August 2, 1996 20:15 Annual Reviews chapter8 AR15-08

Annu. Rev. Microbiol. 1996. 50:259–84

Copyright c 1996 by Annual Reviews Inc. All rights reserved

THE PATHOGENESIS OF
TUBERCULOSIS
G.A.W. Rook
Department of Bacteriology, University College London Medical School, 67-73
Riding House Street, London W1P 7LD, England

Rogelio Hernandez-Pando
Department of Pathology, Instituto Nacional de la Nutricion, Salvador Zubiran, Calle
Vasco de Quiroga 15, Delegacion Tlalpan, 14000 Mexico DF

KEY WORDS: cytokine profiles, immunopathology, adrenal, tumor necrosis factor

ABSTRACT
Tuberculosis patients relapse if treatment is not continued for 6 months, because
chemotherapy fails to convert the patients’ response from the necrotizing pattern
characteristic of disease (Koch phenomenon) to the nonnecrotizing bactericidal
function required for optimal immunity. We need to understand the nature of these
two immunological states and how to convert one to the other. Studies in mice and
humans implicate differences in cytokine profiles and in metabolism of adrenal
steroids. Either enhanced susceptibility or protection can be evoked in mice
with appropriate doses of a killed environmental saprophyte. This emphasizes
the importance of shared epitopes and may explain the geographically variable
efficacy of Mycobacterium bovis Bacillus Calmette Guérin vaccination. Unlike
soluble antigens of M. tuberculosis itself, which tend to evoke necrosis, the shared
mycobacterial epitopes evoke little skin-test reactivity in patients. Preparations
of these epitopes show potential as immunotherapeutic agents to convert the
response from necrotic to bactericidal mode.

CONTENTS
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
The Current World Situation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
The Problem of the Six-Month Treatment Regimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
MECHANISM OF PROTECTIVE IMMUNITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
The Type 1 Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
259
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260 ROOK & HERNANDEZ-PANDO

MHC Class 1–Restricted Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262

T Cell Subsets of Unknown Protective Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Nitric Oxide and the Antimycobacterial Pathways of Macrophages . . . . . . . . . . . . . . . . . 264
TNFα as a Protective Cytokine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
Avoidance of Macrophage-Mediated Killing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
The Role of Antibody . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
The Pattern of Response Associated with Immunity in Human Beings . . . . . . . . . . . . . . . . 265
MECHANISMS OF IMMUNOPATHOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
The Toxicity of M. tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
The Koch Phenomenon: The Pattern of Response Characteristic of Disease . . . . . . . . . . 266
The Cytokine-Sensitivity of Mycobacterial Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Mixed Patterns of Cytokine Expression in Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Mixed Patterns of Cytokine Expression and Tissue Damage . . . . . . . . . . . . . . . . . . . . . . . 268
TNFα-Mediated Toxicity During Murine Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
The Effect of Priming a Mixed Th1 + Th2 or Th0 Response Pattern Before Infection . . . 269
A Hypothesis to Explain the Koch Phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
ANTIGENS INVOLVED IN PROTECTION AND IMMUNOPATHOLOGY . . . . . . . . . . . . . 272
The Role of Epitopes Shared by All Mycobacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
Environmental Mycobacteria and Regulation of the T Cell Response to Pathogens . . . . . 273
Loss of Skin-Test Positivity to the Common Epitopes During Active Disease . . . . . . . . . . 273
Immunotherapy of Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
FACTORS THAT DEREGULATE THE TYPE 1 RESPONSE . . . . . . . . . . . . . . . . . . . . . . . . 275
Vitamin D3 Metabolism in Tuberculous Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Glucocorticoids in Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
The Peripheral Regulation of Cortisol-Mediated Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Adrenal Function in Human Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

INTRODUCTION
The Current World Situation
The World Health Organization has rightly declared tuberculosis to be a global
emergency. One third of the world’s population is infected. Only about 5%
of those infected develop active disease during the first few years following
exposure, but this represents eight million new cases each year and three million
deaths. Moreover, these numbers are increasing. The stresses of poverty,
malnutrition, and war increase the rate of reactivation. Even in developed
countries such as the United Kingdom, the disease distribution in large cities is
again identical to the distribution of poverty (102). The breakdown of health-
care systems is leading to incomplete case and contact tracing, incomplete
treatment, and increases in drug resistance. In many parts of the world, most
of the drugs distributed to patients are fake or out of date (54). Moreover,
tuberculosis is one of the first secondary infections to be activated in HIV-
positive individuals (104).
The Problem of the Six-Month Treatment Regimen
An important reason for the current failure to control tuberculosis is that even
when the best available chemotherapy is used, treatment must be continued for
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PATHOGENESIS OF TUBERCULOSIS 261

at least 6 months. This treatment regimen is not a realistic proposition in most

developing countries, or even in the inner cities of developed ones, because the
patients feel well after a few weeks and stop taking the drugs. The solution is
directly observed therapy (DOT) in which the patient is supervised while taking
every dose.
There are two interrelated reasons for the required six-month regimens. The
first is obvious and often discussed: The chemotherapy kills the vast majority of
the bacteria within a few days, but “persisters” that are presumably not metabo-
lizing (44) are not killed by the drugs. These persisters may be in true stationary
phase (96), or they may be merely replicating extremely slowly in old lesions
or at sites of fibrosis or calcification where oxygen availability may be low.
The other reason for the need for prolonged treatment is usually overlooked
but is, in our opinion, fundamental to an understanding of tuberculosis.
Tuberculosis patients have a necrotizing pattern of response to Mycobacterium
tuberculosis that is analogous to the phenomenon first noted by Koch in guinea
pigs (61). The Koch phenomenon is undeniably not a correlate of optimal pro-
tective immunity to tuberculosis. Indeed, preimmunization of animals, so that
they demonstrate the Koch phenomenon before they are challenged with viru-
lent M. tuberculosis, results in a clear and reproducible increase in susceptibil-
ity to the disease, compared to nonimmunized control animals (112). This and
other aspects of the Koch phenomenon are discussed in detail below. This inap-
propriate pattern of response does not correct itself during treatment. Therefore,
if chemotherapy is stopped at 3 months, relapse rates approach 20% (3)—even
in cases where treatment was an optimal rifampicin-containing chemotherapy
that achieved sputum negativity well before 3 months, and in spite of the fact
that there are very few live organisms in the patients’ tissues at this time.
The task for the immunologist is therefore to understand the differences
between protective immunity and the Koch phenomenon, and the factors that
determine which response pattern is present. The ultimate objective is to learn
how to replace the pathological response with the protective one very early
in treatment. With such knowledge, we should be able to devise ultra-short-
course chemotherapy regimens, supplemented with immunotherapy, that would
provide realistic tuberculosis control in the developing world and elsewhere.

MECHANISM OF PROTECTIVE IMMUNITY

The Type 1 Response
Manipulation of the immune system of mice with neutralizing antibodies or
gene knockout has provided strong evidence that, in mice, immunity correlates
with a type 1 response. The term “type 1” is used in preference to Th1 when
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262 ROOK & HERNANDEZ-PANDO

it is intended to refer to the overall pattern of cytokine release by all cell types
in the infected site, rather than only that produced by the CD4+ helper T cells
that were included in the original scheme of Mosmann (71). In vivo Th1 or
Th2 cells act in concert with CD8+ cells and with numerous other cell types
including macrophages, B cells, and some stromal cells. Collectively, these
interactions give rise to two patterns of cytokine release that are known as type
1 (dominated by IL-2, IL-12, and IFNγ ) and type 2 (dominated by IL-4, 5, 6,
10, and 13) (20, 90).
Disruption of the MHC class 2 genes or of the gene for the β chain of the
α/β T cell receptor (63), resulting in a deficiency of CD4+ α/β T cells, renders
mice susceptible even to the avirulent Mycobacterium bovis BCG. Disruption
of the gene for IFN-γ makes mice very susceptible to M. tuberculosis (death
within 3 weeks), and such mice may even die after many weeks if challenged
with BCG (23, 25, 38). Similarly, supplements of IL-12 can provide some
protection, though the effects are small, perhaps because in the early phase of
infection mice spontaneously produce a type 1 response to M. tuberculosis (41,
24). Future experiments with gene knockout mice with nonfunctional IL-12
genes will be more informative.
MHC Class 1–Restricted Cells
Mice with defective β-2 microglobulin genes, rendered unable to express nor-
mal quantities of class 1 MHC products, show only a trivial increase in suscep-
tibility to BCG (63) but are susceptible to M. tuberculosis (40). This may imply
a role for CD8+ cytotoxic T cells, though proof is lacking. Such cytotoxicity
could release organisms from macrophages that were failing to kill them and
enable uptake of the organisms by fresh activated cells. Circulating cytotoxic T
cells exist that can kill autologous macrophages infected or pulsed with antigen,
but these are usually CD4+ cells (62, 56, 77). However, researchers have re-
ported that M. tuberculosis can escape from the phagosome; this would enable
antigens to gain access to the antigen processing pathway that leads to antigen
presentation by MHC class 1 (73, 68). Interestingly, the more recent report
suggests that the ability to escape may be a property confined to virulent strains
of M. tuberculosis and not present in H37Ra or BCG, which would explain the
limited effect of β-2–microglobulin knockout on the susceptibility of mice to
BCG (63). Other authors remain unconvinced that M. tuberculosis leaves the
phagosome at all (114).
Other explanations exist for the effects of disrupting the gene for β-2 mi-
croglobulin. This gene associates not only with class 1 MHC, but also with
CD1, which, as explained below, is able to present a number of mycobacterial
antigens to CD4− CD8− (double negative) T cells (7).
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PATHOGENESIS OF TUBERCULOSIS 263

T Cell Subsets of Unknown Protective Role

γ /δ T CELLS A large proportion of human peripheral blood γ /δ T cells will pro-
liferate in response to mycobacteria (55). Many of the responding cells express
the Vγ 2/Vδ2 germline genes but show diverse junctional sequences (79). In
vitro, γ /δ T cells secrete a pattern of cytokines similar to the secretion pattern
of Th1 cells and are cytotoxic (72, 42). Circumstantial evidence supports early
involvement of γ /δ T cells in establishing immunity to tuberculosis (5). When
infected with BCG, mice with disrupted δ genes show diminished production
of IFNγ by spleen cells, but they do not show the increase in susceptibility
seen in T cell receptor β chain knockout mice (64). Thus the function of these
cells remains obscure and may be partly regulatory (59). However, these ex-
periments need to be repeated with virulent M. tuberculosis itself, because, as
was shown in mice unable to express β-2 microglobulin, effects may be seen
when using the pathogen that are not apparent with BCG (63, 40). Preliminary
evidence shows that disruption of the δ chain gene does indeed make mice more
susceptible to M. tuberculosis (107).
Considerable effort has gone into identifying the bacterial components rec-
ognized by these T cells. There is evidence for recognition of compounds that
contain 50 triphosphorylated thymidine (22), and also for recognition of isopen-
tenyl pyrophosphate and related prenyl pyrophosphate derivatives (107). The
study of the γ /δ T cell response in mycobacterial disease has therefore focused
attention on the fact that T cells do not recognize peptide epitopes alone.

CD1 RESTRICTED RECOGNITION OF MYCOBACTERIAL LIPIDS AND GLYCOLIPIDS

Another subset of T lymphocytes also recognizes nonpeptide mycobacterial
components. These are CD4− CD8− (double negative) cells that recognize anti-
gens in association with CD1. The CD1 proteins are expressed on dendritic
cells, mantle zone B cells, and cytokine-activated monocytes. They show dis-
tant homology with MHC molecules, and like MHC class 1 they associate with
β-2 microglobulin. However, CD1 molecules are not encoded within the MHC,
and unlike the MHC they are not polymorphic. CD4 and CD8, which are in-
volved in the interactions with MHC class 1 and class 2 respectively, are not
needed for interaction with CD1.
Beckmann et al have demonstrated recognition of mycolic acids by CD4−
CD8− , which are α/β T cell receptor-bearing lymphocytes (7). Mycolic acids
are α-branched, β-hydroxy, long-chain fatty acids that make up the bulk of the
mycobacterial cell wall. Similarly, a CD4− CD8− T cell line grown from the
skin lesion of a leprosy patient recognized mycobacterial lipoarabinomannan
(LAM). The recognition required mannosides with α (1→2) linkages, and the
phosphatidylinositol moiety (97). Although the role of these cells is unknown,
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264 ROOK & HERNANDEZ-PANDO

they appear to be cytotoxic and to secrete the Th1 cytokine pattern, which
suggests that they contribute to immunity.
Nitric Oxide and the Antimycobacterial Pathways
of Macrophages
Ultimately, most bacteria are probably killed by macrophages activated by
the various IFNγ -secreting cell types described above. A relevant effector
pathway in mice is dependent on nitric oxide (NO). Thus, inhibitors of NO
production aggravate tuberculosis infection (as assessed by mortality, bacterial
burden, and histopathology) (18, 17). The mechanism of action of the NO is
uncertain: NO has important signaling and second messenger functions that
may be as important as direct toxicity to the organisms (83). In the mouse,
a possible major role of the IFNγ is activation of the inducible NO synthase.
Also relevant is the Bcg phenotype because it affects the rate of replication of
mycobacteria such as BCG during the early stages of infection (111). The
product of this gene (Nramp-1) affects macrophage activation and may be
involved in NO pathways. Interestingly, the Bcgr and Bcgs alleles may be
differentially regulated by glucocorticoids (13), which is relevant to points
made below about adrenal function in tuberculosis.
TNFα as a Protective Cytokine
In addition to type 1 cytokines, TNFα is also essential for immunity to M.
tuberculosis in mice. Treatment of mice with neutralizing anti-TNFα antibodies
has led to dissemination of BCG infection (60), and treatment with neutralizing
antibodies or knockout of the 55-kDa TNFα receptor has led to rapid death
from M. tuberculosis infection (39). These results further suggest a role for
NO because TNFα is an important trigger of NO release from IFNγ -activated
cells, and because mycobacteria contain multiple inducers of TNFα release,
as do most microorganisms (2, 70). However, other effects of this cytokine
may be important, and, as described below, it probably also plays a role in the
immunopathology of tuberculosis.
Avoidance of Macrophage-Mediated Killing
Mycobacteria use various strategies to avoid being killed by phagocytes (16).
They inhibit acidification of the phagosome (104), modify intracellular traf-
ficking of vesicles (114), and cause quantities of LAM to insert into glyco-
sylphosphatidylinositol (GPI)-rich domains in the cell membrane (53). LAM
is itself a GPI of unusual glycan structure that has the ability to modify numerous
macrophage functions, including the response to IFNγ , and the ability to present
antigen (53). Inhibition of antigen presentation by LAM may be relevant to
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PATHOGENESIS OF TUBERCULOSIS 265

the apparent inability of long-term mycobacterium-infected macrophages to

present antigen to CD4+ T cells (80).
The Role of Antibody
Almost all the current review literature on the mechanism of immunity to tu-
berculosis states that antibody plays no role. We have found no evidence for
this statement. Although antibody alone is certainly not sufficient, it may well
be necessary. Spahlinger reported treatment of human tuberculosis with an-
tisera raised by immunizing horses with M. tuberculosis that had been stored
for prolonged periods, because he felt that stressed organisms were better im-
munogens. His results remain provocative (66, 101) and deserve some thought.
A number of mycobacterial components have potent pharmacological effects.
These include LAM, a variety of cytokine-inducing molecules, and inositol
phosphoglycan-like (IPG) second messengers that were recently discovered in
mycobacteria (GAW Rook, H Caro, E Filley & TW Rademacher, submitted
for publication). Neutralization of some of these by appropriate antibody may
play a role in immunity.
The Pattern of Response Associated with Immunity
in Human Beings
Direct evidence for the nature of protective immunity in human beings is dif-
ficult to achieve. We can, however, deduce that protection is associated with
a type 1 response by comparing patients with exposed but healthy controls
(99). Similarly useful data have come from studies of cytokine expression in
tuberculous lesions. Tuberculous pleuritis provides ideal clinical material, and
in this high-resistance form of disease the cytokine pattern released by cell
populations is heavily biased toward type 1 (4, 6).
There is convincing evidence that human macrophages can be induced to
release large microbicidal quantities of NO if exposed sequentially to Th2 and
Th1 cytokines, or triggered with antibody that cross-links the membrane CD23
(111a). In contrast most workers are unable to achieve this result by exposing
human macrophages to IFNγ and TNFα, which is the optimal stimulus for
murine macrophages. Therefore the significance of this effector mechanism
in the human disease is unclear. Workers unaware that M. tuberculosis has
an active nitrate reductase have added to the confusion, because this makes
the assay of nitrite as a surrogate for NO meaningless unless the medium is
strictly nitrate free. Nevertheless, Hirsch et al have produced evidence that
TNFα can trigger inhibition of the growth of M. tuberculosis by human alve-
olar macrophages (50). Most attempts to make human macrophages inhibit
M. tuberculosis have been unsuccessful, although this is easily achieved with
murine cells by incubating them with IFNγ (87).
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266 ROOK & HERNANDEZ-PANDO

MECHANISMS OF IMMUNOPATHOLOGY
The Toxicity of M. tuberculosis
Live M. tuberculosis is inherently toxic to cells. For instance, human or murine
macrophages that ingest more than about five organisms usually die, whereas
M. avium strains can multiply to remarkable numbers within cells without
killing them (GAW Rook, unpublished observations). The reason for this is
unknown. However, we have noted that M. tuberculosis releases a factor that
greatly increases the sensitivity of infected cells to the toxicity of TNFα (32, 33).
In vitro M. tuberculosis readily infects nonphagocytic cells such as fibroblasts,
and concentrations of TNFα that would be growth-promoting for normal human
fibroblasts will kill these infected cells (32). However, in the absence of TNFα,
M. tuberculosis is less toxic for fibroblasts (which do not themselves release this
cytokine) than it is for macrophages, suggesting that the ability of macrophages
to release TNFα in the presence of mycobacterial components may be a double-
edged sword that sometimes activates successful antimycobacterial activity and
sometimes kills the host cell.
Although M. tuberculosis clearly has some inherent toxicity, this does not
fully explain the pathology of the disease. Tuberculin and purified protein
derivative (PPD) are remarkably nontoxic both in vivo and in vitro, but in
suitably prepared humans or animals they provoke necrosis that is clearly due
to immunopathology.
The Koch Phenomenon: The Pattern of Response
Characteristic of Disease
As outlined above, Koch noted that 4–6 weeks after establishment of infection
in guinea pigs, intradermal challenge with whole organisms or culture filtrate
resulted in necrosis locally and in the original tuberculous lesion (61). A simi-
lar phenomenon occurs in humans. The tuberculin test site frequently becomes
necrotic in subjects who are or have been tuberculous. Necrosis is not an in-
evitable consequence of the delayed hypersensitivity response to tuberculin:
Necrosis does not occur when positive skin-tests to tuberculin are elicited in
normal BCG recipients or in tuberculoid leprosy patients. Koch sought to ex-
ploit this phenomenon for the treatment of tuberculosis and found that injection
of larger quantities of culture filtrate (Old Tuberculin) subcutaneously into tu-
berculosis patients would evoke necrosis in established tuberculous lesions at
distant sites (1). This resulted in necrosis, sloughing, and cure of the lesions of
skin tuberculosis (Lupus vulgaris, usually caused by bovine strains). However,
when similar necrosis was evoked in deep lesions in the spine or lungs, the re-
sults were disastrous, and such treatment merely provided further necrotic tissue
in which the bacteria could proliferate. This treatment was therefore abandoned.
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PATHOGENESIS OF TUBERCULOSIS 267

The error in Koch’s thinking became apparent in the 1940s. When guinea pigs
were preimmunized so that they had a powerful Koch phenomenon in response
to a small dose of tuberculin, they became more susceptible to tuberculosis
than were nonimmunized control animals (112). Obviously, such a response
was seen only if the challenge infection was introduced into the lungs or by
deep intramuscular injection so that necrosis could not result in shedding of the
infected tissue.
The Cytokine-Sensitivity of Mycobacterial Lesions
The ability of soluble bacterial material injected in one site to trigger necrosis in
a distant tuberculous site has some parallels with the Shwartzman reaction (95).
For instance, injections of endotoxin-rich material into a distant site (instead of
the tuberculin used by Koch) will also trigger necrosis in tuberculous lesions
(10, 28, 94), and injections into the flank of another cytokine trigger, muramyl
dipeptide (MDP), causes necrosis in sites of inflammation due to complete
Freund’s adjuvant (113). These observations are compatible with the view
that tuberculous lesions are susceptible to superimposed cytokine-mediated
damage. Two questions remain: Is there any evidence that TNFα, in spite of
its protective role, is also involved in the immunopathology of tuberculosis? If
so, under what conditions do cytokines cause such damage?
Mixed Patterns of Cytokine Expression in Tuberculosis
Many symptoms of tuberculosis, such as fever, weight loss, and tissue damage,
resemble the pathological effects of TNFα. Evidence that these symptoms may
indeed depend on TNFα in human tuberculosis has come from experiments
using thalidomide, which decreases the half-life of the mRNA for this cytokine
(69). Patients treated with thalidomide show rapid symptomatic relief and
weight gain (57). We are therefore faced with a paradox: TNFα is essential for
immunity but may also be responsible for pathology. Recent work provides a
probable resolution of this dilemma, as described below.
Although immunity to tuberculosis requires a type 1 response, in tuberculous
mice type 2 cytokines are also expressed (78). The same is true in human beings,
though less strikingly evident, and is most apparent when peripheral responses
are considered. Studies of peripheral blood mononuclear cells precultured with
mycobacterial antigen in vitro are unreliable, because the rapid production of
IFNγ from NK cells and from the Th1 cells that are almost always present
tends to inhibit full expression of Th2 cytokines. Nevertheless, both Th1 and
Th2 cells are seen by such methods (105). If peripheral blood lymphocytes
are examined without preculture, it becomes apparent that the IL-4 gene is
indeed expressed in patients’ peripheral blood mononuclear cells (92), while
there is a deficit in IL-2 expression (92). This suggests the presence of a Th2
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268 ROOK & HERNANDEZ-PANDO

component in disease, supported by the fact that tuberculosis patients have IgE
antibody (115) and IgG4 antibody (GAW Rook, unpublished observations).
Both of these antibodies are IL-4-dependent in human beings. When using a
laser Doppler velicometer to study tuberculin test sites, Gibbs et al found that
the extent to which blood flow was reduced in the center of the site at both 6 h
and 48 h was related to the level of specific IgE antibody to M. tuberculosis
(43). This appears to indicate incipient necrosis.
Mixed Patterns of Cytokine Expression and Tissue Damage
The above points are of considerable importance because the combination of
Th1 + Th2 + TNFα results in severe pathological damage in other systems.
For instance, the granulomata formed in response to the ova of Schistosoma in
mice (45) depend on the simultaneous presence of all three elements. These
granulomata, like mycobacterial lesions (10, 28, 94, 74), are acutely sensitive
to further tissue damage if systemic cytokine release is induced (15, 31). More-
over, if the Th2 component is reduced by preimmunization with ovum antigens
plus IL-12, the granulomata are much smaller, and, of great significance, the
residual tissue damage and fibrosis are reduced (113).
A correlation is readily demonstrated between the cytokine profile of the
helper T cells that are involved in an inflammatory site and the sensitivity
of that site to TNFα. When mice were immunized with a low dose (85) of
an intensely immunogenic killed mycobacterial preparation (autoclaved My-
cobacterium vaccae), only Th1 cytokine production was primed (75). If as
much as 1 µg of TNFα was injected into delayed hypersensitivity (DTH) re-
sponse sites that were elicited 24 h earlier in such animals, no necrosis was
caused. However, the 100-fold larger dose (109 ) of the same killed M. vaccae
preparation evoked a mixed pattern with priming for both Th1 and Th2 cy-
tokine secretion. Injection of TNFα into DTH response sites that were elicited
in these animals resulted in necrosis (75). Therefore, TNFα released into a
relatively pure Th1-mediated inflammatory site may act as a mere supplemen-
tary macrophage-activating molecule, but when released into a mixed Th1 +
Th2 or possibly Th0 site, it causes damage. Therefore, the interrelatedness
of decreased blood flow in tuberculin test sites and the level of specific IgE
antibody to M. tuberculosis may be relevant (43). In fact, these results must
still be interpreted with caution because we do not know what correlate of the
Th2 response pattern is responsible for the increased tissue damage.
TNFα-Mediated Toxicity During Murine Tuberculosis
Confirmation of the relevance of the observations outlined above has emerged
from a study of the TNFα-sensitivity of DTH response sites elicited in mice
with pulmonary tuberculosis (47). During the first 3 weeks, i.e. the period of
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PATHOGENESIS OF TUBERCULOSIS 269

Figure 1 The effect of 1 µg of recombinant murine TNFα on the swelling of delayed hyper-
sensitivity reactions at different stages of pulmonary tuberculosis in Balb/c mice. Foot-pads were
challenged with 20 µg of M. tuberculosis antigen, and the swelling was determined at 24 h (square).
Then 1 µg of TNFα was injected into the same site, and swelling was re-assessed 20 h later (44 h)
(filled circle). Means ± standard deviation (SD) are shown. Without TNFα, all reactions decline
by 44 h (not shown). From reference 47, with permission.

type 1 response (78), DTH sites were not sensitive to TNFα. After 50 days, the
animals enter a phase of slowly progressing disease that is accompanied by Th2
cytokine production and high IgG1 antibody titres (a Th2-associated murine
subclass). In these animals, DTH sites become TNFα-sensitive (Figure 1). At
this time the adrenals undergo atrophy (Figure 2), which, by compromising
glucocorticoid feedback, may further aggravate toxicity of TNFα (47). This
theme is developed below.

The Effect of Priming a Mixed Th1 + Th2 or Th0 Response

Pattern Before Infection
The argument that the mixed Th1 + Th2 cytokine pattern is associated with
pathology is further strengthened by looking at the consequences of generat-
ing in normal mice the immunological state seen at day 50 in infected mice.
When mice were preimmunized with 107 M. vaccae [the optimal dose for
inducing a Th1 non-TNFα-sensitive response (48)], they were partially pro-
tected (Figure 3). In sharp contrast, when mice were preimmunized using the
dose of 109 killed M. vaccae, they developed the mixed Th1 + Th2 response
pattern with TNFα-sensitive DTH responsiveness described above (48) and
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270 ROOK & HERNANDEZ-PANDO

Figure 2 The weights of the right adrenals of male Balb/c mice infected into the trachea with 106
M. tuberculosis. Means ± SD of groups of 3–5 mice are shown. Points marked with an asterisk
differ from the control value (p < 0.025, Student’s t test). From reference 47, with permission.

Figure 3 The effect of priming with 1 × 107 (triangle) or 1 × 109 (filled circle) autoclaved M.
vaccae or saline (square) 2 months before intratracheal infection on the survival of Balb/c mice.
Depending on the immunization protocol, the “common” epitopes can mediate responses causing
either protection (triangle) or increased susceptibility (filled circle). Asterisks indicate results that
are significantly different from saline controls by Fisher’s exact test.
August 2, 1996 20:15 Annual Reviews chapter8 AR15-08

PATHOGENESIS OF TUBERCULOSIS 271

Figure 4 The effect of priming with 1×107 (triangle) or 1×109 (filled circle) autoclaved M.
vaccae or saline (square) on changes in left adrenal weight induced by intratracheal infection with
M. tuberculosis (1×106 ) 2 months later. Means of 3–5 mice ± SD. Adapted from reference 47
with permission.

were found to be more susceptible to intratracheal M. tuberculosis than were

unimmunized control animals (48) (Figure 3). Moreover, their adrenals atro-
phied within seven days of infection (48) (Figure 4), further illustrating the
parallels between the immunological state evoked by 109 killed M. vaccae and
the state that accompanies late progressive disease.
A Hypothesis to Explain the Koch Phenomenon
Significantly, the Koch phenomenon accompanies progressive disease in guinea
pigs and human beings, so, it is logical to ask whether the immunological state
evoked by 109 M. vaccae in mice is equivalent to the Koch phenomenon in these
species. We have already pointed out that the Koch phenomenon increases
susceptibility to the disease in guinea pigs (112), just as the state evoked by
109 M. vaccae does in mice. We put this forward as a hypothesis, but we
emphasize that these results do not tell us which correlate of the Th2 response
leads to toxicity of TNFα in mixed inflammatory sites or to the increased
susceptibility to disease. The relevant factor may not be one of the conventional
Th2 cytokines but rather some unidentified factor that tends to be activated by
protocols that evoke Th2 T cell responses. This important point can now be
tested by experimentation.
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272 ROOK & HERNANDEZ-PANDO

ANTIGENS INVOLVED IN PROTECTION

AND IMMUNOPATHOLOGY
The Role of Epitopes Shared by All Mycobacteria
As stated above, epitopes common to M. tuberculosis and to an environmental
saprophyte (M. vaccae) are capable of acting as targets for a protective type
1 response or for a detrimental TNFα-sensitive, mixed Th1 + Th2 or Th0
response. This should not surprise immunologists, but it often does. We have
known for many years that the Bacillus Calmette-Guérin (BCG) is as effective
a vaccine against leprosy as it is against tuberculosis (35). Therefore, BCG
must be able to work through common epitopes (Figure 5). Similarly, Fine et al
reviewed evidence that contact with an environmental organism that leads to
mycobacterial skin-test positivity is protecting the population of Malawi from
both tuberculosis and leprosy (36). Also, Silva & Lowrie found that the 65-
kDa heat shock protein of M. leprae can protect mice against M. tuberculosis
(98), and the importance to protective immunity of conserved proteins such
as heat shock proteins has been emphasized repeatedly by other researchers
(116). The 30-kDa proteins are also strongly conserved within the genus and
can vaccinate guinea pigs (52). In spite of these findings, researchers hold a
deep prejudice against the view that protection can be mediated via epitopes that

Figure 5 A diagrammatic representation of the antigenic relationship between environmental

saprophytes and M. tuberculosis. The antigens in the shaded area may include conserved proteins
such as heat shock proteins. They can mediate protection but not the Koch phenomenon, so they ap-
pear to be handled differently by the immune system. Possible explanations are discussed in the text.
August 2, 1996 20:15 Annual Reviews chapter8 AR15-08

PATHOGENESIS OF TUBERCULOSIS 273

are not species specific. This prejudice dates from the era of the early antibody-
mediated vaccines, in which antibodies neutralize microbial components by
binding conformational epitopes on toxins, enzymes, or adhesion molecules.
These substances are often species restricted. The fact that T cells do not
neutralize anything but instead recognize short peptide sequences cleaved from
microbial proteins, together with the fact that T cells are not taxonomists, should
be sufficient to dispel such a prejudice. The concept of species-specificity is
irrelevant to T cell function.

Environmental Mycobacteria and Regulation of the T Cell

Response to Pathogens
Because mycobacteria are not part of the normal commensal flora of human
beings, the nature, route, and dose of mycobacterial contact are variables that
depend on where and how an individual lives. This variable priming of anti-
mycobacterial responses by saprophytes, which, as explained above, can either
protect from or predispose to infection, almost certainly explains the variable
efficacy of BCG in different parts of the world (34) and the variability of the
protective effect of saprophytic species in some environments (36).

Loss of Skin-Test Positivity to the Common Epitopes

During Active Disease
Tuberculosis patients who still maintain necrotizing skin-test positivity to anti-
gens of M. tuberculosis itself have diminished or absent skin-test responses to
environmental saprophytes (58). This remarkable paradox implies that the com-
mon epitopes are handled in quite a different way from the tuberculosis-specific
components.
At least three hypotheses may be proposed for the selective loss of skin-test re-
sponsiveness to common epitopes. First, the common epitopes are by definition
“common” and are encountered from birth in a variety of mycobacteria (and re-
lated genera). Most of this exposure is by the oral route. Therefore, as with other
antigens encountered by this route, there has been possible priming of regulatory
TGFβ-producing T cells (19). According to a first hypothesis, these regulatory
cells may switch off the response to the common epitopes during the infection.
A second hypothesis is that because the common epitopes have been encoun-
tered at low dose over many years, the response to them has become locked into
the Th1 mode and cannot be converted to Th2 or Th0 (11). A third possibility
is that the common epitopes are handled in an intrinsically different manner
by the immune response because they are situated in highly conserved proteins
such as heat shock proteins that are potential targets of autoimmunity (21).
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274 ROOK & HERNANDEZ-PANDO

Figure 6 The effect of a single immunotherapeutic injection of 107 (triangle) or 109 (filled circle)
autoclaved M. vaccae or saline (square), 60 days after intratracheal infection of Balb/c mice. Only
the Th1-inducing dose (triangle) is beneficial. The dose that evokes a mixed Th1 + Th2 pattern,
with increased sensitivity to TNFα, exacerbates the disease (filled circle). Asterisks indicate results
that are significantly different from saline controls by Fisher’s exact test.

Immunotherapy of Tuberculosis
The common epitopes are capable of initiating protective responses, so the loss
of responsiveness to them in the disease state (no matter what the reason) sug-
gests the possibility that they can be used therapeutically. Crude preparations
of M. tuberculosis itself cannot be used because, as Robert Koch found to his
cost, they evoke necrosis (1). However, a killed preparation of an environmen-
tal saprophyte that has the appropriate Th1-adjuvant capability theoretically
may be able to restore Th1 and DTH responses to the common epitopes, while
evoking no necrosis. An autoclaved preparation of M. vaccae contains the
common epitopes and has suitable adjuvant properties (48). When used at the
optimal Th1-inducing dose (85), such a preparation exerts significant benefi-
cial effects in a murine model of pulmonary tuberculosis when given on day
60, during the late mixed Th1 + Th2 or Th0 phase of the disease (Figure 6;
S Baldwin & I Orme, unpublished observations). These effects are equivalent to
immunotherapy of multi-drug-resistant disease in human beings in light of the
fact that no chemotherapy was given. After encouraging pilot studies in human
beings (30, 76, 103), this material is now undergoing Phase 3 efficacy trials in
August 2, 1996 20:15 Annual Reviews chapter8 AR15-08

PATHOGENESIS OF TUBERCULOSIS 275

Durban, Republic of South Africa, in collaboration with Dr. Bernard Fourie of

the South African Medical Research Council. The trial will be decoded in late
1996.
An alternative approach, also based on the need to boost type 1 responses,
is the administration of cytokines. IFNγ may be effective in the rare nonHIV-
infected individuals infected with M. avium (51) because these patients often
have a deficit in production of this cytokine. However, therapy with IFNγ
looks less promising in tuberculosis. Tuberculosis patients have deficient re-
lease of IL-2 from peripheral blood lymphocytes (92); therefore, attempts are
now in progress to treat tuberculosis with this cytokine (G Kaplan, personal
communication).

FACTORS THAT DEREGULATE THE TYPE 1 RESPONSE

We have argued above that an inappropriate Th2 component is present in both
murine and human tuberculosis. Its presence becomes more striking in human
tuberculosis as the disease becomes more severe. What then are the likely
causes of this shift in cytokine profile? Increasing antigen load is likely to be
one factor, owing to the striking linkage of the Th1 + Th2 balance to dose when
immunizing with particulate antigens such as mycobacteria (48) or leishmania
(11). Similarly, prostaglandin release may play a part (109, 49). However,
strong reasons now exist for suggesting that endocrine interactions with the
immune system are important to the changing cytokine profile.
Vitamin D3 Metabolism in Tuberculous Lesions
The macrophages of tuberculosis patients, following activation by IFN-γ , ex-
press an active 1α-hydroxylase and rapidly convert 25(OH)-vitamin-D3 to cal-
citriol (88, 84) (Figure 7). Their T cells may also express this enzyme (14). This
potent phenomenon leads occasionally to leakage of calcitriol into the periph-
ery and to hypercalcemia, although its role in the disease has in the past been
difficult to understand (84). This may be a feedback mechanism that tends to
down-regulate Th1 and enhance Th2 responses, a possibility recently suggested
because the active vitamin D3 metabolite 1,25(OH)2 cholecalciferol (calcitriol)
inhibits production of IFN-γ and IL-2 and increases production of IL-4 and IL-
5 (82, 27). This Th1-to-Th2 switching may well be related to the ability of
calcitriol to inhibit release of IL-12 (65). The true physiological relevance of
these effects in vivo remains unproven but now seems likely. The synthesis of
novel analogues of calcitriol that have less tendency to cause hypercalcemia has
allowed them to be tested as suppressors of Th1 responses in models in vivo.
Some of these analogues are strikingly effective and will prolong allograft sur-
vival as well as reduce the requirement for cyclosporin A in treatment (110).
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276 ROOK & HERNANDEZ-PANDO

Figure 7 The mechanisms controlling the functions of glucocorticoids in lymphoid tissue. Corti-
sol arriving from circulation may be inactivated by the stromal cells, which convert it to cortisone.
Alternatively, its effects may be opposed by unidentified metabolites of DHEA, following desul-
phation of the circulating DHEAS by macrophages. The latter also contain 1α-hydroxylase and
form calcitriol [1,25(OH)2 cholecalciferol], which may further deviate the response towards Th2.

In the 1940s, attempts were made to treat tuberculosis with vitamin D. When
patients with skin tuberculosis (Lupus vulgaris, often due to M. bovis) were
treated with this vitamin, the chronic nonhealing granulomatous lesions of-
ten underwent necrosis followed by resolution (67). However, necrosis and
liquefaction also occurred in deep lesions in the spine and lungs (12), so the re-
sults were as disastrous as the use of Koch’s immunotherapy, described above
(1). A very speculative explanation would be that the additional priming of
macrophages for cytokine release attributable to the calcitriol formed in the le-
sions (89), combined with the Th1-to-Th2 shift that this metabolite also causes,
was sufficient to exacerbate the Koch phenomenon, which resulted in sloughing
of skin lesions and liquefaction of deep ones.
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PATHOGENESIS OF TUBERCULOSIS 277

Glucocorticoids in Tuberculosis
Adrenal steroids may also contribute to the dysfunction of Th1 responses in
tuberculosis. Reactivation or progression of infection with tuberculosis is sen-
sitive to activation of the hypothalamo-pituitary adrenal axis. Exposure of
humans to the stress of war or poverty (102), or cattle to the stress of trans-
portation, is enough to cause reactivation of disease. The disease-promoting
effect of stress has been demonstrated under more controlled conditions in mice
(13, 108). These effects are thought to be mediated via glucocorticoid release,
for cortisol (corticosterone in mice) reduces macrophage activation and Th1 T
cell activity (27) while synergizing with some Th2 functions (37). Thus the
mechanisms that control tuberculosis are sensitive to glucocorticoids, probably
because glucocorticoids provoke a Th1-to-Th2 shift.
Several other features of tuberculosis are compatible with glucocorticoid-
mediated effects. These include a reduced CD4 count, a reduced CD4/CD8 ratio
(85, 86, 100, 106), and a mildly impaired glucose tolerance (117). The almost
total loss of the evening glucocorticoid trough indicates that the periphery is
indeed exposed over a 24-h period to increased cortisol levels, even in those
patients in whom early morning serum cortisol is normal (91).
In contrast, other aspects of tuberculosis suggest reduced adrenal reserve.
Some tuberculosis patients die suddenly and without obvious cause during
treatment, and adrenal deficit has often been the suspected cause (75, 93).
Occasionally the adrenals are themselves infected, but there are patients whose
adrenals are found in postmortem examination to be small and without evidence
of direct infection, as in tuberculous mice (47). Perhaps also of significance,
inhibition of cytokine-mediated tissue damage requires rapid peaks of cortisol
in response to cytokine signals to the hypothalamo-pituitary-adrenal (HPA)
axis (8, 118). TNFα and IL-1 are much more toxic in adrenalectomized than
in control animals (118, 8). Thus, reduced adrenal reserve could play a role
in the toxicity of TNFα, discussed above (57), and in the toxicity of TNFα in
tuberculous mice once they have entered the phase of adrenal atrophy (47). The
atrophic adrenals of these mice were not infected.

The Peripheral Regulation of Cortisol-Mediated Effects

The concept of increased peripheral cortisol effects in the presence of reduced
adrenal reserve is compatible with what we know of the regulation of steroid
synthesis, but previous studies of adrenal function in tuberculosis (reviewed in
81) were mostly confined to the investigation of adrenal reserve using vastly
supraphysiological quantities of adrenocorticotrophic hormone (ACTH). Such
studies failed to address the question in relation to new insights into the way
in which the peripheral effects of cortisol on the T cell system are regulated
August 2, 1996 20:15 Annual Reviews chapter8 AR15-08

278 ROOK & HERNANDEZ-PANDO

(Figure 7). Briefly, cortisol function within lymphoid tissue is regulated by local
production of metabolites of dehydroepiandrosterone sulfate (DHEAS) that
have “antiglucocorticoid” effects (9), and by conversion of cortisol into inactive
cortisone by an 11β-hydroxysteroid dehydrogenase (11βOHSD) present in the
stromal cells (26, 29). Both inhibition of DHEA sulfatase (R Foulkes, personal
communication) and of 11βOHSD (R Daynes, personal communication) have
a profound glucocorticoid-like effect. In contrast, administration of DHEA or
3,17-androstenediol causes an antiglucocorticoid effect and a Th1 bias (9, 26).
Therefore, study of DHEA/cortisol and cortisone/cortisol ratios is important,
as are attempts to understand any changes in the metabolism of DHEA.
Adrenal Function in Human Tuberculosis
Studies of 24-h urine samples in which adrenal steroid metabolites were iden-
tified and quantitated by gas chromatography and mass spectrometry have re-
vealed changes that are compatible with a disturbance in the regulatory balances
outlined above (85a). The total output both of cortisol derivatives and of an-
drogens was frequently reduced by as much as 50%. Cortisol also underwent
reduced conversion to cortisone and cortolones, so that tetrahydrocortisol levels
in urine were normal or even raised. This reduced conversion explains the nor-
mal serum cortisol concentrations reported by others (81) and must be due either
to decreased activity of 11βOHSD or to increased activity of a reductase. The
site of the enzyme changes that cause this cortisone/cortisol imbalance is not
yet known, but the implications for the regulatory system shown in Figure 7 are
clear. Similarly, a decreased DHEA/cortisol ratio was evident, as was decreased
conversion of DHEA to reduced forms (etiocholanolone and androsterone) and
unchanged or increased conversion to 16α-hydroxylated forms. Because we do
not know which metabolites of DHEA exert the “antiglucocorticoid” effects,
interpretation of this finding is not yet possible, but it is suggestive. There is
no reason to suppose that these changes are disease specific, but they may play
a role in pathogenesis. Manipulation of these regulatory circuits has profound
effects on the course of pulmonary tuberculosis in mice. For instance, admin-
istration of “antiglucocorticoid” steroids is protective during the early phase of
murine tuberculosis that is accompanied by adrenal hypertrophy and presum-
ably by corticosterone release (47) (see Figure 2). However, administration
during the subsequent phase of adrenal atrophy (see Figure 2) can be fatal (R
Hernandez-Pando & GAW Rook, manuscript in preparation).

CONCLUSIONS
Studies at the molecular level have yielded much information about the nature
of protection, the difference between protection and immunopathology, the
August 2, 1996 20:15 Annual Reviews chapter8 AR15-08

PATHOGENESIS OF TUBERCULOSIS 279

identity of the most protective groups of antigens, and the crucial immuno-
endocrine interactions. We have now reached the point where we can stand
back from the detail and attempt a physiological view of the entire disease
process, and integrate it with an ecological view of the role of exposure to
mycobacteria in our rapidly changing environment. These considerations lead
to the prospect of simple novel types of clinical intervention that are much
needed in the present global emergency.

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