Remodelacion Pulmonar en Tuberculosis

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Remodeling in TB JID 2005:192 (1 October) 1201

M A J O R A R T I C L E

Lung Remodeling in Pulmonary Tuberculosis

Keertan Dheda,1,2,3 Helen Booth,3 Jim F. Huggett,1 Margaret A. Johnson,2 Alimuddin Zumla,1 and Graham A. W. Rook1

1Centre for Infectious Diseases and International Health, 2Department of Thoracic and HIV Medicine, Royal Free Hospital, and 3Department

of Thoracic Medicine, Middlesex Hospital, Royal Free and University College Medical School, London, United Kingdom

Tuberculosis is a global public health catastrophe responsible for 18 million cases of illness and 2 million

deaths annually. Pulmonary cavitation with cough-generated aerosol is the principle means of spread, and

lung remodeling (healed cavitation, fibrosis, and bronchiectasis) is a major cause of lung disability, surpassing

all other diffuse parenchymal lung diseases combined. Efficient granuloma turnover is mycobactericidal, and

extracellular matrix is disbanded without scarring. In many with progressive disease, however, there is dys-

regulated granuloma turnover, liquefactive necrosis, and pathological scarring. The pathological mechanisms

and the related immunological pathways underpinning these phenomena are reviewed in the present article.

Further studies are needed to identify and develop specific immunotherapeutic interventions that target im-munopathology, since they have the potential to substantially reduce spread.

The lung remodeling associated with pulmonary tuber-

culosis (TB) (healed cavitation, fibrosis, and distorted

architecture) has never been satisfactorily explained. This

is despite TB being an international publichealth priority

and despite cavitation, with associated tissue and lique-

factive necrosis, being the mechanism by which disease

transmission occurs. In addition to addressing the sig-

nificant morbidity associated with lung remodeling, in-

vestigations that can elucidate mechanisms and immu-

nological pathways relevant to tissue necrosis might lead

to strategies for interrupting aerosol-mediated transmis-

sion. Such knowledge can be incorporated into immu-

notherapeutic strategies aimed at halting person-to-per-

son spread of Mycobacterium tuberculosis.

Why do caseous and liquefactive necrosis occur? More-

over, why is fibrosis present in a disease characterized by

a potent interferon (IFN)g response, when this cytokine

generally opposes fibrosis [1]? In this review, we reeval-

uate current knowledge of the immunopathogenesis of

tissue necrosis and fibrosis. Peer-reviewed data for the

Received 16 December 2004; accepted 9 May 2005; electronically published

29 August 2005.

Potential conflicts of interest: none reported.

Financial support: British Lung Foundation (support to K.D.).

Reprints or correspondence: Dr. Keertan Dheda, Centre for Infectious Diseases

and International Health, Royal Free and University College Medical School, 46

Cleveland St., London W1T 4JF, United Kingdom ([email protected]).

The Journal of Infectious Diseases 2005;192:120110

2005 by the Infectious Diseases Society of America. All rights reserved.

0022-1899/2005/19207-0012$15.00

present article were identified by searches of the Medline

and PubMed databases, up to and including October

2004, in all languages, by use of the search terms tu-

berculosis and remodeling, cavitation, fibrosis,

immunopathology, extracellular matrix, protease,

or necrosis. Other sources were the references cited in

retrieved articles and referenced textbooks.

DEFINITIONS

In asthma and chronic obstructive pulmonary dis-

ease, remodeling refers to anatomical and structural

changes that are not easily reversible (laying down of

extracellular matrix [ECM]), in contrast to reversible

changes, such as edema and cellular infiltration) [2, 3].

In this review, we have extended the term remodeling

to include residual cavitation, lung fibrosis or scarring,

distortion of lung architecture leading to volume loss,

and tuberculous bronchiectasis, all of which represent

an inappropriate response to lung injury. An appro-priate response occurs, for example, when granuloma

formation occurs in a coordinated fashion, followed by

disbanding of the granuloma, dissolution of ECM, and

return to normal tissue architecture. Fibrosis implies

a structural alteration, with laying down of collagenous

ECM by fibroblasts and other cell types. The fibrosis

may be interstitial; occur as a capsule around cavities;

be bandlike, with distortion of the lung architecture;


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1202 JID 2005:192 (1 October) Dheda et al.

Figure 1. Principle cell types and cytokines involved in competent granuloma formation. NK T (NKT) cells, CD4+ T cells, CD8+ T cells, and gd

T cells produce type 1 cytokines that activate macrophages, which are mycobactericidal. Granulocytes (not shown) may be important in early granuloma

formation. Mycobacteria (rods) may be present within cells or extracellularly. Mycobacterial killing can occur by macrophage apoptosis, cytotoxic T

cell lysis (jagged arrow), or directly through granulysin (star)mediated destruction. Tumor necrosis factor (TNF)a is a likely requisite for macrophage

mycobactericidal activity, necrosis, and formation of the fibrous capsule. Cellular recruitment into the granuloma is facilitated by a chemokine gradient.

IFN-g, interferon-g; TGF-b, transforming growth factorb.

or be a combination of these. The term tissue necrosis en-

compasses both caseous and liquefactive necrosis.

CLINICAL ASPECTS

Cavitation into airways, with cough-induced aerosol genera-

tion, is the principle method by which TB is spread. Untreated,

there is a fatal outcome in 50% of individuals [4]. Despite che-

motherapy, however, there may be widespread lung destruction

with significant associated mortality [5]. Alternatively, subse-

quent healing can result in extensive fibrosis, traction bronchi-

ectasis [6, 7], and bronchostenosis [8], all of which may result

in volume loss, a restrictive defect during pulmonary function

testing [9, 10], and increased morbidity. Cavitation may erode

blood vessels, and bronchiectasis may cause significanthemopty-

sis [8, 11]. Poor drug penetration into cavities and fibrocaseousfoci, which are immunologically sealed off, may facilitate la-

tency and selection of drug resistance. Residual distortion of the

lung architecture depends on the degree to which the connective-

tissue matrix of a granuloma is degraded and removed. The key

question is what determines whether a granuloma resolves com-

pletely without scarring or whether liquefactive necrosis and/or

extensive scarring occurs.

EFFICIENT GRANULOMA FORMATION

AND DISSOLUTION

The first cell types encountered by inhaled mycobacteria are

the alveolar macrophages; phagocytosis is mediated by varioushost receptors [12, 13]. Lung gd T cells, NK T cells, and gran-

ulocytes are important early arrivals that precede the second

wave of expanded, IFN-g and tumor necrosis factor (TNF)

aproducing effector T cell populations [1416]. Collectively,

these cells initiate a chemokine and cytokine cascade that at-

tracts other macrophages and, later, T cells to the site of in-

fection [17] (figure 1). There is plasma exudation, and a fibrin

clot is formed [18, 19]. Macrophage aggregation to form an

early granuloma core is mediated by hyaluronic acid [20],

which binds to macrophages via CD44 [21]. Detailed histo-

logical analyses of developing granulomata in the rabbit model

[22] led to the view that macrophage activation driven by cell-

mediated immunity is followed by destruction of the same

macrophages, which then accumulate as caseous necrosis, and

is often associated with death of the contained bacilli. An al-

ternative view is that granulocytes are early arrivals that medi-

ate the cell lysis that forms the core of developing caseous

necrosis [16, 23, 24]. Recent pathological studies of granulomas

in tuberculous human lungs indicate that the peripheral lym-


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phocyte zones of the granuloma have secondary lymphoid fol-

licles analogous to those found in lymph nodes [16].

Macrophages and other cell types, such as fibroblasts, endo-

thelial cells, and neutrophils, also produce proteases (metal-

loproteinases [collagenase, gelatinase, and stromelysin]; the ly-

sosomal proteinases [cathepsins]; and the plasminogen/plas-

min system and its activator, urokinase]). Such enzymes may

facilitate granuloma formation by mediating antigen process-ing, removal of ECM and cellular debris, and processing of

cytokines and hormones [25]. They are tightly regulated at

multiple levels, including transcription, proenzyme formation,

and signaling control, as well as by tissue inhibitors of metal-

loproteinases (TIMPs) [26, 27].

Within the granuloma, both T cells and macrophages secrete

TNF-a and lymphotoxin a3. Not only is TNF-a crucial for

host defense [2832], but it also facilitates the structural in-

tegrity of the granuloma by mediating the formation of the en-

capsulating fibrous wall [33], together with transforming growth

factor (TGF)b [34, 35]. Macrophages also secrete insulin-like

growth factor (GF)1, fibroblast GF, fibronectin, and platelet-derived GF [36, 37]. These GFs are chemotactic and support

macrophage proliferation and, hence, the laying down of ECM

comprising collagen, fibronectins, and glycosaminoglycans [38

40]. Caseous necrosiswhich occurs at 23 weeks in the

rabbit model [22]and its associated low oxygen content cre-

ate unfavorable conditions for mycobacterial multiplication

[41]. This, together with macrophage activation and CD3+ ef-

fector cell mechanisms, culminates in mycobacterial steriliza-

tion. It was shown in 1927 that healed primary lesions are usu-

ally sterile within 5 years, although latent bacilli may persist in

other, superficially normal, parts of the lung [42, 43].

Controlled dissolution of the granuloma follows mycobac-

terial containment, although this may be incomplete if there

has been massive production of caseum. Proteases cleave com-

ponents of the ECM [26]. Macrophages phagocytose the part-

ly degraded ECM components, which are terminally degraded

within the lysosome or transported out of the lung [4446].

Minor residual scarring may remain.

DYSREGULATED GRANULOMA TURNOVER

AND LIQUEFACTIVE NECROSIS

In a significant minority of infected individualsthose with pro-

gressive primary and reactivation diseasethere is progressive

disease and liquefactive necrosis. This forms an ideal culture

medium for mycobacteria; they multiply extracellularly to large

numbers [47], since macrophages are unable to survive in ne-

crotic tissue, partly because of its toxic fatty acid content [41].

The proteolytic enzymes [48] compromise the integrity of the

fibrous granuloma capsule. Caseous material may discharge in-

to surrounding blood vessels and airways, thereby facilitating

systemic dissemination, and to the outside environment via

cough-induced respiratory droplets. The cavity often has an

external zone of collagen, internal to which is a zone of gran-

ulation tissue rich in fibroblasts, inflammatory cells, and cap-

illaries [47]. The role of vasculopathy as a primary event in the

facilitation of cavitation is unclear. With antimicrobial therapy,

the cavities may persist as fibrotic walled structures lined by

metaplastic squamous epithelium or as emphysematous bullae,or they may become distorted from without by traction fibrosis

[47].

Although the exact mechanisms of liquefaction are unknown,

the available data suggest that dysregulated proteolysis, direct

mycobacterial toxicity, the Koch phenomenon [49] and Shwartz-

man reaction [50], and host effector cells and cytokines are key

players (figure 2). These concepts are further discussed below.

Dysregulated Proteolysis and Direct Mycobacterial Toxicity

A variety of host proteases are up-regulated in mycobacteri-al infection [48, 5153], and dysregulation of protease control

mechanisms is likely to mediate proteolysis of structural com-

ponents of the lung [54]. Cytokines such as TNF-a and in-

terleukin (IL)1b can up-regulate proteases [5557] in mouse

and human monocytes in response to mycobacterial proteins

[58], and lipoarabinomannan induces collagenases in myeloid

cells [54]. Macrophage destruction by cytotoxic T cells and the

release of lysosomal contents are likely to play a significant role

in tissue destruction and may explain some of the necrosis in

the central part of the granuloma where macrophages pre-

dominate. Granulocytes may be important facilitators of early

necrosis [16, 23]. As discussed below, local tissue damage willbe more likely if the macrophages undergo necrosis rather than

apoptosis. Although thought to be less important, mycobacte-

ria themselves may produce endopeptidases [25] or other pro-

necrotic virulence factors. Recently, however, a polyketide tox-

ic factor, isolated from M. ulcerans, has been shown to have

cytopathic properties and produced necrotic cutaneous le-

sions in guinea pigs [59]. Since the M. tuberculosis genome

contains many polyketide synthesis genes [60], it is reasonable

to speculate that this toxin may represent one of a family of

virulence factors associated with immunopathology in myco-

bacterial diseases. Similarly, the secreted protein early secreted

antigenic target 6 kDa (ESAT-6) is a virulence factor for M.

tuberculosis and appears to cause lysis of lung epithelial cells

and to facilitate local spread [61]. Its contribution to caseation

is not known. Certain deletional mutants of M. tuberculosis

have an unchanged ability to proliferate within the host but

induce much less immunopathology, suggesting that myco-

bacterial virulence factors actively induce tissue-damaging cell-

mediated immune responses [62, 63].


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Figure 2. Factors that might contribute to dysregulated granuloma formation. Mycobacterial antigens mediate uncoupled protease metabolism ac-

tivity, apoptosis, the Koch phenomenon, and, perhaps, cell lysis mediated by early secreted antigenic target 6 kDa (ESAT-6) and induce the release

of cytokines (tumor necrosis factor [TNF]a, mixed Th1/Th2, and transforming growth factor [TGF]b), which collectively facilitate liquefactive necrosis

and deranged extracellular matrix (ECM) turnover. Mycobacteria (solid capsules) multiply extracellularly, compromise the fibrous granuloma capsule,

and may discharge into a bronchial lumen or blood vessel.

The Koch Phenomenon and Shwartzman Reaction

Koch [49] showed that tuberculous guinea pigs developed ne-

crosis locally and at distant sites of infection after rechallenge

with tuberculin. High tuberculin reactivity occurs in experi-

mental animals with liquefaction [64]. Similarly, the tubercu-

lin test is frequently necrotic in humans with TB but not in

healthy bacille Calmette-Guerin (BCG)vaccinated individuals

[47]. More recently, an elegant study showed that M. tuber-

culosisinfected mice developed increased lung inflammation

and elevated TNF-a levels when rechallenged with mycobac-

terial antigens [65]. Moreover, when prophylactic-vaccine can-

didates are tested for therapeutic effects in mice with TB, they

develop increased immunopathology [66] and classical Koch

reactions characterized by cellular necrosis within granuloma-

ta [67]. One explanation may be the systemic Shwartzman re-

action [50], which referred originally to cutaneous necrosis at a

site of a previous endotoxin injection after intravenous injec-

tion of lipopolysaccharide (LPS). The concept is that the initial

skin inflammation causes endothelial activation and accumula-

tion of inflammatory cells. Then, a subsequent systemic cyto-

kine-inducing signal administered 24 h later preferentially

triggers necrosis in the prepared skin site. Indeed, M. tuber-

culosisinfected C57BL/6 mice, which do not conventionally

develop necrosis in this model, develop caseous necrosis after

inoculation with LPS [68]. Moreover, LPS shares many physical

properties and biological functions with a major mycobacterial

antigen, lipoarabinomannan [69].

Host Cytokines and Effector Mechanisms

Necrosis and cavitation can occur in response to nonviable,

nontoxic components of mycobacteria [48, 64, 70]. This sug-

gests that host cytokines and enzymes are responsible for the

necrosis. Although the precise mechanisms inducing progres-

sion from controlled protease release and granuloma forma-

tion to dysregulated protease production with liquefactive ne-

crosis are unknown, a likely facilitator is TNF-a.

TNF-a. Although TNF-a is essential for immunity to TB,

in progressive disease TNF-a is associated with fever and wast-

ing [7173] and correlates with disease activity and immuno-

pathology [29, 7477]. Cells containing M. tuberculosisare ren-

dered exquisitely sensitive to killing by TNF-a [75, 78]. As out-

lined above, TNF-a can up-regulate metalloproteinases and

urokinase and thereby facilitate proteolysis of structural lung

elements. However, under what conditions is the protective

TNF-a molecule toxic? Data, as outlined below, support a

possible role for Th2 cytokines in such toxicity.

Th1 and Th2 cytokines. Recent data have convincingly

demonstrated the presence of Th2 cytokines in human TB [79].

Th2 cells may mediate local tissue damage that is IL-4 depen-

dent [80]. In M. tuberculosisinfected mice, susceptibility to the

toxic effects of TNF-a injected into the footpads coincided

temporally with the emergence of Th2 cytokines in the lungs

[81]. IL-4 may also regulate TNF-amediated enteropathy inTrichinella spiralis infection [82], and necrosis in a schistoso-

miasis model coincides precisely with the superimposition of

Th2 response on an existing Th1 pattern [83]. Mouse (BALB/

c) models of TB showed high IFN-g levels early during infec-

tion, with increased levels of IL-4 during the chronic phase of

infection, which was characterized by progressive fibrosis and

necrosis [84, 85]. The Th2 response may exacerbate tissue dam-

age by enhancing the pathological effect of TNF-a [81]. More


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Figure 3. The roles of the subversive Th2-like component of the immune response in progressive human tuberculosis. This Th2-like interleukin

(IL)4 response, modulated by IL-4d2, may be primed by environmental mycobacteria and helminths and is most striking in developing countries [92,

93]. After exposure to Mycobacterium tuberculosis, certain cell-wall components and protein antigens [9497] are then able to drive and enhance

this IL-4 response, which may contribute to deactivation of macrophages, as well as to necrosis and fibrosis. TGF-b, transforming growth factor b;

TNF-a, tumor necrosis factor a.

recent evidence, from IL-4 gene knockout experiments in BALB/

c mice, showed an absence of TNF-amediated toxicity after

TNF-a challenge in the absence of IL-4 [86]. Collectively, these

murine data suggest that, under the influence of superimposed

Th2 cytokines, TNF-a is toxic in dominantly Th1-mediated le-

sions. It is not unreasonable to suggest that a similar mechanism

operates in humans. Studies of lavage fluid from patients with

TB show the presence of IL-4producing Th2 lymphocyte sub-sets in those with cavitary TB [87] and the presence of a Th1

cytokine profile in those with noncavitary disease [74]. Simi-

larly, expression of IL-4 in peripheral blood lymphocytes cor-

relates with cavitary disease [88].

In other murine knockout models of immunopathology in-

duced by mycobacteria, g/d T cells [89], a/b-positive T cells,

IL-12, IFN-g, and TNF-a [90, 91] also seem to be essential for

necrosis of granulomata (figure 3). It has been suggested that

caseous necrosis is a protective mechanism to reduce the log-

arithmic growth of the organisms [47]. However, it is apoptosis

rather than necrosis that destroys M. tuberculosis (see below),

so it is intriguing to speculate that M. tuberculosishas evolvedcomponents that exploit the hosts tissue-damaging protective

responses by driving a Th2 response and necrosis. It is inter-

esting that particularly virulent Beijing strains ofM. tuberculosis

cause human monocytes to express IL-4 and IL-13 [94].

Apoptosis. Caseation is a mixture of necrosis and apopto-

sis. Large numbers of apoptotic T cells and macrophages are

seen in caseous foci [98]. Immunohistochemical analysis and

in situ hybridization have shown that macrophages surround-

ing caseous foci are negative for the antiapoptotic protein bcl2

but positive for the proapoptotic protein bax, whereas the as-

sociated T cells express IFN-g and FasL [98]. Apoptosis of

macrophages may be beneficial to the host. Both in mice [99]

and in humans [100], CD8+ cytotoxic T cells that use the gran-

ule-mediated pathway to induce apoptosis (as opposed to the

FasFas ligand pathway) lead to killing of the contained my-

cobacteria too. The role of the granule contents, particularly

granulysin, has been reviewed [101]. Apoptosis induced by ATP

[102, 103], TNF-a independent of IFN-g [104], Fas ligand

[105], and hydrogen peroxide [106] all promote killing of vir-

ulent M. tuberculosiswithin macrophages, whereas the necrotic

mode of death does not [105, 107]. Moreover, M. tuberculosishas mechanisms that tend to inhibit apoptosis. Mannose-cap-

ped lipoarabinomannan (Man-LAM) stimulates phosphoryla-

tion of Bad, a proapoptotic protein, and so inhibits apoptosis

[108]. Another group has shown that Man-LAM inhibits ap-

optosis by a mechanism involving calcium-dependent signal-

ing [109]. Recently, cathepsins have been shown to modulate

apoptosis in human pulmonary epithelial cells [110], although

their role in TB has not been investigated. It is, therefore, pos-

sible that the material that accumulates as caseum is, in fact,

a product of inappropriate necrosis. Apoptotic cells are usu-

ally removed by surrounding cells with minimal inflammatory

consequences, whereas necrotic cells accumulate. However, itis also possible that, when a sufficient percentage of the cells

are undergoing apoptosis, the normal clearance mechanism

fails, and apoptotic cells can themselves contribute to caseum.

FIBROSIS IN TB

TNF-a, TGF-b, and the pathogenesis of fibrosis. Extensive

deposition of ECM occurs in the guinea pig model of TB [111].

Available data suggest that TGF-b, together with TNF-a, plays

a key role in the formation of the fibrous wall that encapsu-

lates the tuberculous granuloma [3335]. The importance of

TGF-b with respect to pulmonary fibrosis has been established

in human [38, 112] and animal [113, 114] models. Although


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the exact signaling pathways that drive fibroblasts to lay down

ECM and macrophages to dissolve ECM are poorly under-

stood, it is reasonable to speculate that TGF-b may contribute

to the dysregulation of ECM turnover in TB. Indeed, TGF-b

may also perpetuate fibrogenesis by inhibiting apoptosis of

fibroblasts [115] and mediating localized production of inhib-

itors of TIMP [116]. However, it seems that TGF-b, although

necessary, is not sufficient for fibrosis. The importance of othermolecules, such as TNF-a, in lung fibrosis is illustrated by

models of bleomycin and hypersensitivity pneumonitis, in

which antiTNF-a antibodies ameliorate lung fibrosis [117,

118]. The role of other cell typessuch as alveolar epithelial

cells, which can harbor M. tuberculosis [42] and can be an im-

portant source of cytokines and GFs in idiopathic pulmonary

fibrosis [119]merits further investigation.

Two paradoxes immediately arise. The first is the presence

of increased ECM at the periphery of the granuloma but dis-

solution of ECM in the central part of the granuloma. Possible

explanations include a cytokine gradient within the granuloma

[120], including low IFN-g levels in the central macrophage-

dominant part of the granuloma or selective binding of cyto-

kines to glycosaminoglycans in different parts of the granuloma

[121]. Therefore, in the center of the granuloma, high TNF-a

concentrations, protease activity, and lysis of infected macro-

phages predominate, whereas, in the periphery, TGF-b activity

and fibroblast activation predominate.

The second paradox is the presence of fibrosis where there

are potent IFN-g responses, which down-regulate TGF-b and

production of collagen by fibroblasts [122, 123]. The answer

may lie in the significant Th2 response that develops parallel

to and within the framework of a Th1 response.Role of Th2 cytokines in fibrosis. IL-4 and IL-13 are pro-

fibrotic and enhance collagen production by fibroblasts [123].

Mice, when infected with saprophytic mycobacteria, only de-

velop peribronchial and interstitial fibrosis when primed for IL-

4 [84]. Even a single epitope (16 aa) inducing a Th2 response

can drive fibrosis in a murine model of TB [124].

In all human diseases characterized by marked pulmonary

fibrosis (systemic sclerosis, idiopathic pulmonary fibrosis, ra-

diation-induced pulmonary fibrosis, and chronic lung allograft

rejection; reviewed in [125]), there is expression of type 2 cy-

tokines. The same is true in the bleomycin murine model [125]

and in schistosomiasis, in which fibrosis and tissue remodel-ing do not occur if induction of type 2 cytokines by the ova

is blocked by preimmunization with ova plus IL-12 [126]. No-

tably, there are no data on cytokine profiles in the late stages

of fibrotic sarcoidosis [127]. These observations have led to the

type 2 cytokine hypothesis of fibrosis [125]. This paradigm

implies an initial Th1-type response to antigenic challenge, fol-

lowed by a Th2 response that seeks to wall off, or isolate, a

persistent antigen from the host [128130]. M. tuberculosismay

be exploiting this host response to remain immunologically

sealed off in fibrocaseous foci.

The Th2 phenotype causes fibroblast activation and collagen

deposition in human [131, 132] and animal [114, 133] models.

Collagen synthesis in granulomata is stimulated by Th2 cyto-

kines (IL-4, IL-13, and IL-4d2) and reciprocally inhibited by

Th1 cytokines such as IFN-g and IL-12 [1, 126]. Moreover,

granulomatous inflammation and fibrosis are significantly re-duced in Stat6/ mice [134]; IL-4 and IL-13 are the major

activators of Stat6. Fibrosis is particularly pronounced in mice

overexpressing IL-13 [125]. This cytokine, like IL-4 and IL-4d2

[135], activates fibroblasts and promotes collagen formation.

However, IL-13 also drives expression and activation of TGF-

b [125]. Significantly, the increase in expression of type 2 cy-

tokines in human TB extends to IL-13, which, like IL-4 and

IL-4d2, is increased 80100-fold [136, 137].

Smoking can reactivate TB, probably because nicotine switches

off secretion of TNF-a by macrophages, leaving IL-10 secretion

unchanged [138]. Similarly, TNF-amediated fibrotic lung dis-

eases like sarcoidosis and extrinsic allergic alveolitis [139, 140]are less common in smokers, and smoking improves survival in

a Th2-type fibrotic lung condition, idiopathic pulmonary fibro-

sis [141, 142]. The common denominator facilitating fibrosis in

all of these disorders might be the presence of a Th2 cytokine

component acting synergistically with TNF-a.

IL-4 or IL-4d2 from CD8+ T cells and their role in fibrosis.

In systemic sclerosis, Th2 cytokine expression is associated with

pulmonary fibrosis [135]. Interestingly, in several patients, the

IL-4, made mostly by the CD8+ T cells, was in fact not IL-

4 at all but rather IL-4d2, raising the likelihood that the CD8+

T cells making IL-4 in TB reported by van Crevel et al. might

be really making IL-4d2 (van Crevel et al. used reagents that

do not distinguish between the 2 cytokines [88]). IL-4d2 is

antagonistic to IL-4 with regard to lymphocyte function [143,

144], but it is an agonist on fibroblasts [135].

ARE THERE ANTIGENS THAT PREFERENTIALLY

DRIVE NECROSIS AND FIBROSIS?

IMPLICATIONS FOR IMMUNOTHERAPY

It is not yet clear whether there are antigens that preferentially

drive Th2, or whether M. tuberculosis merely contains Th2

adjuvant activity. The recent discovery that virulent Beijing

strains contain lipids that cause human monocytes to make

IL-4 and IL-13 suggests that adjuvanticity is part of the mech-

anism [94]. Similarly, dendritic cells derived from BCG-in-

fected precursors can drive a Th2-like response [145]. Nev-

ertheless, there does seem to be some antigenic specificity to

the Th2 response. ESAT-6 fails to drive IL-4 production [146],

but certain epitopes from within the 16-kDa heat-shock pro-

tein do so [95]. Identification of the antigens or epitopes that

drive IL-4 production will allow design of vaccines that sup-


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press the unwanted Th2 component [79]. Agents like M. vac-

cae, which attenuate Th2 responses [147, 148], have demon-

strated the ability to modulate lung remodeling and radiographic

absorbance in both drug-sensitive and resistant TB [149, 150];

clinical trials using multiple dose regimes are currently under

way [151].

In conclusion, further research into the genetic, molecular,

immunological, and cellular pathways that drive cavitation andfibrosis are required. This could yield clinical benefit and has

the potential to interrupt transmission. For instance, vaccines

that target immunopathology (either host responses or bacte-

rial virulence factors), even if they are not completely protec-

tive, may have the ability to reduce global disease burden by

minimizing cavitation and interrupting transmission. Like the

antiTNF-a agents [152154], other immunotherapeutic mo-

dalities could target pathways relating to cytokine signaling, ap-

optosis, protease activity,and ECM turnover. However, such goals

are tenable only if adequate funding is committed by government

agencies, the pharmaceutical industry,and internationalcharities.

Moreover, there will have to be a global organizational structurecommitted to achieving such goals.

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Remodelacion Pulmonar en Tuberculosis

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