Immunology and Cell Biology (2000) 78, 349–355

Special Feature
Novel mechanisms in the immunopathogenesis of leprosy nerve
damage: The role of Schwann cells, T cells and Mycobacterium
leprae
E R I C S P I E R I N G S , 1 T J I T S K E D E B O E R , 1 L AU R E N C E Z U L I A N E L L O 1 , 2 a n d
TO M H M OT T E N H O F F 1

Departments of 1Immunohematology and Blood Transfusion and 2Infectious Diseases, Leiden University Medical
Center, Leiden, The Netherlands

Summary The major complication of reversal (or type 1) reactions in leprosy is peripheral nerve damage. The
pathogenesis of nerve damage remains largely unresolved. In situ analyses suggest an important role for type 1
T cells. Mycobacterium leprae is known to have a remarkable tropism for Schwann cells that surround peripheral
axons. Reversal reactions in leprosy are often accompanied by severe and irreversible nerve destruction and are
associated with increased cellular immune reactivity against M. leprae. Thus, a likely immunopathogenic mecha-
nism of Schwann cell and nerve damage in leprosy is that infected Schwann cells process and present antigens of
M. Leprae to antigen-specific, inflammatory type 1 T cells and that these T cells subsequently damage and lyse
infected Schwann cells. Previous studies using rodent CD8+ T cells and Schwann cells have revealed evidence for
the existence of such a mechanism. Recently, a similar role has been suggested for human CD4+ T cells. These cells
may be more important in causing leprosy nerve damage in vivo, given the predilection of M. leprae for Schwann
cells and the dominant role of CD4+ serine esterase+ Th1 cells in leprosy lesions. Antagonism of molecular inter-
actions between M. leprae, Schwann cells and inflammatory T cells may therefore provide a rational strategy to
prevent Schwann cell and nerve damage in leprosy.

Key words: cytotoxicity, histocompatibility antigen class II, human, leprosy, Mycobacterium leprae, pathology,
Schwann cells, T-lymphocyte.

Leprosy of approximately 600 000 new cases annually. It is likely that

transmission continues to occur despite intense and well-
Leprosy is a chronic infectious disease that is caused by the
controlled MDT programs. Consequently, a large number of
intracellular pathogen Mycobacterium leprae. Although
M. leprae infected individuals that present clinical symptoms
leprosy has been found in many parts of the world in the past,
remains at risk of developing nerve damage during the clini-
the disease currently occurs mainly in tropical and subtropi-
cal course of disease, regardless of MDT.6
cal countries. Overall, approximately 2 million individuals
It is well established that host immunity to M. leprae
are disabled as a result of the disease.1 Leprosy is the leading
dictates the clinical outcome of leprosy. More than 99% of
cause of all non-traumatic peripheral neuropathies world-
the population is believed to develop adequate protective
wide.2 It frequently results in severe and irreversible nerve
immunity on infection and does not develop clinically
tissue damage, leading to deformities of hand, feet, face and
detectable symptoms.7,8 The minority of individuals that
eyes and to permanent loss of nerve function. This is the main
develop clinical leprosy can be classified in a five group
reason that leprosy represents a major social stigma. The
spectrum, depending on disease dissemination and the level
introduction of multiple drug therapy (MDT) in 1982 has
of cellular immunity (Fig. 1).9 On one side of the leprosy
caused a major decline in the prevalence of leprosy world-
spectrum are polar lepromatous leprosy patients, who have a
wide:3 the estimated number of leprosy patients declined
high humoral immune response and a low cellular response.
from 12 million in 1985 to less than 2 million in 1995 as a
These patients show an M. leprae-specific cellular non-
result of this.4,5 Despite this drop in prevalence, the number
responsiveness and fail to clear the bacteria. On the other side
of newly detected leprosy cases has remained stable at a level
of the spectrum polar tuberculoid leprosy patients can be
found, who have a low humoral immune response but display
strong acquired cellular immunity and delayed type hyper-
Correspondence: Eric Spierings, Department of Immunohema- sensitivity against M. leprae and typically have low bacterial
tology and Blood Transfusion, Leiden University Medical Center, loads. Most patients, however, are positioned in between
PO Box 9600, 2300 RC Leiden, The Netherlands. these two poles and are classified as borderline leprosy cases.
Email: H.T.Spierings@lumc.nl These cases are further subdivided as borderline leproma-
Received 1 May 2000; accepted 1 May 2000. tous, mid-borderline and borderline tuberculoid leprosy.
350 E Spierings et al.
Figure 1 Schematic representation of the clinical and immuno-
logical spectrum of leprosy. CMI, cell-mediated immunity; ENL,
erythema nodosum leprosum; TT, tuberculoid leprosy; BT,
borderline tuberculoid leprosy; BB, mid-borderline leprosy; BL,
borderline lepromatous leprosy; LL, lepromatous leprosy.
Leprosy reactions and nerve damage
Superimposed on the leprosy spectrum, leprosy reactions can
occur. Leprosy reactions can occur before treatment,10 but are
mainly observed during or after MDT. Leprosy reactions typ-
ically represent acute inflammatory episodes. Two major
types of reactions are discriminated: (i) erythema nodosum
leprosum (ENL) or type 2 leprosy reactions, which predom-
inantly occur in patients on the lepromatous side of the spec-
trum; and (ii) reversal reactions (RR), also designated as type
1 leprosy reactions, which occur particularly in patients with
borderline leprosy, especially during treatment.11 Type 1
reactions are thought to represent episodes in which cell-
mediated responses towards M. leprae are strongly increased,
resulting in an inflammatory response in the areas of the skin
and nerves affected by the disease.12 Estimates of the overall
prevalence of reversal reactions range from 8 to 30% in
leprosy.13
From the point of view of clearing bacteria, such
increased cellular immune responses may be beneficial,
because they promote bacterial killing mechanisms. How-
ever, the accompanying inflammation in and around infected
nerve tissue or around nerves in close vicinity of inflamed
lesions can result in severe and irreversible damage within a
matter of days, if not treated adequately. Clinically detectable
neural involvement occurs in approximately 10% of
paucibacillary and 40% of multibacillary leprosy patients,
particularly in patients with reversal reactions.14 It has,
however, been suggested that subclinical neural involvement
Figure 2 Myelinating (a) and non-myelinating (b) Schwann
cells and (c) the structure of peripheral nerves.
may take place in virtually all leprosy patients and that 30%
of the nerve fibres need to be destroyed before sensory
impairment becomes detectable.15
A nerve fibre consists of an axon that is almost com-
pletely enveloped in a sheath of Schwann cells. Axons can be
divided into myelinated and unmyelinated axons. Myelinated
peripheral axons have a myelin sheath interposed between the
Schwann cells and the axon (Fig. 2a). This myelin sheath is
derived from the Schwann cells. Unmyelinated axons lack a
myelin sheath and lie in deep grooves in the surface of the
Schwann cells, with multiple axons enveloped by the same
cell (Fig. 2b). Externally, Schwann cells are covered by a
basal lamina, which, in turn, is surrounded by endoneurial
tissue (Fig. 2c). Several Schwann cell/axon units, which are
embedded in endoneurium, are surrounded by the relatively
impermeable perineurium, which consists of randomly ori-
entated and highly concentrated collagen fibers. On the other
side, tight junctions between the endothelial cells of the cap-
illaries and the endothelial basement membrane separate the
endoneurium from the circulation. The resulting physical
‘blood/nerve barrier’ is believed to be important for main-
taining an appropriate physicochemical environment for
axons and for protecting these against potentially harmful
agents, including effector cells of the immune system. Nev-
ertheless, the junctions in particular can provide a route
through which bacteria or leucocytes can ultimately enter the
peripheral nervous system.
Mycobacterium leprae–Schwann cell interactions
Mycobacterium leprae almost exclusively infects macro-
phages and Schwann cells.16 Various receptor-mediated
mechanisms, similar to those exploited for macrophage inva-
sion, may play a role in invasion of human Schwann cells by
 Immunopathogenesis of leprosy nerve damage
Figure 3 Phagocytosis of mycobacteria by human Schwann
cells. (a) Mycobacterium leprae, (b) Mycobacterium smegmatis.
Mycobacterium smegmatis adhesion to Schwann cells is observed
(b), but it significantly reduced compared to M. leprae (a).
Adhesion of mycobacteria to non-professional APC (COS1 cells;
c, M. leprae; d, M. smegmatis) underlines the existence of
receptors for the entry of pathogens that are not restricted to
Schwann cells.
mycobacteria. Candidates are Fc receptors,17 complement
receptors,17,18 the fibronectin binding protein19 and mannose
receptors.20 These mechanisms are, however, not restricted to
Schwann cells and thus do not explain why M. leprae specif-
ically homes to neural tissue. The neurotropism of M. leprae
may be attributed to its affinity for the G-domain of laminin-
α2, an extracellular matrix protein that is present in the basal
lamina of Schwann cells.21 In turn, M. leprae/laminin-α2
complexes bind to α/β dystroglycan complexes expressed on
the Schwann cell surface.22 Recently, a 21 kDa laminin
binding receptor on M. leprae has been identified, being a
histone-like protein (HLP).23,24 This mycobacterial receptor
may function as a critical surface adhesin for the G-domain
of laminin-α2.
Although these interactions may play a major role in
M. leprae/Schwann cell attachment and perhaps invasion, it
is not unlikely that other receptors may also be involved.
Indeed, blocking of the dystroglycan complex could not
inhibit M. leprae/Schwann cell adhesion completely.22 Other
candidate (co)receptors may include integrins, which are also
able to bind to laminin-α2, and an as yet uncharacterized
25 kDa phosphoprotein that is expressed by Schwann cells,
to which M. leprae has been reported to bind.25 Thus, other
receptor/ligand interactions may also be involved in
M. leprae/Schwann cell attachment and invasion.
T-cell mediated and Schwann cell damage
Several pathogenic mechanisms may be responsible for nerve
damage in leprosy, including biochemical interference of
M. leprae with host cell metabolism, mechanical damage due
to the large influx of cells and fluid, or immunological
damage. Because RR are accompanied by an increased cell-
mediated immunity (CMI) and because acute nerve damage
particularly occurs during these reactions, a role for the
immune system in causing nerve damage during RR has long
been suspected.12,26 CD4+ T cells are more abundant in skin
351
lesions of patients with RR compared with lesions of leprosy
patients without reactions. The T cells in the granulomata are
predominantly CD4+, whereas CD8+ T cells are mostly
present in the mantle area surrounding the granuloma.12,27,28
A strong increase of type-1 cytokines has been noted during
reversal reactions28,29,30 and, indeed, T cell clones isolated
from skin biopsies of patients with RR are predominantly of
the Th1 type.31,32 The microanatomical location of serine
esterase-positive cells within tuberculoid granulomata and
RR overlaps with the CD4+ CD45RO+ subpopulation,28 indi-
cating that these T cells contain cytotoxic granules. Further-
more, analysis of M. leprae-reactive CD4+ cytotoxic T cell
clones has confirmed that these cells are indeed highly cyto-
toxic for a variety of human target cells.33 It is therefore likely
that Th1-like cytotoxic T cells may not only contribute to pro-
tective immunity, but also to the immunopathology of leprosy
neuritis in which Schwann cells function as their target.
Murine Schwann cells have already been shown to function
as antigen presenting cells for CD8+ cytotoxic T cells in an
MHC class I-restricted, mycobacterial antigen-dependent
manner.34 As a result of antigen recognition, Schwann cells
were killed. Rodent Schwann cells are also able to stimulate
CD4+ T cells via MHC class II.35,36 It remains unknown to
what extent these rodent studies can be extrapolated to
leprosy neuritis, largely as a result of the inability to culture
human Schwann cells, precluding such analyses in humans.
We have recently succeeded in establishing human
Schwann cell cultures that yield sufficient numbers of cells
for further studies. These cells express the Schwann cell
markers S-100β, glial fibrillary acidic protein (GFAP),
and 2′,3′-cyclic nucleotide-3′-phosphohydrolase (CNPase),
whereas control fibroblasts and peripheral blood mono-
nuclear cells do not express these molecules. A number of
molecules involved in antigen presentation and T-cell stimu-
lation, such as MHC class I and II, ICAM-1, and CD80 is
also detectable (E Spierings et al., unpubl. data, 1997). The
expression of HLA class II on human Schwann cells in vivo
has been a point of controversy. Although a number of studies
has failed to demonstrate expression,37–39 other studies have
reported HLA class II molecules on Schwann cells.40,41
Furthermore, inflammatory cytokines such as IFN-γ and
TNF-α, as well as Schwann cell invasion by M. leprae, have
been reported to result in upregulation of MHC class II by
rodent Schwann cells.42–44 In leprosy, Schwann cells have
been found to express MHC class II.45 Schwann cells may
therefore well be actively involved in the immunopathology
of leprosy neuritis by presenting M. leprae antigens to cyto-
toxic T cells. Thus, although human Schwann cells may not
express HLA class II molecules under non-pathological con-
ditions, infection with M. leprae and/or the subsequent local
immune response probably induce MHC expression by
human Schwann cells.
In order to analyse specific M. leprae antigen presentation
by Schwann cells, we have pulsed human Schwann cells with
M. leprae or Mycobacterium smegmatis (Fig. 3). Incubation
for 30 min resulted in bound bacilli to the surface of Schwann
cells. Membrane-anchored bacilli, entering Schwann cells,
could be detected within 1 h (Fig. 3a), while M. leprae inter-
nalization was clearly detectable after an overnight incubation
period, as confirmed by confocal microscopy analyses (data
not shown). In addition, M. smegmatis internalisation was
352 E Spierings et al.
observed after an overnight incubation, but the number of
internalized bacilli was significantly lower (Fig. 3b). Cell
surface binding analyses of M. leprae and M. smegmatis to
COS1 cells clearly showed mycobacterial adhesion to non-
professional antigen-presenting cells (Fig. 3c,d). However,
binding of M. leprae to these cells was much reduced when
compared to the invasion of Schwann cells.
Using the described ex vivo isolated human Schwann cell
cultures, we have been able to demonstrate that human
Schwann cells can process and present intact M. leprae bac-
teria and M. leprae antigens to CD4+ cytotoxic T cells. Pre-
sentation induces T cell proliferation (Fig. 4a) and IFN-γ
production (Fig. 4b), and is MHC class II restricted (data not
shown). Importantly, as shown in Fig. 3c, M. leprae-pulsed
Schwann cells are highly susceptible to killing by type 1
CD4+ T cell clones from leprosy patients. Schwann cell
killing is antigen dependent and HLA class II restricted (data
not shown). These results clearly show that human Schwann
cells can process and present M. leprae to M. leprae-specific
CD4+ cytotoxic T cells and are subsequently killed during
this event. Particularly during inflammatory CD4+ T cell-
mediated RR, this mechanism may play an important role in
causing local peripheral nerve damage in leprosy. We propose
that this may represent a novel immunopathogenic mecha-
nism of nerve damage in leprosy.
Effector mechanism of T cell-mediated Schwann cell
killing
Different mechanisms may be involved in the lysis of
infected Schwann cells. First, following recognition of
infected Schwann cells via MHC/peptide/T cell receptor
interactions, CD4+ Th1 cells can secrete lytic granules that
contain granulysin, granzymes and perforins.46 Granulysin
and perforin have been reported to act in concert in attacking
infected macrophages: perforin permeabilizes the eucaryotic
cell membrane, allowing the granulysin to enter the cells,47
which subsequently affects intracellular bacteria by altering
their membrane integrity, thus inducing bacterial killing.
Knocking out perforin, however, does not alter the capability
of mice to control M. tuberculosis or Mycobacterium bovis
Bacillus Calmette–Guérin (BCG) infection, indicating that
alternative killing pathways are likely to exist.48
Apart from granule-mediated lysis, killing of target cells
via the Fas or Fas-related ‘death-receptors’ appears to be an
Figure 4 Presentation of myco-
bacterial antigens by human
Schwann cells. Human Schwann
cells are able to present antigens
from intact Mycobacterium leprae
bacilli to CD4+ T cells, which
respond with proliferation (a), the
production of IFN-γ (b) and
killing of the Schwann cells (c).
important pathway. Interaction between Fas and Fas-L on
target and effector, respectively, initiates an intracellular
cascade that finally results in apoptosis of the target cell.49
There has been some debate on the issue of whether this
pathway also results in elimination of intracellular bacteria.
Reduced bacterial viability has been reported by some,50
while others see no effect.51,52 These latter results are
supported by the finding that the course of M. bovis BCG
infection in Fas-receptor-defective mice was not altered.48
A third mechanism of target cell killing is induction of
apoptosis via extracellular ATP.53 The ATP, which may also be
produced by immune effector cells, can interact with P2Y or
P2Z receptors on target cells and induce apoptosis.54 Extra-
cellular ATP has not only been shown to kill targets via P2
receptors,55 but also affects the viability of intracellular
bacteria.56 Interestingly, individuals can be classified into
three groups, based upon their response to ATP:57 some
individuals show responses to ATP in the absence of IFN-γ,
while others only respond intermediately. The response of
the intermediate group can be enhanced by IFN-γ. A third
group responds neither to ATP alone, nor to ATP in combi-
nation with IFN-γ. These responses are correlated with the
level of P2 receptors on their APC and may thus explain dif-
ferences in susceptibility to ATP-mediated apoptosis between
individuals.
Because the pathway of Schwann cell killing may well
influence the fate of mycobacteria, we have tested the
involvement of these different killing mechanisms in
Schwann cell killing. Although human Schwann cells were
found to express Fas (Fig. 5a) and are susceptible to ATP-
mediated lysis (Fig. 5b), apoptosis-inducing Fas antibodies
were not able to induce Schwann cell killing. The ATP
inhibitor hexokinase strongly reduced ATP- but not T cell-
mediated lysis of Schwann cells in response to specific
peptides or to the mitogenic lectin ConA (Fig. 5b,c). Addition
of MgCl2-EGTA, however, reduced antigen-specific, T cell-
mediated lysis by approximately 35–40%, indicating that
granule-mediated, but not Fas- or ATP-dependent, lysis is
likely an important pathway for T cell-mediated Schwann cell
killing (Fig. 5d).
Nerve destruction as collateral damage
In addition to nerve damage resulting from cognate T
cell/Schwann cell interactions, non-specific bystander effects
 Immunopathogenesis of leprosy nerve damage
Figure 5 Susceptibility of human Schwann cells to FAS-, ATP-
and granule-mediated cytotoxicity. (a) Human Schwann cells
express FAS molecules on their surface. Cytotoxicity inducing
FAS antibodies, however, did not induce Schwann cells lysis
(not shown). Schwann cells are susceptible to extracellular
ATP-induced cell lysis (b, ,). Addition of 50 µg/mL ATP-
inhibitor hexokinase (m) reduced lysis by exogenously added
ATP (b), but not by T cells, either in response to Mycobacterium
leprae or to the mitogen Con A (c). (d) MgCl2 + EGTA blocked
antigen-dependent T-cell mediated Schwann cell lysis with
±35% of the peptide response, indicating that human Schwann
cells are susceptible to granule-mediated lysis.
during inflammation may also be involved in triggering
nerve damage. Possible mediators are TNF-α, proteases and
urokinase.58 In relation to leprosy, TNF-α mRNA and protein
are more abundant in lesions of patients with RR.30,59 It is pre-
dominantly produced by M. leprae-responsive type 1 T cells
derived from patients undergoing RR,31 but infected and
activated macrophages can also be responsible for the pro-
duction. Tumour necrosis factor-α hardly has a toxic effect on
Schwann cells on its own, but in combination with trans-
forming growth factor (TGF)-β it has been reported to cause
significant Schwann cell detachment and lysis.60 Little is
known about the effect of TNF-α-mediated target killing on
mycobacterial survival. Tumour necrosis factor-α-mediated
lysis has been reported to have a similar effect on myco-
bacterial viability to Fas/Fas-L-mediated lysis,50 but for both
Fas and TNF-α this topic is highly disputed.
Mycobacterium leprae-specific versus autoreactive
T cells in leprosy lesions
So far it is unknown which antigens are recognized by
lesional T cells. Mycobacterium leprae-specific T cells can
be isolated from both inflamed skin31 and nerve tissue
(E Spierings et al., unpubl. obs., 1997). It is possible that
nerve damage may be caused or enhanced by autoreactive
353
Figure 6 The potentially harmful effect of protective anti-
mycobacterial immunity. dc, Dendritic cell; mø, macrophage.
T cells, in addition to M. leprae-specific T cells. Such
autoreactive T cells may be primed by cross-reacting
mycobacterial antigens (molecular mimicry). An obvious
candidate auto-antigen is HSP60. Mycobacterial HSP60-
reactive murine T cells are indeed able to lyse uninfected
macrophages61,62 and IFN-γ-stressed target cells.63 Further-
more, transfer of an HSP60-specific CD8+ T-cell clone into
immunocompromised mice leads to severe immunopathol-
ogy.61,64 These data indicate that presentation of peptides from
endogenous proteins can be responsible for cell-mediated,
autoimmune-like tissue destruction. However, it is also
possible that, during inflammation, T cells are primed against
non-cross-reacting Schwann cell or nerve-associated auto-
antigens, perhaps by crosspriming, and that such autoreactive
T cells can contribute to peripheral neuropathy in leprosy.
Analysis of the antigen specificity of lesion-infiltrating T
cells will be needed to address the role of self-antigen versus
M. leprae antigen recognition in the immunopathology of
leprosy neuritis.
Conclusion
In summary, human Schwann cells may be central players in
leprosy nerve damage. Destruction of Schwann cells, and
subsequently of the nerves they surround, is likely not only as
the result of collateral damage, but also from the direct effect
of CD4+ cytolytic T cells. These T cells are instrumental in
controlling the outgrowth of M. leprae bacilli in lesions by
activating, as well as killing, M. leprae-infected macro-
phages. Unfortunately, however, when infected Schwann
cells are killed as well, this may lead to nerve damage, which
may progress to irreversible loss of peripheral nerve tissue
(Fig. 6). Although this process can involve both CD834 and
CD4 (Spierings et al., unpubl. data, 1999) cytotoxic T cells,
particularly, the latter type may be of importance, because
CD4+ T cells are present in high numbers in the centre of
granulomas of leprosy patients with RR.
354 E Spierings et al.
Acknowledgements
These studies received financial support from the Netherlands
Leprosy Relief Foundation (NLR), WHO-IMMYC, the Heiser
Foundation and the QM Gastmann-Wichers Foundation.
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