The Immunophysiology and The Immunopathology of Tuberculosis

Item

Title
The Immunophysiology and
The Immunopathology of
Tuberculosis
extracted text
'-3°

THE immunophysiology and

of leprosy
• Med. Bull.

5

immunopathology of
tuberculosis

(1974) The
rthus reac»/., 91, 26331 tubercu■ literature.

f.M. Grange

ind pathooathy and
with aller■ Sysf., 2,
zulosis in
48 proved
40 (Suppl
aingitis as
geon. Am.

Nogales,
lie genital
136 cases.

f the placial refer;t lesions
nfect. Dis.

uberculo(1990)
Blackwell

adrenals,
glands in
cropsies.

i

I
!

phages bear a resemblance to epithelial cells
Ihe course, characteristics and outcome of
and are therefore termed 'epithelioid cells'.
tuberculosis vary enormously from patient to
Some of the macrophages fuse to form
patient. Almost without exception, these
multinucleate giant cells (Langerhans cells)
variations are attributable to the immune
responses of the host rather than to differ­ which, though not unique to tuberculosis,
strongly support the histological diagnosis.
ences in the virulence of the causative organ­
ism. The mechanism of virulence of the 5.1 THE NATURAL HISTORY OF
tubercle bacillus remains shrouded in TUBERCULOSIS
mystery but it has been apparent for almost a
Despite the enormous variation in the clinical
century that it does not owe its virulence to
the synthesis of toxic substances but to its features of tuberculosis, the disease never­
theless tends to follow a common pattern or
ability to survive the host's various immune
defence mechanisms. More recently, it has 'timetable' of events (Table 5.1)[1]. Most cases
of human tuberculosis are the result of
become clear that virtually all the clinical and
inhalation of small, moist, expectorated drop­
pathological manifestations of tuberculosis,
lets containing tubercle bacilli. These lodge in
as well as the infectivity of some patients, are
the alveoli or terminal air passages of the
the result of inappropriate, tissue-damaging
immune reactions. Thus, in tuberculosis, the lung and establish a local focus of disease
host's immune response is a two-edged termed the Ghon focus. Bacilli are trans­
ported to the lymph nodes at the hilum of the
sword - mediating protective responses but
lung where additional foci of disease deve­
also facilitating progression of the disease in
lop. The Ghon focus together with the hilar
the patient and in the community.
lymphadenopathy is termed the_primary
The characteristic lesion of tuberculosis,
, .
■ - ’ ^. Bacilli disseminate
and indeed of most chronic infections, is the complex (of
^ank
cH-eams
granuloma (Plate 6). This consists of aa comcom- further by the lymphatic
lymphatrc and
an blood
bloo I streams
pact aggregate, many layers thick, of macromacro­ and lodge m many organs of the body^ Thus,
phages in an activated
activated form
around
tuberculosrs is
rs a systemic infection.
mfecton.
form around the
the primary tuberculosis
:omplexes may also be acquired by
pathogen and a peripheral zone containing Primary complexes
a peripheral zone
lymphocytes responsible
responsible for
for macrophage
macrophage ingesting tubercle bacilh, usu^ “
y
K
7
■
■
.........
------milk, in which case the implantation tocus
activation. The closely interdigitated’ macroClmical Tuberculosis. Edited by P.D.O. Davies. Published in 1994 by Chapi.man & Hall, London. ISBN 0 412 48630 X

i

56

!

Immunophysiology and immunopathology

Table 5.1

I
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The 'timetable of tuberculosis'

Stage

Duration

Principal features

1

3-8 weeks

Development of primary complex. Conversion to tuberculin
positivity

2

3 months

3

3-4 months

4

Up to 3 years

Serious forms of tuberculosis due to haematogenous
dissemination: miliary and meningeal disease
Tuberculous pleurisy due to haematogenous spread or
direct spread from enlarging primary lesion
Resolution of primary complex. Appearance of more slowly
developing extrapulmonary lesions: bone and joint and
renal tuberculosis

Adapted from A. Wallgren, Tubercle, 1948, 29, 245-51.

I

will be in the tonsil or intestinal wall and the
disease, resulting in very large lesions, which
lymphatic lesion will be in the cervical or
often rupture and discharge their necrotic
mesenteric nodes. A minority of primary
contents into the bronchi, thereby forming
lesions follow traumatic inoculation, most
pulmonary cavities (Fig. 5.1). Unlike primary
typically as an occupational hazard of anat­ disease, the regional lymph nodes are rarely
omists and pathologists - the lesion being
involved and associated disease in other
termed 'prosector's wart'[2J.
organs is uncommon. Post-primary tuber­
In most cases, the host's immune defences
culosis is therefore more localized and con­
overcome the primary infection, which often tained than the primary form of the disease.
passes unnoticed. In the minority of cases. On
the
<”
. ........
J °Iher
hand, secondary lesions may
the Ghon focus may enlarge progressively develop in the same and opposite lung and
1 opposite
lung and
nd possibly rupture into the pleural cavity, the larynx due to spread of
badlli through
the
causing pleurisy. The hilar lymph node bronchi and trachea. Bacilli may be^walbroncSh m
may be S“fflCient to compress a lowed and cause secondary indurated lesions
hus, causing collapse of a lobe of the in the alimentary tract. This spread of disease
ung, or it may erode into the pericardial is, however, quite distinct from I' '
the haemato-,*'
Altern "y51118 tuberculous pericarditis, genous spread in primary tuberculosis.
Alternatively, one of the foci of infection in
TZ____
’ formation and containment of
The
cavity
more distant organs may progress, leading to disease iin post-primary tuberculosis is the
the serious non-pulmonary sequelae of prim- i___L
.
result of' active
immune responses. Old
ary tuberculosis including bone and joint, patients and those whose immunity
; is sup­
renal and meningeal disease.
-pressed
------ J
• AIDS,
------ renal
3 failure
by, rfor example,
Healed primary complexes may remain and post-transplant immunosuppressive
dormant; in about 10% of infected persons, therapy, tend to develop spreading pulmon­
reactivation eventually occurs, resulting in ary lesions with little or no cavity formation
/ post-primary tuberculosis. Exogenous re­ and widespread haematogenous dissemina­
infection may, of course, also cause this form tion of the disease.
of tuberculosis.
For reasons that are not known, post­ 5.2 HOST RESPONSES IN EARLY
primary tuberculosis of whatever origin INFECTION
tends to occur in the upper parts of the lung. Little is known of the events occurring in the
occurring in the
The necrotic element in the p.
post-primary first few days after primary infection of
lesion is much more evident than
m in primary human beings by the tubercle bacillus: our

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Host responses in early infection

57

berculin
s

or
2 slowly
and

s, which
necrotic
forming
primary
re rarely
n other
/ tubermd condisease.
>ns may
jng and
>ugh the
>e swal1 lesions
disease
aemato;is.
ment of
s is the
es. Old
• is supil failure
pressive
oulmon■rmation
•semina-

ig in the
:tion of
lus: our

it

jcn

Fig. 5.1 Post-primary tuberculosis showing
spread of bacilli.

r

a cavity and secondary lesions resulting from bronchial

plantation and initially consists of an
accumulation of blood-derived white cells,

respond non-spttctftcally
bactenal components and

princtpaUy
tamune responses have developed[4].
*_
___ 5 infiltratemacrophages
the
Subsequently,
mftltrate the tmm
lesion leading first to a mixed appearance of
'and’chronic granulomatous early stages of the infecHon are unable to
acute pyogenic <---distinct prevent dissemination of the bacilli by the
inflammation and eventually to a
lymphatic system to the regional lymph
epithelioid cell granuloma. The early inflam­
nodes, resulting in formation of the primary
mation and granuloma formation is induced
' , or further dissemination by the
non-specifically by various components of complex,
blood
stream to more distant organs.
the mycobacterial cell wall and probably 1

A*

58

hntnunophysiology arid immunopathology

5.3 INDUCTION OF IMMUNE
..
RESPONSIVENESS IN TUBERCULOSIS
- i T ,
$V,ded into distinct functional
a.
z >
‘-ULOSIS
subclusters. In the mouse, helper T cells are
Antigens of M. tuberculosis are taken up and dlvisible into two such subclusters, one of
processed by the antigen-presenting cells and whlch C1^1) secretes interleukin' 2 and
presented in close association with products gamma interferon and helps cell-mediated
/Mun maj°r histocomPatibility complex Immunity reactions and the other (Tu2)
(MHC) genes to antigen-specific T cells. Secretes ^terleukins 4 and 5 and helns
two classes of MHC gene products andbody P^duction[7]. Human helper T
and these determine the subsets of T cells to Cel?S, aPPear to be divisible into analogous
which the antigen is presented. The T cells subcIuster
s[8].
subclusters[8].
HeIp immune functions
(CD4 T cells) recognize antigens in associa­
tion with the Class II MHC antigens, coded 5.4 GENETIC CONTROL OF IMMUNE
or by the HLA-D genes, while T cells with RESPONSES IN tuberculosis
suppressor and cytotoxic funchons (CD8+) The existence of .genes that determine resist­
MHrniZe antigen in association with Class I ance to tuberculosis has long been suspected,
MI 1C antigens, coded for by the HLA-A and
n the mouse, a beg gene confers resistance to
-D genes.
early stages of infection by BCG and other
The repertoire' of antigens that may be intracellular pathogens[9], apparently by
presented on the surface of the antigen- nh!a f thr,innate ability of the macro
to inhibit or kill the pathogens. There
presenting ceil is affected by genetically phages
?
determined factors and varies from one person is suggestive evidence for a similar gene
to another. This genetic polymorphism determmmg disease susceptibHity in man.
affecting antigen recognition is thought to be
here have been many unsuccessful
an evolutionary mechanism to ensure that attempts to find linkages between susceptibiity to tuberculosis and the class I HLA genes
no single pathogen can eliminate an entire
(HLA-A and -B). Studies on class II (HLA-D)
mammalian species[5].
After binding to the antigen/MHC com­ genes have been more promising and have
plex, the antigen-specific T cells undergo revealed that the HLA-DR2 gene appears to '
activation and clonal expansion and then predispose to the development of tuberculo­
participate in the wide range of possible sis, particularly radiologically advanced
immune reactions. Thus T cells.responsible smear-posRjve disease[10-12]. The HLA-DR2
or the induction and suppression of protec- specificity may affect antigen recognition as
hve immunity, delayed hypersenXivity, Pisons of this genotype have higher levels
cytolysis and antibody production as well as of antibody to epitopes on a 38 kilodalton }
memory cells, with varying kinetics of protein unique to M. tuberculosis than those
appearance and disappearance, are produced lacking this genotype(lO).
It has been suggested that the class II genes
rAireXnSe 1° dlaIlen8es by M. tuberculosis
[6], Although clones of T cells capable of may determine the functional type of T cell
recognizing mycobacterial antigens have (e-g- Th1 or Th2) to which mycobacterial
been produced m vitro, it has not been easy to antigen is presented. On the other hand, the
relate the subset of T cells to the type of lack of a very close linkage between tuber­
culosis and HLA has led to the concept that
immune response, whether protective or
the selection of the type of immune response
by mycobacteria is a multifactorial event
™
°n SPedfic
recognition
evidence that the CD4+ and CDS' cells may but’i's';
-O on more primitive systems that

’I

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Mycobacterial persistence

and nitrogen dioxide. Activated human
macrophages, unlike those of the mouse, are
able to utilize vitamin D to induce further
activation and, as outlined below, this
phenomenon may account for further differ­
ences between immune responses in mice
and man.
While the isolated human macrophage
may be of limited effectiveness against tuber­
cle bacilli, collectively they may form a
powerful defence mechanism in the form of
the granuloma. Being metabolically very
1 'ey’llngenes3also affect reactivity to skin active, the macrophages,

agnize a range of common bacterial com' nents|8|. A predetermined tendency to an
nduction of predominantly T„l- or T„2mediated responses to mycobacterial antiof
ecns in man is suggested by a study
study _pf
hr dthv hospital workers exposed to tubercu­
lous patients. Some of these workers reacted
strongly to PPD and had low levels of
\ntibody to M. tuberculosis (suggesting a TH1
response) while others reacted poorly to PPD
but had higher antibody levels (suggesting a

fictional
cells are
one of
2 and
mediated
r (Th2)
1 helps
elper T
alogous

testing with tuberculin. Thus, skin testing
with a range of mycobacterial sensitins
revealed that persons lacking the HLA-DR3
oene tend to respond poorly to all sensitins,

? resistpected.
ance to
d other
tly by
macro. There
r gene
man.
.cessful
reptibit genes
ILA-D)
d have
ears to
erculoanced,
A-DR2
tion as
levels
'dalton
those

genes
T cell
icterial
id, the
tuber?t that
ponse
event
.nition
5 that

59

while those of HLA-DR4 phenotype respond
relatively strongly to species-specific antigens
of M. tuberculosis[14].

5.5 PROTECTIVE IMMUNITY AND THE
ROLE OF THE MACROPHAGE

i

In the classical theory of cell-mediated immu­
and other intracellular
nity to mtycobacteria
’
pathogens, antigens of the pathogens are
specifically recognized by helper T cells,
activate macrophages nonwhich then
I
"/ so that they are then able to
specifically
destroy a wide range of intracellular patho­
gens! 15). The experiments that led to this
theory were conducted principally with mice.
Problems have been encountered with this
theory in respect to human tuberculosis as
this differs considerably from the disease in
the mouse. Thus the latter is more resistant
than human beings to tuberculosis and the
disease is principally an intracellular one.
Furthermore, although activated mouse
macrophages undoubtedly kill tubercle
bacilli, attempts to demonstrate such killing
by human macrophages have, with few
exceptions, been unsuccessful[16J. Mouse
macrophages may owe their greater mycobactericidal powers to their ability to generate
toxic nitrogen metabolites, i.e. nitric oxide

diffusing into the granuloma so that the
interior region becomes anoxic and necrotic a xprocess termed caseation on account of the
cheese-like appearance of the necrotic material. The acidic and anoxic conditions within
the granuloma inhibit the growth of myco­
bacteria and may be bactericidal. This,
together with bacterial inhibition by the
activated macrophages, leads to quiescence.
The granuloma becomes dormant and is
entombed in fibrous scar tissue, which may
become calcified. Unfortunately, a few mycobacteria may’ remain viable within these
biological sarcophagi and re-emerge as the
cause of disease years or decades later.
5.6 MYCOBACTERIAL PERSISTENCE

The nature of the mycobacteria that persist
for many years within the tissues is one of the
mysteries of mycobacteriology[17]. It has
been shown that mycobacteria may remain
viable for long periods without replication
under anaerobic conditions[18]. This could
explain dormancy, but several authors have
advanced more elaborate theories, including
the existence of cell-wall-free forms or micro­
(Much'ss granules)!
granules)[17,19].
Host
spores (Much
, J.
immunity certainly plays a part in mamtainJ--------- ’ as reactivation is often asso­
ing dormancy
ciated with a weakening of immune
defences. This suggests that persisting bacilli
are not truly dormant but undergo replica­
tion, perhaps intermittently and slowly, at a

!|

4

60

hnmunophysiology and immunopathology

rate that is matched by their destruction by
immune or other mechanisms. Overt disease
would then develop if the rate of hostmediated bacterial destruchon failed to keep
up with the replication rate. This possibility is
suggested by the fact that a 6-12 month
course of isoniazid, a drug that is reported to

J

tion and the other

manifestations of post­
primary tuberculosis are a consequence of the
necrotizing reaction_ known as delayed
hypersensitivity. Although obviously caus­
ing extensive tissue damage, this reactivity
may have some protective value. Thus, in
to primary tuberculosis, bacilli rarely
^nHrnIrh0SVUberClebadnithatareactiveIy contrast
sPread from
the''
site
— —— ot disease via the
replicating, eliminates these persistors in a
lymphatic or blood streams. (As mentioned
high proportion of infected people.
earlier, they may spread to other parts of the
lung through the bronchial tree.) Also, the
5.7 POST-PRIMARY TUBERCULOSIS
tissue destruction may lead to massive fibro­
This form of tuberculosis usually occurs in sis and scarring that, in turn, may wall off the
the upper part of the lung. The immunologi­ active lesions, leading to quiescence. In the
cal reaction with granuloma formahon is pre-chemotherapeutic era, spontaneous resolution occurred in about one-fifth of patients
initially similar to that seen in primary with
cavitary post-primary tuberculosis[20].
disease but tissue necrosis is much more
In
the
chemotherapeutic era, such excessive
evident, resulting in very large caseous
scarring
may be distinctly disadvantageous
lesions termed tuberculomas. Proteases
by
favouring
bacillaiy dormancy and inhibit­
released by activated macrophages cause
ing
the
diffusion
of antituberculosis agents
softening or liquefaction of the caseous
into the lesion[21].
material. The acidic and anoxic conditions
To understand the immunological pheno­
within the lesion, together with free fatty
mena
responsible for the extensive tissue
acids in the softened caseous material, do not
necrosis and other characteristics of post-

I

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rellesions
.atively ?back
rimaiy
present. Many
to the^
“
eventually erode into bronchi and thek^hdiscovered the tubercle bacillus in 1882.
ened contents are discharged, resulting in the
formation of cavities. The environment of the
cavity wall is quite different from that of the 5’8 THE KOCH PHENOMENON AND
solid tuberculoma. Air enriched with carbon DELAYED HYPERSENSITIVITY
neutralizes the previously acidic conditinne

As a result, thesis a

i •

i_

m,'

,h- -■ studies
—
previous year' led him to

3

fOT

numbers of acid-fast bacilli in the cavitv wall
and many gain access to the sputum, rendermg the patient infechous. Bacilli are also able
to spread to other parts of the tong through
the bronchial tree and to set un additinml
foci of disease. In the days before eHecHv
chemotherapy, surgical pXedu":d^

innr. 1 i
22 ' Durin& these studies, he
lent totercirSby
d^T
and
ik
1^adermal ejection
Fig 5 r "XrdiSeaSe
ri 8 i
j
f 10-14 days, a small nodule
, 31
inoculaHon site. This subse^aXalTed^
““

to obliterate pulmonary cavities appeared to
limit the progression^ theXTa^ to

worn
aZ

encourage resolution

i

• ’ , e re81onal lymph nodes
1
late'

, , he dlsease spread to many

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I
The tuberculin reaction
of post­
ice of the
delayed
;ly caus­
eactivity
Phus, in
illi rarely
via the
mtioned
ts of the
dso, the
ve fibro­
ll off the
*. In the
>us resopatients
osis[20J.
xcessive
itageous
inhibit; agents
pheno2 tissue
if postto look
h, who
82.

studies
him to
ure for
ies, he
of viruijection
disease
nodule
; subse■n until
i nodes
h later,
many
i 3 and
found.

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61

tive reaction. This, unfortunately, did not
occur: the remedy was ineffective for pul­
monary disease and a few patients died of
'tuberculin shock' but some patients with
long-standing skin tuberculosis made
dramatic recoveries. These findings sug­
gested that the necrotic 'Koch phenomenon'
was protective when the disease was con­
fined to the skin and could be sloughed off
but was ineffective in those cases in which
the disease involved internal organs.
Tissue damage may be an unavoidable con­
sequence of a protective immune reaction.
Nevertheless, some tissue-damaging immune
processes appear to confer no benefit to the
host and are referred to as hypersensitivity
reactions. Four types were defined by Cell
and Coombs - the first three are relatively
rapid in onset and are the result of various
Fig. 5.2 A
A diagrammatic
diagrammatic representation
representation or
of me
the forms of antigen-antibody reactions[23J.
•---- The The
first first Type IV reactions, of which the Koch pheKoch phenomenon •in the guinea-pig.
challenge (left side) leads to an ulcer at the nornenOn is the classical example, appears to
inoculation site and enlarged draining lymph be mediated by cells rather than antibody and
nodes (primary complex) and further haematoe delayed onset than the former
genous dissemination. Subsequent challenge
Thus it is usually termed delayed type
(right side) leads to a flat ulcer with sloughing off tnree. inusiis
y
of the badlli-laden dermis and no involvement of hypersensitivity (DiH).
the draining lymph nodes.
5.9 THE TUBERCULIN REACTION
however, that if infected guinea-pigs were
or,orif
re-inoculated at another site 4-6 weeks after Although abandoned as a therapeutic agent,
the initial inoculation, the ensuing reaction Koch's Old Tuberculin was used as a skin­
was quite different. Within a day or two, testing reagent by the Austrian physician f
an area of skin 0.5 to 1 cm across at the Clemens von Pirquet. On the basis of exten­
inoculation site became darkened and, after a sive clinical and post-mortem studies, von
further few days, it became necrotic and Pirquet established that reactivity to tubercu­
sloughed off, leaving a shallow ulcer that lin indicated that the person had previously
been infected by the tubercle bacillus[24]. The
rapidly healed. Regional lymph nodes were
not involved and it appeared that the second procedure for skin testing has been some­
infection had been successfully eliminated. what modified over the ensuing decades. In
Koch then found that an identical reaction the original test, a drop of Old Tuberculin
occurred after injection of killed tubercle was placed on the skin, which was scratched
bacilli and also of a filter-sterilized broth through the drop, but reagents are now
culture of the bacilli concentrated by evap­ administered by intradermal injection (Man­
oration. Koch named this preparation Old toux method) or by multiple pronged devices
and tine tests). Old Tuberculin has
Tuberculin and administered it to tuberculo- (Heaf
v--«
sis patients by subcutaneous injection in the been replaced by Purified Protein Derivative
belief that it would induce a systemic protec- (PPD), the reagents are now standardized

62

Immunophysiology and immunopathology

fionaMeiir rSt7ngth iS
m Interna­
tional Units (previously termed Tuberculin
Units). Nevertheless, the principle of the test
remains unchanged and, in countries where
tuberculm reactivity has not been artificially
induced by BCG vaccination, provides a

of tubend'rtlOn °f>,the eXten‘ °f transmiss|on

’• -1

related to the mechanisms, discussed below
that are responsible
responsible for
for the
the tissue
tissue necrosis
and pulmonary cavity formation in post
pnmaiy tuberculosis.
F
I
Each mycobacterial species contains anti- I
gens unique to that species and also those
that are common to all mycobacteria. As both
groups of antigens may elicit tuberculin
reactions, exposure to other mycobacterial
species in the environment may induce cross- 1

of tuberculosis in the community[25]
Histological examination of biopsies of the
bercuhn reaction reveals a dense infiltra­
tion of blood-derived white cells around
the capillanes, hair follicles and sweat culin T reSp°nses on skin testing with tuberglands[26,27]. Some of the mononuclear ceBs culm. In some countries or regions, cross(macrophages and lymphocytes) imierate
'
dearIy diffcrent'ated by their
migrate
from these inflammatory foci into the
inter­ size from genuine responses to tubercuhn bu
• tn others the distinction between genuine
vening dermis, especially into the
sub-- and cross-reactions is not clear. For this
epidermal region. This migration is, at least
m part, m response to specific mycobacterial reason, the diameter of a tuberculin reaction
varies fr bemg diaKn03tically significant
ntigens as more migration occurs in re­
"T0" tO re8i°n- In veterinary
actions to tuberculin than to leprosin in nraet^
tuberculosis patients and vice versa in leprosy practice, simultaneous testing of cattle with
patients. There is no correlation between the reagents prepared from M. hovis and from
number of celIs
tes(
a
.environmental mycobacterium
the percentage of the dermis occupied by the (M. avium) is used to distinguish specific
reactivity from cross-reactivity but thiftech­
matoXSCf r anH PeriaPPendicular inflam­
matory foci, and the presence or extent of nique is rarely used in human studies.
Skin testing studies with reagents prepared
IndX 7 eViwnt SWeilin8 and biduration.
from filter-sterilized ultrasonicates of many
r Sub,ects
who
are
clinically
brlln'naSative may have an intense mycobacterial species (new tuberculins) have
revealed three categories of reactor[29,30]
cellular mfitagtg in
dermis
Persons
m Category 1 fail to react to any
although the reaction is cell-mediated, it is
reagent, even if they have been infected by
M. tuberculosis or have received BCG vaccine
I his non-reactivity appears to have a genetic
The greatly increased
cellularity of the basis (p. 59). Categmy 2 responders mact to
dermis at the tuberculin
-------- test site leads to
increased c
------- consumption and a com- any mycobacterial species, even if it is not
oxygen
tti«ennln thi? envlronment' indicating that
pensatory increase in blood flow
respond tQ cQmmon 6
accounting these p
or the zone of erythema that su'rro^nds"^
bacterial antigens. Category 3. responders
have h‘
ahOn' B1°Od fl°W moasurements
have, however, revealed that in many tuber­ thm th
tO Certain mycobacteria, indicating
culin reactions, notably the larger and more common7 reCOgn'uZe sPecies-specific, but not
obviously indurated ones, there is a central common, mycobacterial antigens. While
slowing of the blood flow[28]. This results in most healthy people are Category 2 retissue anoxia, acidosis and, in a few rersCm°nfSk0Vert hSSIUe necrosis- The mechan­
ism of this central relative slowi
How is unknown but it is likely’that it is
mycobacterial antigens, which may include

XLr

'

°f the bUlk the

I
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J

Delayed hypersensitivity

ains anti•Iso those
i. As both
uberculin
□bacterial
ice crossith tuberis, crossby their
culin but
genuine
For this
reaction
gnificant
2terinary
ttle with
nd from
acterium
specific
lis techas.
•repared
>f many
as) have
'[29,30].
to any
cted by
zaccine.
genetic
react to
t is not
ng that
myco’onders
Heating
aut not
While
2 reosis or
/ Catey have
mmon
nclude

vitamin D3 (calcitriol)[36]. This increases the
ability of the macrophages to inhibit the
intracellular replication of M. tuberculosis but
it also sensitizes them to the triggering of the
on p 66.
release of tumour necrosis factor (TNF) and
other cytokines[16]. One potent trigger of
5 10 PROTECTIVE IMMUNITY AND
TNF
release from such sensitized macro­
DELAYED HYPERSENSITIVITY
phages is M. tuberculosis and the active
The relation between protective and non- substance is a cell wall component termed
protective immune reactions in tuberculosis, lipoarabinomannan B (LAM)[37].
and the relation of both to tuberculin reacti­
Under normal circumstances, TNF plays a
vity, has been the topic of considerable protective role in infections by rapidly acti­
debate and confusion for many decades[31]. vating phagocytic cells and contributing to
Much of the confusion is due to nomen­ the process of granuloma formation. By
clature, as both types of reaction have been contrast, excessive release as occurs, for
grouped under the umbrella title of 'cell- example, in Gram-negative septicaemia,
mediated immunity' (CMI).
causes the toxic shock syndrome. TNF is also
During his pioneering studies on tuber­ termed cachectin and is said to be responsible
culin testing, von Pirquet observed that for the severe wasting (consumption, phthi­
patients with very advanced tuberculosis sis or cachexia) seen in advanced untreated
were often tuberculin-negative[32]. He thus tuberculosis. TNF is, however, undetectable
concluded that a positive tuberculin reaction in sera from tuberculosis patients without
was a correlate of protective immunity. This such advanced disease and, indeed, these
idea has been challenged on many occasions patients have a circulating inhibitor of the
and there is still controversy as to whether toxic effects of TNF. The question has thus
protective immune responses and necrotic been raised as to whether the relatively low
DTH reactions are quite distinct or whether levels of TNF released from tuberculosis
they are manifestations of the same response, granulomata are protective or lead to
but differing in intensity. This controversy
necrosis.
has been extensively reviewed[31,33-35] but,
Rook and his colleagues have shown that
although several questions remain un­ infection of cell lines by M. tuberculosis, or
answered, modern immunological and mole­ indeed the mere addition of crude culture
cular biological approaches are close to
supernatants of this bacillus, greatly
permitting a resolution of the issue.
enhances the susceptibility of the cells to
killing by TNF[16,38]. In vivo, injection of
5.11 THE NATURE AND MECHANISM OF
tuberculin followed 24 h later by an
DELAYED HYPERSENSITIVITY
injection, at the same site, of a minute
Following their activation and clonal expan­ amount of TNF leads to a necrotic reaction.
sion, helper T cells secrete gamma interferon This sensitization appears to be T cell(IFN-g) and other cytokines that activate the dependent.
Thus the sequence of events in a necrotic
macrophages (Fig. 5.3). In vitro studies show
that IFN-g per se does not increase the tuberculin reaction or tuberculous lesion
resistance of human macrophages to M. could be as follows. Mycobacterial antigen is
tuberculosis but that it has another important recognized by T cells, which then release
effect. It induces a 1-hydroxylase in human gamma interferon and other cytokines that
macrophages, which converts the inactive 25- activate macrophages and induce the 1OH vitamin D3 to the active 1,25 (OH)2, hydroxylase enzyme, which, by generating
protective epitopes. The significance of this
finding to the development of effecrive
immunotherapy is discussed in section 5.14

ed below,
? necrosis
in post-

r

63

T

. A

64

Immunophysiology and immunopathology

3 3(^0 q

CD4

( CD4 /

Antigen
presenting
cell

(CD4 )

INF-g

I
i o 0
Q

Macrophage

0

0 <
0
Activated
o
macrophage
o

o

O

O

O

°

O

o

o $
O 0 c
<=> o

O

^O0o

25 - OH vitamin D'3

o

—*

1 - Hydroxylase

o

O

;

1,25 (OH)2 vitamin D3 (calcitriol)

o

presenting celUo an i^duc^T^UCm+rThis ^ydCobacten^ antigen is presented by the antigen
population secretes gamma interferon amI oLr^tok^

1-hydroxylase enables the macrophage to convert' inactive 25 OH
vitamin D3, resulting in further activftion.
25’°H

calcitriol, primes these cells for TNF release.
Other T cell products sensitize cells at the site
to the toxic effects of TNF. Mycobacterial
components, notably LAM, then trigger TNF
release from the primed macrophages and
this kills the sensitized cells in the neighbour­
hood (Fig. 5.4). (In this context it is
noteworthy that sarcoid granulomata pro­
duce large quantities of 1,25 (OH)2
vitamin D3, enough indeed to induce hypercalcaemia, but necrosis of the lesions is very
uncommon, presumably as there is no LAM
or other TNF releasing factor of bacterial
origin.)
At first view, it might seem that this
explanation of necrosis occurring in tuber-

theTre-lting cell
r

H ^acroPhage- Induction of a
" °3 tO the active r'25 (°H)2

culosis would imply that all reactions,
whether lesions or tuberculin test sites,
would be necrotic and counter-protective'
Non-necrotic reactions may be explained by
postulating that, while T cell products may
sensitize cells to the toxic effects of TNF, this
is the property of a particular subset of T
cells. Antigen recognition by other subsets
might have the opposite effect. Although the
mechanism is unknown, there is very strong
evidence that the immune system may make
a 'decision' between a necrotic and nonnecrotic response to infection by A4. tuberculo­
sis and that an inappropriate decision may be
reversed by an appropriate immunothera­
peutic intervention.

Immunosuppression and tuberculosis

65

Priming
factor

INF-g

/

Tissue cell
Antigen

I
M. tuberculosis

Macrophage

I

LAM

I
1,25(OH)2 vitamin D3
(calcitriol)

Activated
macrophage

triol)

e antigen
ilting cell
ction of a
25 (OH)2

.•actions,
st sites,
otective.
lined by
cts may
NF, this
set of T
subsets
>ugh the
y strong
ty make
id noniberculomay be
lothera-

primed to release TNF and T cell
I ig. 5.4 The role of tumour necrosis factor (TNF). Macrophages are primed to release 1NF and ce
factors
lipoarabinomannan
Rook and R. Al Attiyah, Tubercle, 1991, 72, 13-20.)
There is no real form of tuberculosis
5.12 'SPECTRUM' OF IMMUNE REACTIVITY
equivalent to anergic lepromatous leprosy.
IN TUBERCULOSIS
Although disseminated, multibacillary tuber­
Attempts have been made to classify cases of culosis may occur, this is usually a conse­
tuberculosis according to a 'spectrum' of quence of generalized .mmunosuppression
immune reactivity similar to that evident in rather than the specific failure to recognize
leprosy. There are, however, fundamental antigens of the pathogen. Also, M. tuber­
differences between the two diseases that culosis is much more toxic and rapidly grow­
render such a comparison difficult[39J. In ing than M. leprae so that, unless treated,
leprosy, there is a hyper-reactive (tuber­ disseminated tuberculosis rapidly progresses
culoid) form with extensive granuloma for­ to a fatal outcome.
mation but very few bacilli and an anergic
Ridley and Ridley thus described a three(lepromatous) form in which there are huge group 'spectrum' of tuberculosis, with group
numbers of bacilli and a very specific sup­ 1 corresponding to chronic cutaneous disease
pression or absence of cellular immune re­ and group 3 to disseminated disease in
sponses to the leprosy bacillus and various immunosuppressed persons. Most cases of
borderline forms in which the immune tuberculosis are of the localized pulmonary
responsiveness is unstable and liable to cause and non-pulmonary types and belong to
severe reactions. The nearest equivalent in group 2[40J.
tuberculosis to tuberculoid leprosy is lupus
5.13 IMMUNOSUPPRESSION AND
vulgaris, a very chronic cutaneous form
TUBERCULOSIS
of tuberculosis in which there are wellorganized, non-necrotic epithelioid cell It has long been known that suppression of
immune reactivity may lead to endogenous
granulomata and very few bacilli.

66

Imtnunophystologi/ and immunopathology

reactivation of tuberculosis and this fact has
been particularly evident since the advent of 5.14 VACCINATION AND
the HiV pandemic[41]. Persons dually IMMUNOTHERAPY
infected by HIV and M. tuberculosis have a Bacille Calmette-Guerin (BCG) was produced
much greater chance of developing reachva- from a tubercle bacillus of bovine origin bv
hon tuberculosis than those only infected by repeated subculture on potato-bile medium
ie latter, i.e. an increase in the annual
This approach to vaccine development was
reactivation rate from 1% to 10%. Tuberculo­ based on the finding that children who
sis in HIV-positive patients differs from that developed, and recovered from, tuberculous
in non-immunocompromised patients
r—............
in that cervical lymphadenopathy (scrofula) as a
as a
the disease is imuch
’ less
’
contained and cavity
consuming milk contaminated with
formation is less
apparent. Thus,
2ss anrarpnf
Tk..„ the’dTeZ
J M.bovis appeared to be protected «- '
against the
may present as a spreading pulmonary lesion more serious pulmonary forms of tuber­
with rather non-specific radiological features culosis later in f'
“
life (Marfan's
law)[45J. In
disseminated disease. This emphasizes
With this theoiy/ BCG
.
.
1 was initially
that both cavity formation
and the 'walling- given as an oral suspension to infants
oft' process seen in post-primary disease although, for reasons of safety and standardihave an immunological basis.
“tton tt is now given by intradermal injec­
Not only does HIV infection predispose to tion. The mode of acHon of BCG is unknown
uberculosis, the latter may adversely affect H is particularly effective in preventing the
the progress of the former. Tuberculosis, senous, non-pulmonary
-pulmonary forms of primary
primary
even if effectively treated, often leads to a
ubercu,osis such as meningitis. Thus its
! „ ■ . , „
meningitis. Thus its
principal
effect
rapid progression of HIV infection to AIDS
P
nnc,PaJ ef
^ct m; ’be to prevent disseminabacilli fr
from'th.
This appears to be due to tumour necrosis tion of baC11Ii
°m the Primary infection,
to some extent against
factor, which induces the production of a lpriBCG
CG protects, t0
46J] and
and aagainst
i^phad^sX
to
nuclear factor, which in turn activates the lepmsyl
Prosy[46
gainst’lymphadenitis
due“to
transcription of the DNA provirus of the HIV en,VironmentaI mycobacteria in children[47]
indicating n,,.
that ---------some/ or Ilk
leading to viral replication[42],
md.r^n.
.. . .
Tuberculosis itself may induce a degree of nants of protection are to be found among the
immunosuppression, which reverts to normal antigens common to all mycobacteria
The efficacy of BCG varies greatly from
after successful therapy of the disease. Vari­
region
to region (see Fig. 14b. 1, p. 299). In
ous defects m immune function have been
described in tuberculosis and, in particular, regions where the vaccine is relatively inef­
HIV negative patients with active disease fective, greater protection is obtained by
vaccinating children shortly after birth[481
may show a CD4+ T cell lymphopenia[43],
anous explanations have been given for the
Relatively high numbers of CDS cells were
found in broncho-alveolar lavage (BAL) fluid regional variation: one of the more plausible
rom patients with miliary tuberculosis. The ones is that immunity to mycobacterial dis­
time taken for the radiographs to clear on ease may be conferred by exposure to envir­
therapy was related to the number of these onmental mycobacteria and that subsequent
cells suggesting that they had an adverse BCG vaccination cannot add substantially to
effect on protective immunity. The number of the level of protection. Alternatively, some
lymphocytes in BAL fluid was much higher species or populations of environmental
after 8 weeks of therapy and there was a mycobacteria may induce inappropriate
dis met shift from CDS* to CD4+ dominance tissue-damaging responses that BCG cannot
counteract or may even boost[49J. In this
144 J.
respect, tuberculin reactions may be divided

I

■
Other immunological phenomena
I

produced
origin by
medium,
nent was
ren who
Jerculous
la) as a
ited with
.ainst the
’f tuber-

)[45J. In
initially
infants
andardilal injeciknown.
ting the
primary
Thus its
;semination.
against
s due to
ren[47],
letermiong the
ly from
299). In
ly inefned by
rth[48].
for the
ausible
ial dis> envirequent
tally to
, some
mental
opriate
cannot
In this
livided

into non- necrotic 'Listeria-type' and necrotic
•Kixh-tvpe' responses by careful clinical
,nspection|50] and detection of central slowing of the blood flow by laser Doppler
vclicometry|51|.
There is therefore abundant evidence that,
depending on various factors, immune re­
sponses may confer protection or cause
excessive tissue damage and permit bacillary
replication in the cavity wall. Any means of
switching from the latter to the former would
be of great therapeutic benefit. Skin testing
with mixtures of sensitins prepared from
various mycobacteria showed that necrotic
Koch-type reactions are converted to nonnecrotic reactions by the inclusion of antigens
ot the non-pathogenic, rapidly growing
species such as M. vaccae[52]. Subsequent
extensive studies revealed that an injection of
)()*' killed M. vaccae has a systemic effect in
replacing Koch-type reactivity with a protec­
tive response[21J. It also restores immune
recognition of the common imycobacterial
antigens, which, as described above, is absent
in patients with active mycobacterial disease.
The precise mode of action of M. vaccae has
not been determined but clinical studies
indicate that it is a valuable adjunct to shortcourse chemotherapy, possibly permitting
the duration of therapy to be reduced from 5
months or more to 2 months or less[53).
5.15 OTHER IMMUNOLOGICAL
PHENOMENA IN TUBERCULOSIS

I

I

Attention has focused recently on the possi...........
’
’ may, to>
bility that immunity to mycobacteria
some extent, involve lysis of cells harbouring
mycobacteria, a process that would also
contribute to the immunopathological
features of the tissue reactions. Such cell
killing may be due to antigen-specific cytotoxic (CD8+) T cells as, in the mouse, these
have been shown to confer resistance to
infection by A4. tuberculosis by in vivo deple­
tion and adoptive transfer studies[54]. As
yet, however, there is no cevidence for

67

the involvement of cytotoxic CD8+ cells in
human tuberculosis[44]. In addition, natural
killer (NK) and CD4" CD8" T cells have been
implicated in non-specific intracellular killing
of mycobacteria, as well as killing of infected
macrophages[55). Large numbers of cytolytic
gamma-delta T cells have been found in the
necrotic lesions of tuberculous lymphadenitis[56], although their precise role in such
lesions is not clear.
There have been extensive studies on
antibody assay in tuberculosis in the hope of
developing a serological test for this disease.
Unfortunately no test has proved sensitivej or
specific enough to justify its introduction into
routine diagnostic services[57]. Serological
studies have been used to relate immune
responses to various mycobacterial epitopes
to susceptibility to tuberculosis in the hope of
delineating those antigens that confer protec­
tive immunity. Thus, for example, healthy
subjects exposed to open tuberculosis have
high levels of antibody to a 14 kDa protein of
M. tuberculosis while those with progressive
tuberculosis have low levels of that antibody[58] (Chapter 17a, p. 369).
A characteristic of tuberculosis is an
increase in the proportion of a form of
immunoglobulin in the IgG class that lacks a
terminal galactose from a sugar component of
this macromolecule. Raised levels of this socalled 'agalactosyl IgG' also occur in other
diseases, including rheumatoid arthritis (RA)
and Crohn's disease, which are characterized
by tissue damage due to cytokines released
by T cells and an acute-phase protein
response!
16].
i x
_ A tenuous connection between
tuberculosis and RA has emerged from studies on the so-called heat-shock proteins
(HSP). These form a class of structurally
highly conserved proteins found in all living
creatures and are also termed 'chaperone' or
'nurse-maid' proteins as they assist in the
folding and assembly of other protein macro­
molecules. It has been shown that T cells
from patients with RA react to mycobacterial
HSPs and to the human homologues and that

68

3

I

Immunophysiology and immunopathology

adjuvant arthritis in rats is adoptively trans­
ferable by T cell clones reacting to a 65 kDa endogenously generated calcitriol. The TNF
mycobacterial HSP[59], Clearly, tuberculosis release is triggered by mycobacterial cell wall
is not a regular cause of RA (although a very components, especially lipoarabinomannan
few patients develop an arthritis-like con­ TNTuru°teCt,Ve ,mmune espouses, however
dition termed Poncet's disease), but myco­ TNF has a more beneficial effect by activating
bacteria could, by antigen mimicry, be one of macrophages and facilitating granuloma
the triggers for the onset of RA. Whether or formation. The factors determining the
re -r°J tHe resP°nse are Poorly under­
not this proves to be the case, mycobacteria TtUq
stood.
The immunopathological response is
may, by antigen mimicry, induce auto­
characterized by elevated levels of an abnorimmune phenomena that contribute to tissue
ma ^m^’lO8lObl!Iin ^^ctosy1 teQ, sugdamage in both tuberculosis and leprosV(60]
A further factor suggesting a link between - ..■ ®
d^eguMon.
r
'
------------ In addition,
the immunopathology of tuberculosis and of patients with active tuberculosis often fail to
RA is the finding that the HLA-DR4 pheno­ react in skin testing to shared mycobacterial
antigens.
type, which is known to predispose to RA is
Both the protective immune responses and
associated with large dermal reactions to
he
necrotic hypersensitivity responses
specific antigens of M. tuberculosis but not to
responsible
for walling off the infechon are
those of other mycobacteria[14J.
suppressed in HIV positive and other immu­
nocompromised tuberculosis patients so that
5.16 CONCLUSIONS
progressive disseminated disease is com­
Immune reactions in tuberculosis are com­ monly seen. The immune response in tuber­
culosis activates the HIV so that tuberculosis
plex and, depending on various genetic and
predisposes to the rapid onset of AIDS
environmental factors, result in either protec­
The mode of action of BCG is not under­
tive immunity or excessive tissue damage
stood.
Its efficacy varies enormously from
Tuberculosis passes through two stages region
to
region but, in all regions, it is most
PrinW and post-primary. In the former,
effective
when
given neonatally. Thus exbacilli disseminate to regional lymph nodes
tnnsic
factors,
probably
exposure to environ­
and to more distant sites. Nevertheless, most
mental
mycobacteria,
may
induce inapproprimary lesions resolve although a few bacilli
™mune reactions that administration
may persist within healed lesions and subse­
quently reactivate. Post-primary disease is of BCG cannot override. There is, however
Ch.aracte2zed by excessive tissue necrosis, strong evidence that the administration of
led cells of a rapidly growing mycobacterwhich though having some protective effect
mm
M. vaccae, which is rich in shared
by walling off the active lesions, generates
mycobacterial
antigens, replaces a necrotic
cavities that favour massive bacillary multi­
Koch-type
response
by a non-necrotic protecplication, rendering the patient infectious,
ve
one.
Such
immunomodulation
may be
and dissemination of disease throughout the
the key to future prevention and treatment of
lung by bronchial spread. This necrotic
hypersensitivity is analogous to the Koch tuberculosis.
phenomenon in the guinea-pig.
There is evidence that necrotizing immune references
responses are the result of the sensitization of
1. Wallgren A. (1948) The 'time-table' of tubercutissues by T cell-derived factors to killing by
1OS1S. Tubercle, 29, 245-51.
2’ ^rf.n8e
Noble, W.C., Yates, M.D. and
tumour necrosis factor (TNF) released by
ohns^
C.H.
(1988) Inoculation mycobactermacrophages primed for such release by
loses. Chn. Exp. Dermatol., 13, 211—20.

■

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I- The TNF
ial cell wall
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. however,
/ activating
granuloma
ining the
rly underesponse is
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ten fail to
obacterial

arises and
responses
action are
ier immuits so that
is com­
in tuber>erculosis
IDS.
)t undersly from
it is most
Thus exenvironinapprotistration
lowever,
ation of
?obactershared
necrotic
2 protec­
may be
ment of

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obacter-

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