement of innate and cell-mediated immu-nity by antimycobacterial antibodies. Infect Immun 73:6711–6720.
Dhodapkar KM, Kaufman JL, Ehlers M, Banerjee DK, Bon-vini E, Koenig S, Steinman RM, Ravetch JV, DhodapkarMV. 2005. Selective blockade of inhibitory Fcg receptorenables human dendritic cell maturation with IL-12p70production and immunity to antibody-coated tumorcells. Proc Natl Acad Sci 102: 2910–2915.
Donald PR, Marais BJ, Barry CE, 3rd. 2010. Age and theepidemiology and pathogenesis of tuberculosis. Lancet375: 1852–1854.
Driver ER, Ryan GJ, Hoff DR, Irwin SM, Basaraba RJ, Kram-nik I, Lenaerts AJ. 2012. Evaluation of a mouse model ofnecrotic granuloma formation using C3HeB/FeJ micefor testing of drugs against Mycobacterium tuberculosis.Antimicrob Agents Chemother 56: 3181–3195.
Dromer F, Charreire J, Contrepois A, Carbon C, Yeni P. 1987.Protection of mice against experimental cryptococcosisby anti–Cryptococcus neoformans monoclonal antibody.Infect Immun 55: 749–752.
Encinales L, Zuniga J, Granados-Montiel J, Yunis M, Grana-dos J, Almeciga I, Clavijo O, Awad C, Collazos V, Vargas-Rojas MI, et al. 2010. Humoral immunity in tuberculinskin test anergy and its role in high-risk persons exposedto active tuberculosis. Mol Immunol 47: 1066–1073.
Ernst JD. 2012. The immunological life cycle of tuberculosis.Nat Rev Immunol 12: 581–591.
Fairchok MP, Rouse JH, Morris SL. 1995. Age-dependenthumoral responses of children to mycobacterial antigens.Clin Diagn Lab Immunol 2: 443–447.
Fletcher HA, Tanner R, Wallis RS, Meyer J, Manjaly ZR,Harris S, Satti I, Silver RF, Hoft D, Kampmann B, et al.2013. Inhibition of mycobacterial growth in vitro follow-ing primary but not secondary vaccination with BCG.Clin Vaccine Immunol 20: 1683–1689.
Flynn JL, Chan J. 2001. Immunology of tuberculosis. AnnuRev Immunol 19: 93–129.
Flynn JL, Klein E. 2010. Pulmonary tuberculosis in mon-keys. In A color atlas of comparative pulmonary tuberculo-sis histopathology (ed. Leong J). Taylor & Francis, Oxford.
Fortin A, Abel L, Casanova JL, Gros P. 2007. Host genetics ofmycobacterial diseases in mice and men: Forward geneticstudies of BCG-osis and tuberculosis. Ann Rev GenomicsHum Genet 8: 163–192.
Giri PK, Verma I, Khuller GK. 2006. Enhanced immuno-protective potential of Mycobacterium tuberculosis Ag85complex protein based vaccine against airway Mycobac-terium tuberculosis challenge following intranasal admin-istration. FEMS Immunol Med Microbiol 47: 233–241.
Glatman-Freedman A. 2006. The role of antibody-mediatedimmunity in defense against Mycobacterium tuberculosis:Advances toward a novel vaccine strategy. Tuberculosis(Edinb) 86: 191–197.
Glatman-Freedman A, Casadevall A. 1998. Serum therapyfor tuberculosis revisited: Reappraisal of the role of anti-body-mediated immunity against Mycobacterium tuber-culosis. Clin Microbiol Rev 11: 514–532.
Glatman-Freedman A, Mednick AJ, Lendvai N, CasadevallA. 2000. Clearance and organ distribution of Mycobacte-rium tuberculosis lipoarabinomannan (LAM) in the pres-ence and absence of LAM-binding immunoglobulinM. Infect Immun 68: 335–341.
Glatman-Freedman A, Casadevall A, Dai Z, Jacobs WR Jr.,Li A, Morris SL, Navoa JA, Piperdi S, Robbins JB,Schneerson R, et al. 2004. Antigenic evidence of preva-lence and diversity of Mycobacterium tuberculosis arabi-nomannan. J Clin Microbiol 42: 3225–3231.
Gonzalez-Juarrero M, Turner OC, Turner J, Marietta P,Brooks JV, Orme IM. 2001. Temporal and spatial arrange-ment of lymphocytes within lung granulomas induced byaerosol infection with Mycobacterium tuberculosis. InfectImmun 69: 1722–1728.
Good RA, Zak SJ. 1956. Disturbances in g globulin synthesisas experiments of nature. Pediatr Rev 18: 109–149.
Grosset J. 2003. Mycobacterium tuberculosis in the extracel-lular compartment: An underestimated adversary. Anti-microb Agents Chemother 47: 833–836.
Grover A, Ahmed MF, Singh B, Verma I, Sharma P, KhullerGK. 2006. A multivalent combination of experimentalantituberculosis DNA vaccines based on Ag85B and re-gions of difference antigens. Microbes Infect 8: 2390–2399.
Guirado E, Amat I, Gil O, Diaz J, Arcos V, Caceres N, AusinaV, Cardona PJ. 2006. Passive serum therapy with poly-clonal antibodies against Mycobacterium tuberculosis pro-tects against post-chemotherapy relapse of tuberculosisinfection in SCID mice. Microbes Infect 8: 1252–1259.
Gupta S, Bhatia R, Datta KK. 1997. Serological diagnosis ofchildhood tuberculosis by estimation of mycobacterialantigen 60-specific immunoglobulins in the serum.Tuber Lung Dis 78: 21–27.
Hamasur B, Haile M, Pawlowski A, Schroder U, WilliamsA, Hatch G, Hall G, Marsh P, Kallenius G, Svenson SB.2003. Mycobacterium tuberculosis arabinomannan-pro-tein conjugates protect against tuberculosis. Vaccine 21:4081–4093.
J.M. Achkar et al.
18 Cite this article as Cold Spring Harb Perspect Med 2015;5:a018432
ww
w.p
ersp
ecti
vesi
nm
edic
ine.
org
Press on November 13, 2020 - Published by Cold Spring Harbor Laboratoryhttp://perspectivesinmedicine.cshlp.org/Downloaded from
Hamasur B, Haile M, Pawlowski A, Schroder U, Kallenius G,Svenson SB. 2004. A mycobacterial lipoarabinomannanspecific monoclonal antibody and its F(ab0) fragmentprolong survival of mice infected with Mycobacteriumtuberculosis. Clin Exp Immunol 138: 30–38.
Hernandez J, Velazquez C, Valenzuela O, Robles-Zepeda R,Ruiz-Bustos E, Navarro M, Garibay-Escobar A. 2010.Low number of peripheral blood B lymphocytes in pa-tients with pulmonary tuberculosis. Immunol Invest 39:197–205.
Hetland G, Wiker HG, Hogasen K, Hamasur B, Svenson SB,Harboe M. 1998. Involvement of antilipoarabinomannanantibodies in classical complement activation in tuber-culosis. Clin Diagn Lab Immunol 5: 211–218.
Hoff DR, Ryan GJ, Driver ER, Ssemakulu CC, De GrooteMA, Basaraba RJ, Lenaerts AJ. 2011. Location of intra-and extracellular M. tuberculosis populations in lungs ofmice and guinea pigs during disease progression and afterdrug treatment. PLoS ONE 6: e17550.
Huygen K, Content J, Denis O, Montgomery DL, YawmanAM, Deck RR, DeWitt CM, Orme IM, Baldwin S,D’Souza C, et al. 1996. Immunogenicity and protec-tive efficacy of a tuberculosis DNA vaccine. Nat Med 2:893–898.
Igietseme JU, Eko FO, He Q, Black CM. 2004. Antibodyregulation of T-cell immunity: Implications for vaccinestrategies against intracellular pathogens. Expert Rev Vac-cines 3: 23–34.
Ireton GC, Greenwald R, Liang H, Esfandiari J, LyashchenkoKP, Reed SG. 2010. Identification of Mycobacterium tu-berculosis antigens of high serodiagnostic value. Clin Vac-cine Immunol 17: 1539–1547.
Isaacs D. 2013. Infectious risks associated with biologics.Adv Exp Med Biol 764: 151–158.
Johnson CM, Cooper AM, Frank AA, Bonorino CB, WysokiLJ, Orme IM. 1997. Mycobacterium tuberculosis aerogenicrechallenge infections in B cell-deficient mice. Tuber LungDis 78: 257–261.
Kalergis AM, Ravetch JV. 2002. Inducing tumor immunitythrough the selective engagement of activating Fcg recep-tors on dendritic cells. J Exp Med 195: 1653–1659.
Karakousis PC, Yoshimatsu T, Lamichhane G, Woolwine SC,Nuermberger EL, Grosset J, Bishai WR. 2004. Dormancyphenotype displayed by extracellular Mycobacterium tu-berculosis within artificial granulomas in mice. J Exp Med200: 647–657.
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J,Schwieterman WD, Siegel JN, Braun MM. 2001. Tuber-culosis associated with infliximab, a tumor necrosis fac-tor a-neutralizing agent. N Engl J Med 345: 1098–1104.
Keyser A, Troudt JM, Taylor JL, Izzo AA. 2011. BCG sub-strains induce variable protection against virulent pul-monary Mycobacterium tuberculosis infection, with thecapacity to drive Th2 immunity. Vaccine 29: 9308–9315.
Kim MJ, Wainwright HC, Locketz M, Bekker LG, WaltherGB, Dittrich C, Visser A, Wang W, Hsu FF, Wiehart U,et al. 2010. Caseation of human tuberculosis granulomascorrelates with elevated host lipid metabolism. EMBOMol Med 2: 258–274.
Kohama H, Umemura M, Okamoto Y, Yahagi A, Goga H,Harakuni T, Matsuzaki G, Arakawa T. 2008. Mucosalimmunization with recombinant heparin-binding hae-
magglutinin adhesin suppresses extrapulmonary dissem-ination of Mycobacterium bovis bacillus Calmette–Gue-rin (BCG) in infected mice. Vaccine 26: 924–932.
Kondratieva TK, Rubakova EI, Linge IA, Evstifeev VV, Ma-jorov KB, Apt AS. 2010. B cells delay neutrophil migrationtoward the site of stimulus: Tardiness critical for effectivebacillus Calmette–Guerin vaccination against tuberculo-sis infection in mice. J Immunol 184: 1227–1234.
Kozakiewicz L, Chen Y, Xu J, Wang Y, Dunussi-Joannopou-los K, Ou Q, Flynn JL, Porcelli SA, Jacobs WR Jr., Chan J.2013a. B cells regulate neutrophilia during Mycobacteri-um tuberculosis infection and BCG vaccination by mod-ulating the interleukin-17 response. PLoS Pathog 9:e1003472.
Kozakiewicz L, Phuah J, Flynn J, Chan J. 2013b. The role of Bcells and humoral immunity in Mycobacterium tubercu-losis infection. Adv Exp Med Biol 783: 225–250.
Kunnath-Velayudhan S, Salamon H, Wang HY, Davidow AL,Molina DM, Huynh VT, Cirillo DM, Michel G, TalbotEA, Perkins MD, et al. 2010. Dynamic antibody responsesto the Mycobacterium tuberculosis proteome. Proc NatlAcad Sci 107: 14703–14708.
Kunnath-Velayudhan S, Davidow AL, Wang HY, MolinaDM, Huynh VT, Salamon H, Pine R, Michel G, PerkinsMD, Xiaowu L, et al. 2012. Proteome-scale antibody re-sponses and outcome of Mycobacterium tuberculosisinfection in nonhuman primates and in tuberculosis pa-tients. J Infect Dis 206: 697–705.
Leemans JC, Juffermans NP, Florquin S, van Rooijen N,Vervoordeldonk MJ, Verbon A, van Deventer SJ, vander Poll T. 2001. Depletion of alveolar macrophages exertsprotective effects in pulmonary tuberculosis in mice. JImmunol 166: 4604–4611.
Leemans JC, Thepen T, Weijer S, Florquin S, van Rooijen N,van de Winkel JG, van der Poll T. 2005. Macrophages playa dual role during pulmonary tuberculosis in mice. JInfect Dis 191: 65–74.
Lewinsohn DA, Gold MC, Lewinsohn DM. 2011. Views ofimmunology: Effector T cells. Immunol Rev 240: 25–39.
Lin PL, Rodgers M, Smith L, Bigbee M, Myers A, Bigbee C,Chiosea I, Capuano SV, Fuhrman C, Klein E, et al. 2009.Quantitative comparison of active and latent tuberculosisin the cynomolgus macaque model. Infect Immun 77:4631–4642.
Locci M, Havenar-Daughton C, Landais E, Wu J, KroenkeMA, Arlehamn CL, Su LF, Cubas R, Davis MM, Sette A,et al. 2013. Human circulating PDþCXCR32CXCR5þ
memory Tfh cells are highly functional and correlatewith broadly neutralizing HIV antibody responses.Immunity 39: 758–769.
Lopez Y, Yero D, Falero-Diaz G, Olivares N, Sarmiento ME,Sifontes S, Solis RL, Barrios JA, Aguilar D, Hernandez-Pando R, et al. 2009. Induction of a protective responsewith an IgA monoclonal antibody against Mycobacteriumtuberculosis 16 kDa protein in a model of progressivepulmonary infection. Int J Med Microbiol 299: 447–452.
Lux A, Aschermann S, Biburger M, Nimmerjahn F. 2010.The pro and anti-inflammatory activities of immuno-globulin G. Ann Rheum Dis 69 (Suppl 1): i92–i96.
Lyashchenko K, Colangeli R, Houde M, Al Jahdali H, Men-zies D, Gennaro ML. 1998. Heterogeneous antibody re-sponses in tuberculosis. Infect Immun 66: 3936–3940.
B Cells and Antibodies in TB
Cite this article as Cold Spring Harb Perspect Med 2015;5:a018432 19
ww
w.p
ersp
ecti
vesi
nm
edic
ine.
org
Press on November 13, 2020 - Published by Cold Spring Harbor Laboratoryhttp://perspectivesinmedicine.cshlp.org/Downloaded from
Lyashchenko KP, Greenwald R, Esfandiari J, Greenwald D,Nacy CA, Gibson S, Didier PJ, Washington M, Szczerba P,Motzel S, et al. 2007. PrimaTB STAT-PAK assay, a novel,rapid lateral-flow test for tuberculosis in nonhuman pri-mates. Clin Vaccine Immunol 14: 1158–1164.
Lyashchenko KP, Greenwald R, Esfandiari J, Chambers MA,Vicente J, Gortazar C, Santos N, Correia-Neves M, Bud-dle BM, Jackson R, et al. 2008. Animal-side serologicassay for rapid detection of Mycobacterium bovis infec-tion in multiple species of free-ranging wildlife. VetMicrobiol 132: 283–292.
Lyashchenko KP, Greenwald R, Esfandiari J, Mikota S, MillerM, Moller T, Vogelnest L, Gairhe KP, Robbe-Austerman S,Gai J, et al. 2012. Field application of serodiagnostics toidentify elephants with tuberculosis prior to case confir-mation by culture. Clin Vaccine Immunol 19: 1269–1275.
Ma CS, Deenick EK, Batten M, Tangye SG. 2012. The ori-gins, function, and regulation of T follicular helper cells. JExp Med 209: 1241–1253.
Maglione PJ, Chan J. 2009. How B cells shape the immuneresponse against Mycobacterium tuberculosis. Eur J Im-munol 39: 676–686.
Maglione PJ, Xu J, Chan J. 2007. B cells moderate inflam-matory progression and enhance bacterial containmentupon pulmonary challenge with Mycobacterium tubercu-losis. J Immunol 178: 7222–7234.
Maglione PJ, Xu J, Casadevall A, Chan J. 2008. Fcg receptorsregulate immune activation and susceptibility duringMycobacterium tuberculosis infection. J Immunol 180:3329–3338.
Malik ZA, Denning GM, Kusner DJ. 2000. Inhibition ofCa2þ signaling by Mycobacterium tuberculosis is associat-ed with reduced phagosome–lysosome fusion and in-creased survival within human macrophages. J Exp Med191: 287–302.
Manivannan S, Rao NV, Ramanathan VD. 2012. Role ofcomplement activation and antibody in the interactionbetween Mycobacterium tuberculosis and human macro-phages. Indian J Exp Biol 50: 542–550.
McClelland EE, Nicola AM, Prados-Rosales R, Casadevall A.2010. Ab binding alters gene expression in Cryptococcusneoformans and directly modulates fungal metabolism. JClin Invest 120: 1355–1361.
Moir S, Fauci AS. 2009. B cells in HIV infection and disease.Nat Rev Immunol 9: 235–245.
Mossalayi MD, Vouldoukis I, Mamani-Matsuda M, Kauss T,Guillon J, Maugein J, Moynet D, Rambert J, Desplat V,Mazier D, et al. 2009. CD23 mediates antimycobacterialactivity of human macrophages. Infect Immun 77: 5537–5542.
Nimmerjahn F, Ravetch JV. 2008. Fcg receptors as regulatorsof immune responses. Nat Rev Immunol 8: 34–47.
Niu H, Hu L, Li Q, Da Z, Wang B, Tang K, Xin Q, Yu H,Zhang Y, Wang Y, et al. 2011. Construction and evaluationof a multistage Mycobacterium tuberculosis subunit vac-cine candidate Mtb10.4-HspX. Vaccine 29: 9451–9458.
North RJ, LaCourse R, Ryan L, Gros P. 1999. Consequence ofNramp1 deletion to Mycobacterium tuberculosis infectionin mice. Infect Immun 67: 5811–5814.
Nosanchuk JD, Steenbergen JN, Shi L, Deepe GS Jr., Casa-devall A. 2003. Antibodies to a cell surface histone-like
protein protect against Histoplasma capsulatum. J ClinInvest 112: 1164–1175.
Nussbaum G, Yuan R, Casadevall A, Scharff MD. 1996. Im-munoglobulin G3 blocking antibodies to the fungalpathogen Cryptococcus neoformans. J Exp Med 183:1905–1909.
Olivares N, Leon A, Lopez Y, Puig A, Cadiz A, Falero G,Martinez M, Sarmiento ME, Farinas M, Infante JF,et al. 2006. The effect of the administration of human g
globulins in a model of BCG infection in mice. Tubercu-losis (Edinb) 86: 268–272.
Ottenhoff TH. 2012. New pathways of protective and path-ological host defense to mycobacteria. Trends Microbiol20: 419–428.
Ottenhoff TH, Kaufmann SH. 2012. Vaccines against tuber-culosis: Where are we and where do we need to go? PLoSPathog 8: e1002607.
Palma C, Iona E, Giannoni F, Pardini M, Brunori L, FattoriniL, Del Giudice G, Cassone A. 2008. The LTK63 adjuvantimproves protection conferred by Ag85B DNA-proteinprime-boosting vaccination against Mycobacterium tu-berculosis infection by dampening IFN-g response. Vac-cine 26: 4237–4243.
Pethe K, Alonso S, Biet F, Delogu G, Brennan MJ, Locht C,Menozzi FD. 2001. The heparin-binding haemagglutininof M. tuberculosis is required for extrapulmonary dissem-ination. Nature 412: 190–194.
Pillai S. 2013. Love the one you’re with: The HIV, B cell andTFH cell triangle. Nat Med 19: 401–402.
Pohl MA, Rivera J, Nakouzi A, Chow SK, Casadevall A. 2013.Combinations of antibodies to anthrax toxin manifestemergent properties in neutralization assays. Infect Im-mun 81: 1880–1888.
Rafiq K, Bergtold A, Clynes R. 2002. Immune complex-me-diated antigen presentation induces tumor immunity. JClin Invest 110: 71–79.
Roca FJ, Ramakrishnan L. 2013. TNF dually mediates resis-tance and susceptibility to mycobacteria via mitochon-drial reactive oxygen species. Cell 153: 521–534.
Rodriguez A, Tjarnlund A, Ivanji J, Singh M, Garcia I, Wil-liams A, Marsh PD, Troye-Blomberg M, Fernandez C.2005. Role of IgA in the defense against respiratory in-fections IgA deficient mice exhibited increased suscepti-bility to intranasal infection with Mycobacterium bovisBCG. Vaccine 23: 2565–2572.
Roy E, Stavropoulos E, Brennan J, Coade S, Grigorieva E,Walker B, Dagg B, Tascon RE, Lowrie DB, Colston MJ,et al. 2005. Therapeutic efficacy of high-dose intravenousimmunoglobulin in Mycobacterium tuberculosis infectionin mice. Infect Immun 73: 6101–6109.
Rubbert-Roth A. 2012. Assessing the safety of biologicagents in patients with rheumatoid arthritis. Rheumatol-ogy (Oxford) 51 (Suppl 5): v38–v47.
Ruderman EM. 2012. Overview of safety of non-biologicand biologic DMARDs. Rheumatology (Oxford) 51(Suppl 6): vi37–vi43.
Russo RT, Mariano M. 2010. B-1 cell protective role in mu-rine primary Mycobacterium bovis bacillus Calmette–Guerin infection. Immunobiology 215: 1005–1014.
Sada E, Ferguson LE, Daniel TM. 1990. An ELISA for theserodiagnosis of tuberculosis using a 30,000-Da native
J.M. Achkar et al.
20 Cite this article as Cold Spring Harb Perspect Med 2015;5:a018432
ww
w.p
ersp
ecti
vesi
nm
edic
ine.
org
Press on November 13, 2020 - Published by Cold Spring Harbor Laboratoryhttp://perspectivesinmedicine.cshlp.org/Downloaded from
antigen of Mycobacterium tuberculosis. J Infect Dis 162:928–931.
Saylor C, Dadachova E, Casadevall A. 2009. Monoclonalantibody-based therapies for microbial diseases. Vaccine27 (Suppl 6): G38–G46.
Schmitt N, Ueno H. 2013. Blood Tfh cells come with colors.Immunity 39: 629–630.
Schoels M, Aletaha D, Smolen JS, Wong JB. 2012. Compar-ative effectiveness and safety of biological treatment op-tions after tumour necrosis factor alpha inhibitor failurein rheumatoid arthritis: Systematic review and indirectpairwise meta-analysis. Ann Rheum Dis 71: 1303–1308.
Schwebach JR. 2002. “The carbohydrate surface of M.tuberculosis: Antigenicity and antibody immunity.” The-sis. Sue Golding Graduate Division of Medical Sciences.Albert Einstein College of Medicine, Bronx, NY.
Slight SR, Rangel-Moreno J, Gopal R, Lin Y, Fallert JuneckoBA, Mehra S, Selman M, Becerril-Villanueva E, Baquera-Heredia J, Pavon L, et al. 2013. CXCR5þ T helper cellsmediate protective immunity against tuberculosis. J ClinInvest 123: 712–726.
Smith MB, Boyars MC, Veasey S, Woods GL. 2000. Gener-alized tuberculosis in the acquired immune deficiencysyndrome. Arch Pathol Lab Med 124: 1267–1274.
Suga M, Tanaka F, Muranaka H, Nishikawa H, Ando M.1996. Effect of antibacterial antibody on bactericidal ac-tivities of superoxide and lysosomal enzyme from alveo-lar macrophages in rabbits. Respirology 1: 127–132.
Sutherland JS, Loxton AG, Haks MC, Kassa D, Ambrose L,Lee JS, Ran L, van Baarle D, Maertzdorf J, Howe R, et al.2013. Differential gene expression of activating Fcg re-ceptor classifies active tuberculosis regardless of humanimmunodeficiency virus status or ethnicity. Clin Micro-biol Infect 20: O230–O238.
Tameris MD, Hatherill M, Landry BS, Scriba TJ, SnowdenMA, Lockhart S, Shea JE, McClain JB, Hussey GD, Ha-nekom WA, et al. 2013. Safety and efficacy of MVA85A, anew tuberculosis vaccine, in infants previously vaccinat-ed with BCG: A randomised, placebo-controlled phase2b trial. Lancet 381: 1021–1028
Teitelbaum R, Glatman-Freedman A, Chen B, Robbins JB,Unanue E, Casadevall A, Bloom BR. 1998. A mAb recog-nizing a surface antigen of Mycobacterium tuberculosisenhances host survival. Proc Natl Acad Sci 95: 15688–15693.
Teixeira FM, Teixeira HC, Ferreira AP, Rodrigues MF, Aze-vedo V, Macedo GC, Oliveira SC. 2006. DNA vaccineusing Mycobacterium bovis Ag85B antigen induces partialprotection against experimental infection in BALB/cmice. Clin Vaccine Immunol 13: 930–935.
Tjarnlund A, Rodriguez A, Cardona PJ, Guirado E, Ivanyi J,Singh M, Troye-Blomberg M, Fernandez C. 2006. Poly-meric IgR knockout mice are more susceptible to myco-bacterial infections in the respiratory tract than wild-typemice. Int Immunol 18: 807–816.
Townsend MJ, Monroe JG, Chan AC. 2010. B-cell targetedtherapies in human autoimmune diseases: An updatedperspective. Immunol Rev 237: 264–283.
Tsai MC, Chakravarty S, Zhu G, Xu J, Tanaka K, Koch C,Tufariello J, Flynn J, Chan J. 2006. Characterization of the
tuberculous granuloma in murine and human lungs: Cel-lular composition and relative tissue oxygen tension. CellMicrobiol 8: 218–232.
Ulrichs T, Kosmiadi GA, Trusov V, Jorg S, Pradl L, TitukhinaM, Mishenko V, Gushina N, Kaufmann SH. 2004.Human tuberculous granulomas induce peripheral lym-phoid follicle-like structures to orchestrate local host de-fence in the lung. J Pathol 204: 217–228.
Vinuesa CG. 2012. HIV and T follicular helper cells: A dan-gerous relationship. J Clin Invest 122: 3059–3062.
Vinuesa CG, Tangye SG, Moser B, Mackay CR. 2005. Follic-ular B helper T cells in antibody responses and autoim-munity. Nat Rev Immunol 5: 853–865.
Vordermeier HM, Venkataprasad N, Harris DP, Ivanyi J.1996. Increase of tuberculous infection in the organs ofB cell-deficient mice. Clin Exp Immunol 106: 312–316.
Vouldoukis I, Mazier D, Moynet D, Thiolat D, Malvy D,Mossalayi MD. 2011. IgE mediates killing of intracellu-lar Toxoplasma gondii by human macrophages throughCD23-dependent, interleukin-10 sensitive pathway. PLoSONE 6: e18289.
Weiner LM, Surana R, Wang S. 2010. Monoclonal antibod-ies: Versatile platforms for cancer immunotherapy. NatRev Immunol 10: 317–327.
Williams A, Reljic R, Naylor I, Clark SO, Falero-Diaz G,Singh M, Challacombe S, Marsh PD, Ivanyi J. 2004. Pas-sive protection with immunoglobulin A antibodiesagainst tuberculous early infection of the lungs. Immu-nology 111: 328–333.
Xue T, Stavropoulos E, Yang M, Ragno S, Vordermeier M,Chambers M, Hewinson G, Lowrie DB, Colston MJ,Tascon RE. 2004. RNA encoding the MPT83 antigeninduces protective immune responses against Mycobacte-rium tuberculosis infection. Infect Immun 72: 6324–6329.
Yano M, Gohil S, Coleman JR, Manix C, Pirofski LA. 2011.Antibodies to Streptococcus pneumoniae capsular poly-saccharide enhance pneumococcal quorum sensing.mBio 2: e0076-11.
Yao S, Huang D, Chen CY, Halliday L, Wang RC, Chen ZW.2014. CD4þ T cells contain early extrapulmonary tuber-culosis (TB) dissemination and rapid TB progression andsustain multieffector functions of CD8þ T and CD3-lymphocytes: Mechanisms of CD4þ T cell immunity. JImmunol 192: 2120–2132.
Yu X, Prados-Rosales R, Jenny-Avital ER, Sosa K, CasadevallA, Achkar JM. 2012. Comparative evaluation of profilesof antibodies to mycobacterial capsular polysaccharidesin tuberculosis patients and controls stratified by HIVstatus. Clin Vaccine Immunol 19: 198–208.
Zhang M, Zheng X, Zhang J, Zhu Y, Zhu X, Liu H, Zeng M,Graner MW, Zhou B, Chen X. 2012. CD19þCD1dþCD5þ
B cell frequencies are increased in patients with tubercu-losis and suppress Th17 responses. Cell Immunol 274:89–97.
Ziegenbalg A, Prados-Rosales R, Jenny-Avital ER, Kim RS,Casadevall A, Achkar JM. 2013. Immunogenicity of my-cobacterial vesicles in humans: Identification of a newtuberculosis antibody biomarker. Tuberculosis (Edinb)93: 448–455.
B Cells and Antibodies in TB
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