INT J TUBERC LUNG DIS 16(11):14241432
2012 The Union
http://dx.doi.org/10.5588/ijtld.12.0479
The knowns and unknowns of the immunopathogenesis
of tuberculosis
T. H. M. Ottenhoff
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
In this review, we discuss the knowns and unknowns of
host defence towards Mycobacterium tuberculosis. With
regard to the knowns, both protective and immuno-
pathogenic mechanisms are discussed, including recently
discovered new pathways of host defence and inflamma-
tory immunopathology. With regard to the unknowns,
there will be emphasis on unanswered key questions,
TUBERCULOSIS (TB) remains a disease of dramatic
proportions, killing around 1.5 million individuals each
year and inflicting incredible human suffering on many
individuals, communities and populations in under-
privileged and under-resourced settings. TB is respon-
sible for more casualties than any other single patho-
gen,1 and combined with human immunodeficiency
virus (HIV) co-infection it forms a particularly deadly
alliance. Active HIV co-infection compromises host
defence and leads to higher TB prevalence, worse out-
comes and difficult to treat TB disease. The increasing
prevalence of multidrug-resistant (MDR-) and exten-
sively drug-resistant (XDR-) TB, as well as the appear-
ance of totally drug-resistant (TDR) Mycobacterium
tuberculosis strains further threaten TB control.
Based on tuberculin skin test (TST) surveys, more
than 2 billion people are thought to be latently in-
fected with M. tuberculosis, and thus at risk of TB re-
activation.1 Cell-mediated immunity has long been
known to play a key role in the control of mycobac-
terial infections,2 involving the coordinated activity
of many cells and cell types, particularly phagocytes
and CD4+ T-helper (Th) cells. This is illustrated by
the fact that active HIV infection targets CD4+ Th
cells and increases TB reactivation rates from 310%
per lifetime to 510% per life-year.3
Nevertheless, most M. tuberculosis-infected indi-
viduals are able to contain infection in a latent or
subclinical stage: over 90% of TST-converted indi-
viduals never develop clinical signs of TB disease, as
long as they carry no other risk factors that compro-
mise host immunity.2,4 During persistent latency, non-
or slow-replicating M. tuberculosis bacilli remain
present, and may be reactivated when host immunity
Correspondence to: Tom H M Ottenhoff, Department of Infectious Diseases, Leiden University Medical Center, Leiden,
The Netherlands. Tel: (+31) 71 526 3809. Fax: (+31) 71 521 6751. e-mail: t.h.m.ottenhoff@lumc.nl
[A version in French of this article is available from the Editorial Office in Paris and from the Union website www.theunion.org]
STATE OF THE ART
SUMMARY
accompanied by a perspective on needs and priorities
for future research. The role of the inflammatory re-
sponse and its dysregulation in tuberculosis-related im-
mune reconstitution inflammatory syndrome will also
be discussed.
K E Y W O R D S : Mycobacterium tuberculosis; immuno-
pathogenic mechanisms; immunopathology
decreases, even decades later. In addition to HIV co-
infection, other conditions may also impair human
host defence, albeit more subtly, and increase the risk
of TB reactivation, including other co-infections (hel-
minths, non-tuberculous mycobacteria, viral infec-
tions), comorbidities (e.g., type-2 diabetes) as well as
immunosenescence. Latent M. tuberculosis infection
can also be reactivated inadvertently following treat-
ment with biologicals such as tumour necrosis factor-
alpha (TNF-)/interleukin (IL) 12/IL-23 blockers,
which are increasingly used in inflammatory diseases
such as rheumatoid arthritis, Crohns disease, psoria-
sis and others.5
Some individuals are able to achieve complete or
sterile elimination of M. tuberculosis bacteria, rather
than developing latent infection. There is indirect evi-
dence in favour of this: around 1020% of individu-
als remain persistently TST-negative and do not de-
velop disease despite high-intensity exposure and
thus likely infection.6,7 As the TST depends on the ac-
tivity of T-cells, it is believed that the innate immune
response of these non-converters might control infec-
tion at an early stage, preceding the induction of an
ensuing adaptive immune response (see below). A sci-
entific challenge is to elucidate the protective mecha-
nisms involved so as to translate these to new inter-
ventional strategies to control TB.
WHAT DO WE KNOW ABOUT IMMUNITY,
IMMUNE PROTECTION AND IMMUNE
PATHOLOGY IN TUBERCULOSIS?
Upon reaching the alveolar space, airborne M. tuber-
culosis bacilli are rapidly taken up by phagocytic

cells, particularly alveolar macrophages, local den-
dritic cells (DCs), interstitial macrophages and possi-
bly also epithelial cells, perhaps already when passag-
ing the bronchiolar linings. Compared to other
pathogens, M. tuberculosis has a unique ability to de-
lay the initiation of adaptive immune responses, both
in humans and in mice.8 Recently developed mouse
models, in which genetically engineered T-cell re-
ceptors specific for M. tuberculosis antigens were
expressed, have made it possible to show that M. tu-
berculosis is able to delay the onset of M. tuberculo-
sis antigen-specific T-cell responses by 23 weeks.
The likely underlying mechanism of action is that
M. tuberculosis-infected cells, presumably DCs, fail
to migrate from the infected lung focus to the local
draining lymph nodes in which T-cell priming takes
place for a period of at least 2 weeks.911 This delay
may allow M. tuberculosis to establish a critical
mass of bacilli before adaptive immunity can develop
sufficiently to control infection. From the resulting
bacterial population, at least three types of bacterial
populations can be generated through stochastic or en-
vironmentally induced events: truly non-replicating
persisting bacilli, persisting bacilli that enter into a
low metabolic and slow-replication stage in infected
cells and, in the case of acute TB or reactivation TB,
replicating, metabolically active bacteria.
In addition to this remarkable ability to retard the
initiation of adaptive immune responses, M. tuber-
culosis is also able to manipulate and persist in the
hostile milieu of infected host cells, particularly pro-
fessional phagocytes. M. tuberculosis exploits a myr-
iad of immune evasion strategies, the most important
of which are inhibiting the maturation of bacterial
phagosomes and their fusion with lysosomes; inhibit-
ing autophagy, an endogenous vacuolar sequestration
pathway with strong antimicrobial activity in profes-
sional phagocytes; inhibiting apoptosis, an inducible
cell death pathway with strong antimicrobial activ-
ity; inhibiting antigen processing and presentation to
T-cells to avoid recognition; inhibiting interferon-
gamma (IFN-) receptor-mediated signalling, a major
pathway that regulates all of these antimicrobial host
defence mechanisms; inhibiting and scavenging toxic
oxygen and nitrogen intermediates; and egression from
the hostile milieu of the phagosome into the more
favourable cytoplasma. All of these strategies assist
M. tuberculosis in resisting and escaping from host
defence,1216 and they have been reviewed in more
detail elsewhere.17
Following initial infection by M. tuberculosis and
phagocytosis, new macrophages start being recruited
to the site of infection during the early innate response,
forming cellular infiltrates that further develop into
primary granulomas. In contrast to previous beliefs,
these granulomas are dynamic structures from which
host cells can rapidly influx and efflux,18 at least in
the zebrafish model in which this was studied. When
The immunopathogenesis of TB 1425
the adaptive immune response has eventually been
initiated, specific T-cells also infiltrate the granuloma,
typically leading to the formation of larger, well-
organised granulomas in which M. tuberculosis or-
ganisms and macrophages are mostly located cen-
trally, and T-cells peripherally. This host response is
generally believed to be protective, as it localises and
sequesters infection in situ, although, as mentioned,
bacteria may disseminate from granulomas as well,
at least in the zebrafish model.18 If local control of in-
fection and inflammation is not properly balanced,
central caseous necrosis will develop,19 which strongly
facilitates the extracellular growth of high numbers
of M. tuberculosis bacteria. When these necrotising
granulomas liquefy and start damaging airway linings,
large numbers of M. tuberculosis bacteria can be re-
leased into the airways and transmitted by aerosol. The
immune response to M. tuberculosis is thus instru-
mental in the containment of infection, but is also in-
volved in facilitating TB transmission. This obviously
has an impact on TB vaccine design, among others, as
better vaccines than bacille Calmette-Gurin (BCG)
not only need to induce better immunity to M. tuber-
culosis, they also need to induce a well-balanced re-
sponse that favours protective mechanisms and avoids
those that are pathogenic.
Cellular host defence against M. tuberculosis
The M. tuberculosis-specific immune response involves
many different cell types, ranging from classical and
non-classical T-cells to neutrophils, B-cells and natu-
ral killer (NK) cells. The role of CD4+ Th1-cells in TB
is best understood. Th1-cells secrete IFN- and TNF
cytokines, which are crucial for protective immunity
against mycobacteria. The induction of IFN- is reg-
ulated by IL-12, which is secreted by activated phago-
cytes.4 Genetic mutations that affect proteins essen-
tial to the induction (IL-12p40 sub-unit, IL-12R1)
or function (IFN-R1, IFN-R2, Stat1) of Th1-cells,
as well as the discussed depletion of CD4+ Th1-cells
during HIV infection, all enhance susceptibility to se-
vere infections due to mycobacteria.4,20 The impor-
tance of cellular immunity in TB is further empha-
sised by the enhanced TB incidence rates during
treatment with biologicals targeting TNF.5
CD4+ Th1-cells recognise M. tuberculosis antigens
that are presented via major histocompatibility com-
plex (MHC) class II molecules at the cell surface of
phagocytes such as DCs and macrophages.2123 An
important new finding has been that MHC class II re-
stricted antigen presentation to CD4+ T-cells in TB
granulomas is not optimal, at least in a mouse model
of TB granuloma formation. This translated into
greatly impaired CD4+ Th1-cell activation, thus lim-
iting the induction of a protective cytokine response
in situ. The factors involved in this sub-optimal pre-
sentation may be multiple, and include limited anti-
gen/MHC class II availability or the inhibition of
1426 The International Journal of Tuberculosis and Lung Disease
supportive cytokines and other accessory molecules
needed to support full T-cell activation.24
In addition to the CD4+ Th1-cells, there is also
prominent activation of another CD4+ Th subset,
notably Th17 cells. This is a recently discovered T-
cell subset that produces IL-17A, IL-17F, TNF, often
also IL-22 and in some cases also IFN-. Th17 cells
are pro-inflammatory cells that primarily mediate
immunity against extracellular bacteria and fungi,
particularly at mucosal surfaces. Th17 cells are likely
to be of significance in the early phases of infection,
at least in mouse models of TB:25,26 they emerge in
the early phase of adaptive immunity and contribute
to host defence against M. tuberculosis.25 IL-17A is
essential to the formation of mature pulmonary gran-
ulomas in BCG and M. tuberculosis infection mod-
els.27 Their role in the later infection process remains
less clear, however:28 hyperactivity of Th17 cells was
detrimental and led to increased immunopathology,
accompanied by an influx of neutrophils and the in-
duction of tissue destruction, rather than contain-
ment of infection.28,29 TNF may be a significant con-
tributing factor here as well (see below). IL-17 can
also be produced by cells other than Th17 cells; for
example, a major source early in infection is from
T-cell receptor gamma-delta () cells, a T-cell popu-
lation bearing both adaptive and innate immunity-like
properties, which acts in the early phase of TB.27,29
Although the role of CD8+ T-cells in TB is less
clear than that of CD4+ T-cells, they are generally
considered to contribute to optimal immunity and
protection.23,30 CD8+ T-cells recognise antigen in the
context of MHC class I molecules, which are classi-
cally loaded with antigenic peptides that originate
from cytosolic antigens in infected cells. As M. tuber-
culosis is localised mostly in vacuolar compartments,
immunologists found it hard to explain initially how
CD8+ T-cells could recognise M. tuberculosis anti-
gens. It is now clear, however, that DCs in particular
possess multiple pathways to load MHC class I mole-
cules with peptides from phagosomal bacteria: this
can be mediated via the above-mentioned classical
cytosolic processing pathway, as active transport or
passive diffusion across micro-damaged membranes
of M. tuberculosis containing vesicles can deliver an-
tigens to the classical cytosolic proteasome/MHC
class I presentation pathway. Second, the finding that
M. tuberculosis may actively escape from the phago-
some into the cytoplasm and thereby directly access
MHC-class I processing /presentation provides another
mechanism.16 Third, M. tuberculosis induces infected
cells to undergo apoptosis, which leads to the forma-
tion of apoptotic vesicles that are subsequently taken
up by DCs, which in turn cross-present their anti-
genic contents through MHC class I and class II mol-
ecules.31,32 A fourth pathway, autophagy, bears some
similarities to the apoptotic pathway, and also con-
tributes to cross-priming of T-cells against intracellu-
lar pathogens, including M. tuberculosis.33,34 Fifth, al-
ternative processing pathways for phagosome-located
pathogens and endosome-located antigens exist by
which the latter can be loaded onto MHC class I.30
There are therefore multiple pathways for activation
of CD8+T-cells by phagosomal antigens.
An interesting and relatively new development is
the discovery of so-called alternative CD8+ T-cell sub-
sets, which comprise mostly MHC class Ib-restricted
CD8+ T-cells. These new subsets include histocom-
patibility complex antigen-E (HLA-E) restricted CD8+
T-cells,35,36 which recognise M. tuberculosis antigens
presented by the virtually non-polymorphic HLA-E
molecules; lung mucosal-associated invariant T-cells
(MAIT), which recognise M. tuberculosis antigens in
the context of the non-classical and highly conserved
MR1 molecule;37 and CD1-restricted T-cells, which
mostly recognise lipid antigens derived from M. tu-
berculosis.38 CD1b molecules are loaded with anti-
gen along the established MHC class II presentation
route, but very little is known about the precise li-
gands and loading mechanisms for MR1 and HLA-E
presentation molecules. HLA-E is enriched in the
M. tuberculosis phagosome, and is thus probably
physically accessible for loading by M. tuberculosis
peptides.39
An important contrast to CD4+ Th-cells is that
CD8+ T-cells are able to recognise antigens on non-
phagocytic cells such as epithelial cells, which can
also be infected by M. tuberculosis:40 all nucleated cells
express MHC class I molecules, but only professional
phagocytesor cells activated by IFN-express
MHC class II molecules and can thus be recognised
by CD4+ T-cells. This implies that CD8+ T-cells are
able to survey a much larger array of potentially in-
fected cell types than CD4+ T-cells. In addition, as
mentioned above, CD8+ T-cells are able to survey the
presence of antigens in the intracellular milieu of
the cytoplasm of infected cells through a variety of
antigen processing /presentation routes, whereas CD4+
Th-cells mostly survey the vacuolar compartment
that is continuous with the extracellular space. CD8+
T-cells thus provide important complementarities to
CD4+ T-cell immunity.
CD8+ T-cells also possess a number of antimicro-
bial effector mechanisms that are less prominent or
even absent in CD4+ Th1 and Th17 cells. CD8+
T-cells secrete granules with cytotoxic molecules, the
most important of which are perforin, granzymes and
granulysin. These molecules can kill infected host
cells, and granulysin is able to kill M. tuberculosis
and other bacteria directly. CD8+ T-cells can also kill
infected cells by inducing apoptosis, which was dis-
cussed above as an antimicrobial effector mecha-
nism during innate immune responses.17 However,
CD8+ T-cells also bear similarities to CD4+ Th1-cells
in that a subset (type-1 CD8 T-cells) is able to pro-
duce IFN-, TNF and often also IL-2. While these

different effector pathways have been well documented
for classical MHC class Ia restricted and CD1 (type-
1) restricted CD8+ T-cells in humans,4147 they are
probably also shared by MHC class Ib-restricted
CD8+ T-cells, such that both classical and non-
classical CD8+ T-cells are likely to contribute to opti-
mal immunity in TB.
Although it is obvious that T-cells and phagocytes
dominate in infected lesions, other cell types also par-
ticipate in the immune response to M. tuberculosis.
New evidence points to an accessory role for NK cells
and B-cells in immunity against TB.17,48 Several lines
of recent evidence also strongly suggest that neutro-
philic granulocytes are associated with TB disease ac-
tivity and may play an important role in TB patho-
genesis.4951 Human genome-wide gene expression
studies found a strong neutrophil-associated type-1
IFN signalling expression signature49,51 in TB patients,
which normalised following curative treatment. Thus,
other cells also contribute to host defence, and may
provide new biomarker signatures of pathogenesis,
disease activity, and protective immunity in TB.
In addition to the effector and memory CD4+ and
CD8+ T-cell subsets described above, M. tuberculo-
sis also induces the activation and expansion of regu-
latory T-cells (Treg). These cells execute inhibitory
and anti-inflammatory functions. Several Treg popu-
lations have been identified, including naturally oc-
curring, broadly reactive CD4+CD25+FoxP3+ Tregs,
and M. tuberculosis-specific-induced CD4+ Tregs52,53
and CD8+ Tregs, the latter of which have mostly been
identified in human mycobacterial infection.35,54,55
Tregs are capable of suppressing CD4+ Th-cell activ-
ity through the secretion of inhibitory cytokines such
as IL-10, transforming growth factor beta (TGF-)
or chemokine (C-C motif) ligand 4 (CCL4), or
through cell-cell membrane contact-dependent mech-
anisms; they can deactivate phagocytes and thus in-
hibit priming of CD4+ T-cell responses; they can in-
hibit the influx of CD4+ T-cells into draining lymph
nodes, inhibit T-cell proliferation and expansion,52
and thus delay and inhibit the onset of adaptive im-
munity to M. tuberculosis. Although Tregs obviously
can beand areexploited by M. tuberculosis in its
own favour, Treg cells play an important role in main-
taining immunological homeostasis by preventing ex-
cessive inflammation and auto-immunity.55 As will be
discussed below, the fine-tuning of the inflammatory
balance in TB is of key importance for optimal infec-
tion control, and it is likely that Tregs have evolved
to help create and maintain that balance.
A multitude of interlinking cells and mechanisms
are therefore involved in the immune response to
M. tuberculosis infection, its regulation and fine-
tuning, including activating /effector and inhibitory/
regulatory functions. The balance of the response and
the ability to deliver effective hits to M. tuberculosis-
infected target cells dictates whether the host response
The immunopathogenesis of TB 1427
will lead to control of infection and possibly bacterial
eradication, or whether infection will progress with
increasing numbers of bacteria, lung tissue damage
and transmission of M. tuberculosis organisms to
new susceptible hosts.19
Current and new tuberculosis vaccines: what type
of immunity should they induce?
The current BCG vaccines, all of which are derived
from the original BCG lots obtained by Calmette and
Gurin, are among the most widely administered vac-
cines worldwide, and have been given probably over
4 billion times. Despite BCGs overall impressive safety
record, it has recently become apparent that infants
with active HIV infection are susceptible to develop-
ing disseminating BCG-osis. This is a significant risk
in HIV-burdened populations,56 which has prompted
the World Health Organization Global Advisory
Committee on Vaccine Safety to recommend not us-
ing BCG any longer in HIV-positive children.
While BCG is effective in preventing severe TB in
infants, its main limitation is its inability to protect
significantly and consistently against pulmonary TB
in adults. It is unclear why BCG fails in this aspect.57
It is possible that BCG fails to adequately activate
immune cells or mechanisms that are essential for
protective immunity to TB. At this stage, this is hard
to prove, as we do not fully understand which mech-
anisms are key to protection against TB. Most TB
vaccinologists would argue that effective new TB vac-
cines, as a minimum, need to induce a broad reper-
toire of CD4+ and CD8+ T-cells, preferably with
multi-functional characteristics.58 Multi- or poly-
functionality refers to the simultaneous production
of multiple cytokines (IFN-, IL-2, TNF, IL-17) and/
or the expression of multiple effector functions (per-
forin, granulysin, cytolysis, etc.) by single T-cells. In
addition to executing several effector functions and
producing multiple cytokines simultaneously, these
cells typically also produce higher levels of cytokines.
However, contrary to initial expectations, these cells
do not appear to correlate with BCG-induced protec-
tion in infants59 and adults.6062 Moreover, they are
also present in active TB, although they may never-
theless be part of the protective host response at-
tempting to limit infection61 rather than contributing
to active disease. Finally, very little is known regard-
ing the ability of BCG to activate additional immune
cells that participate in the immune response to M. tu-
berculosis, such as MAIT, other HLA class Ib/CD1
restricted T-cells, NK cells, T-cell receptor (TCR)
cells as well as additional, innate cells, which can also
develop certain forms of immunological memory.63
In addition to the possibility that BCG fails to
adequately activate immune cells or mechanisms es-
sential to protection, the alternative possibility is
that other factors inhibit this, such as the immuno-
modulatory role of NTM,57 co-infections (besides
1428 The International Journal of Tuberculosis and Lung Disease
HIV, helminths, viruses), Tregs induced by BCG,54 or
the eventual waning of immune memory into adoles-
cence, which is the most critical period for TB (re)-
infection and its progression towards active disease.
A recent study showed that helminth-infected mice
have impaired innate pulmonary immune responses
to M. tuberculosis mediated by IL-4 activity.64
There is a strong need to develop vaccines that can
either boost BCGs early protective effects, or replace
it by superior vaccines (reviewed in Ottenhoff and
Kaufmann2). These vaccines should not only induce
better immunity, they should also circumvent inhibi-
tory pathways activated by BCG. Several interna-
tional efforts are ongoing, following three conceptu-
ally different strategies.65 The first strategy aims to
improve BCG, either by genetically complementing it
with the expression of additional antigens (e.g., early
secreted antigenic target 6 [ESAT-6], culture filtrate
protein 10 [CFP-10], regions of difference 1 [RD1] or
others), or by genetically modifying it to improve its
effectiveness in inducing immunity (such as via au-
tophagy or apoptosis-mediated cross-priming). The
second strategy aims to derive genetically attenuated
M. tuberculosis with high safety features and higher
efficacy than BCG, assuming that such M. tuberculo-
sis strains express broader sets of antigens which
BCG has lost. Both these approaches aim at replacing
current BCG, although the growing concerns about
disseminating BCG infections in immunocompromised
infants may urge strategies to replace BCG with safer
alternatives.56 The third approach is to develop non-
replicating subunit vaccines. These vaccines are con-
sidered to be most useful as booster vaccines follow-
ing BCG priming. However, they may also be used to
prime against antigens to which BCG fails to induce
immunity, such as RD1 antigens (ESAT-6, CFP-10
and RD1), which are genetically absent from BCG,
and M. tuberculosis DosR regulon-encoded antigens,
which are expressed by M. tuberculosis under vari-
ous forms of intracellular stress, but which are not
recognised following BCG vaccination.66,67
WHAT WE DO NOT KNOW OR UNDERSTAND
ABOUT THE IMMUNOLOGY AND
IMMUNOPATHOGENESIS OF TUBERCULOSIS
Immunology and inflammation
Although we have obtained many new insights into
the nature of the human immune response to M. tu-
berculosis and the participating cells and molecules, a
more holistic, integrated understanding of how these
cooperate to execute protection remains elusive. We
still do not fully understand exactly what constitutes
protection. A major challenge therefore is to obtain
such an integrative understanding, as this will be key
to designing better vaccines and identifying TB bio-
markers of protection.68 It is clear that no single cell
or function can be linearly correlated to protection.
We know most about the crucial role of CD4+ Th1-
cells, and their role in protection against myco-
bacteria is firmly established. But even established
knowns, such as the concept that CD4+ Th1-cells
mediate protection by secreting IFN-, are not beyond
doubt: recent studies in mice have suggested that
CD4+ Th1-cells might control M. tuberculosis repli-
cation through IFN--independent mechanisms. Vari-
ous explanations have been offered that are beyond
the scope of the discussion here, but which have been
described elsewhere.17 The role of CD8+ T-cells in TB
remains incompletely resolved, including the roles of
alternative CD8+ T-cell subsets, as discussed above.
Current thinking is that CD8+ T-cells may be particu-
larly important for protection in later phases of the
immune response, and/or in the recognition of heav-
ily infected host cells, which are less potently recog-
nised by CD4+ T-cells.30 This remains an important
issue for further study, given the possibility of acti-
vating CD8+ T-cells by specifically designed vaccines.
In addition, the role of Th17-cells in TB remains
unclear as yet. These cells are detectable in the im-
mune response to M. tuberculosis infection and BCG
vaccination in humans69,70 and mice, but emerging
data suggest that their beneficial vs. detrimental con-
tribution depends on the previous immune status
of the host: as discussed above, in the early phase of
adaptive immunity, Th17-cells in mice contribute to
host defence,25,27 but in a hyper-immune setting they
become pathogenic and induce lung pathology in-
stead of controlled immunity.28 This underscores the
necessity of inducing balanced immunity during in-
fection and following vaccination. In this light, it is
also not yet clear why genetic defects in the IL-12/
IL-23/IFN- axis rather selectively increase suscepti-
bility to mycobacterial disease,4,20 whereas defects in
the IL-23/IL-17 axis mostly predispose to infections
with other bacteria or Candida spp.71
In relation to IL-17, the role of neutrophils in TB
is incompletely understood. Neutrophilic granulocytes
are rapidly recruited to the site of infection, among
others in response to IL-17. They phagocytose M. tu-
berculosis,72 release antimicrobial defensins and fa-
cilitate the initiation of CD4+ Th1-cell responses.73
In addition to these protection-associated roles in
early host defence to M. tuberculosis, neutrophils
have also been implicated in transporting and dis-
seminating bacteria, and as mentioned are thought to
play a role in the pathogenesis of TB later in the in-
fection process, analogous to the dual role of IL-17.
A prominent peripheral blood neutrophil-derived bio-
signature was reported in active TB.49 Clearly, the
role of neutrophils in TB is multifaceted and needs
further study.72
An equally important issue is to achieve a better
understanding of the local immune response to in-
fection in the main target organ, the lung. Most
immunological studies in humans rely on analyses of

samples from the peripheral blood, or sometimes
pleural fluid, for obvious reasons. The study of the
mucosal immune response in the lung is very difficult,
and bronchoalveolar lavage cells may not be repre-
sentative of the deeper lung tissue. These issues are
hard to solve, and can only be pioneered in animal
studies. High-resolution positron emission tomogra-
phy and computed tomography (CT) scanning tech-
nologies are being developed that may help to study
aspects of inflammation and immunity in the human
lung using non-invasive approaches. Underlining the
impact of mucosal immunity in TB models in ani-
mals, the mucosal delivery of TB vaccines can induce
pulmonary T-cell responses controlling M. tuberculo-
sis infection at an early stage;7476 simultaneous intra-
nasal and parenteral immunisation with TB vaccines
increases the level of protection significantly com-
pared to classical routes.77 Although the precise mech-
anisms triggered by mucosal vaccination need to be
unravelled further, these results underscore the po-
tential of mucosal immunity and vaccination in TB.
As mentioned, this may involve new T-cell subsets
discovered in the lung mucosa, such as MAIT, as well
as more conventional T-cells expressing specific lung-
homing receptors, such as C-X-C chemokine recep-
tor type 6 expressing T-cells in mice.78
Inflammation and inflammatory pathology
in tuberculosis: tuberculous meningitis and immune
reconstitution inflammatory syndrome as extremes
It is well known that active TB disease has a strong
inflammatory component, but it is less clear what
regulates the inflammatory balance during infection.
It has been reported that virulent but not avirulent
M. tuberculosis inhibits apoptosis to avoid intracellu-
lar killing.79 By inhibiting apoptosis, M. tuberculosis
promotes alternative cell death via necrosis, which
propagates infection. Inhibition of apoptosis also al-
lows M. tuberculosis to escape from intracellular
killing and prevent or delay the initiation of T-cell
immunity (see above). Recent work in mouse and
zebrafish models of TB now suggests that the induc-
tion of necrosis and pathology is attributable, at least
in part, to host lipid mediators which are induced
by mycobacterial infection, the balance of which is
determined by host genetic factors.80,81 The down-
stream key event is regulation of TNF-, a major
pro-inflammatory cytokine involved in both protec-
tive and pathological immunity in TB. In a rabbit
model, almost 15 years ago, Kaplan et al. showed
that TNF-, although essential to protection, was
also a main determinant of pathogenesis and disease
progression.82 Indeed, incomplete anti-inflammatory
treatment regulating TNF improved TB outcomes.83
These results have now been confirmed and extended
in the M. marinum zebrafish infection model. The
new results show that the balance between the anti-
inflammatory host lipid mediators, lipoxin A4 (LXA4),
The immunopathogenesis of TB 1429
which inhibits apoptosis and DC-dependent cross-
priming of T-cell responses in mice,80 and the pro-
inflammatory leukotriene B4 (LTB4), dictates whether
balanced or dysregulated inflammation will ensue. Ex-
cess LXA4 leads to low TNF-, poor initial inflam-
mation and high bacterial burden, with subsequent
induction of necrotic cell death. Conversely, excess
LTBA4 leads to high TNF-, excessive inflammation
and direct macrophage necrosis.84 In both cases, ex-
cess necrosis was the end result, resulting in progres-
sive infection and pathology in the zebrafish model.
Interestingly, human genetic polymorphisms were
found in the same enzyme that controls this balance
in zebrafish, called LTA4H. These polymorphisms cor-
related with pathogenic vs. favourable outcome in hu-
mans, and made it possible to demonstrate that dexa-
methasone treatment gave a survival benefit only in TB
meningitis patients with the pro-inflammatory LTA4H
genotype, and not in those with the converse geno-
type. This elegant work thus showed that both in-
sufficient as well as excessive inflammation is likely
involved in TB pathogenesis, while balanced inflam-
mation is needed for optimal control.81
Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome (IRIS)
is an important complication during HIV treatment
in TB co-infected patients.85 Although IRIS is highly
heterogeneous in its clinical manifestations and poses
differential diagnostic challenges, a useful case defini-
tion for TB-IRIS has recently been developed.86 Apart
from pulmonary manifestations, TB-IRIS has a signif-
icant systemic component, it can affect multiple or-
gans, it can continue for several months and it has a
considerable mortality rate. IRIS is hallmarked by ex-
cessive, unbalanced inflammatory responses, but the
precipitating factors and its precise aetiology and
pathogenesis remain poorly understood. IRIS occurs
in 1040% of HIV-infected patients starting on anti-
retroviral treatment (ART) with low CD4+ T-cell
counts, and is correlated to the bacterial load. The
recovery of CD4+ T-cell responses during treatment
is thought to result in M. tuberculosis-specific pro-
inflammatory T-cell activation and expansion without
proper regulation. Dynamic Th1 activity has been as-
sociated with TB-IRIS in several studies,87 although it
has been difficult to establish causality, also given the
fact that not all TB-IRIS cases feature this phenotype.
In a recent study, IRIS was associated with pre-existing,
polyfunctional, highly differentiated effector CD4+
T-cell responses towards the co-infecting pathogen,88
confirming that T-cell dysregulation is specifically di-
rected to the co-infecting microbial pathogen. No
phenotypic defects in CD4+FoxP3+ Tregs have been
found in TB-IRIS, although their possible functional
impairment has not been rigorously assessed.89
However, it is also possible that innate responses
are the primary initiating factor in TB-IRIS. In this
1430 The International Journal of Tuberculosis and Lung Disease
context, it is relevant to note that M. tuberculosis
organisms present within host cells exert inhibitory
activity on these cells, particularly in the absence of
strong immune pressure and IFN-. When increas-
ingly higher levels of IFN- start to be produced by
T-cells restored following ART, and particularly when
M. tuberculosis is killed concomitantly by chemo-
therapy, the inhibitory effects of M. tuberculosis on
host cells are discontinued, allowing strong innate pro-
inflammatory cytokine responses to appear. These in
turn may also accelerate exuberant T-cell responses
through enhanced antigen presentation as a second-
ary effect. In a recent study, TB-IRIS patients had in-
creased levels of pro-inflammatory cytokines and
chemokines in vitro as well as in the serum, both in
response to M. tuberculosis stimulation. IL-6 and
TNF levels were the most consistently elevated, and
decreased in serum during corticosteroid treatment.90
Not only T-cells, but also myeloid cells and DCs, in-
crease in the circulation under ART.91 These data
suggest that both T-cell activity and cytokine release
can contribute to the inflammatory pathology of TB-
IRIS. Better insights into the immunological mecha-
nisms underlying IRIS are needed, including the pre-
cise contribution of T-cell subsets, innate immune
responses and other risk factors, to find better targets
for prevention and treatment of TB-IRIS.
CONCLUSION
Both the induction and potentiation of protective
immune responses, such as through vaccination,
which targets the adaptive arm of the immune sys-
tem, as well as the balancing of the inflammatory re-
sponse, a prominent function of the innate immune
system, are important to achieve a favourable out-
come to M. tuberculosis infection and bacterial con-
trol. The major challenge for TB researchers is to
better unravel these processes and identify the best
targets to optimise host defence and minimise inflam-
matory damage.
Acknowledgements
The author gratefully acknowledges the support of the following
organisations: the Bill & Melinda Gates Foundation Grand Chal-
lenges in Global Health (grants GC6#74 and GC12#82), the Euro-
pean and Developing Countries Clinical Trials Partnership (AE-TBC
Project), the Netherlands Leprosy Relief Foundation, the Turing
Foundation, and the Q M Gastmann Wichers Foundation. The re-
search also received funding from the European Unions Seventh
Framework Programme (FP7/2007-2013) for projects NEWTBVAC
IDEA and ADITEC (Accelerating the Development of Novel and
Powerful Immunisation Technologies; No. 280873). The author
thanks all members of the laboratory for their great support and
helpful discussions.
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Dans cette revue, nous discutons les lments connus
autant que les inconnus en matire de dpendance
de lhte contre Mycobacterium tuberculosis. En ce qui
concerne les donnes connues , on discute la fois les
mcanismes protecteurs et immunopathognes, y com-
pris de nouvelles voies de dfense de lhte et dim-
munologie inflammatoire rcemment dcouvertes. En ce
En el presente anlisis se comenta lo que se conoce y lo
que se desconoce sobre la defensa del hospedero frente a
Mycobacterium tuberculosis. En cuanto se refiere a lo
que se conoce, se examinan los mecanismos protectores e
inmunopatognicos, entre ellos las vas de defensa y los
mecanismos inmunopatolgicos descubiertos reciente-
mente. En lo referente a lo que se desconoce, se ponen
The immunopathogenesis of TB i
RSUM
qui concerne les donnes inconnues , on insistera sur
les questions-cl encore sans rponse accompagnes
dune perspective sur les ncessits et les priorits de re-
cherches ultrieures. Le rle de la rponse inflammatoire
et sa drgulation dans le syndrome inflammatoire de
reconstitution immunitaire li la tuberculose seront
galement discuts.
RESUMEN
en relieve las preguntas fundamentales que aun no se
han dilucidado y se expone una perspectiva de las nece-
sidades y las prioridades de la investigacin en el futuro.
Se comenta asimismo la funcin de la respuesta infla-
matoria y de su desarreglo en el sndrome inflamatorio
de reconstitucin inmunitaria.