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Acta Neuropathol
DOI 10.1007/s00401-007-0296-4
R EV IE W
Immune system irregularities in lysosomal storage disorders
Julian A. Castaneda · Ming J. Lim ·
Jonathan D. Cooper · David A. Pearce
Received: 1 June 2007 / Revised: 11 September 2007 / Accepted: 13 September 2007
© Springer-Verlag 2007
Abstract Lysosomal storage disorders (LSDs) are genetically inherited diseases characterized by the accumulation
of disease-speciWc biological materials such as proteolipids
or metabolic intermediates within the lysosome. The lysosomal compartment’s central importance to normal cellular
function can be appreciated by examining the various
pathologies that arise in LSDs. These disorders are invariably fatal, and many display profound neurological impairment that begins in childhood. However, recent studies
have revealed that several LSDs also have irregularities in
the function of the immune system. Gaucher disease, mucopolysaccharidosis VII, and -mannosidosis are examples
of a subset of LSD patients that are predisposed towards
immune suppression. In contrast, GM2 gangliosidosis,
J. A. Castaneda · D. A. Pearce (&)
Center for Aging and Developmental Biology,
University of Rochester School of Medicine and Dentistry,
601 Elmwood Ave, Box 645, Rochester, NY 14642, USA
e-mail: [email protected]
D. A. Pearce
Department of Biochemistry and Biophysics,
University of Rochester School of Medicine and Dentistry,
Rochester, NY 14642, USA
D. A. Pearce
Department of Neurology,
University of Rochester School of Medicine and Dentistry,
Rochester, NY 14642, USA
M. J. Lim · J. D. Cooper
Pediatric Storage Disorders Laboratory,
Department of Neuroscience and Centre for the Cellular
Basis of Behaviour, MRC Centre for Neurodegeneration
Research, Institute of Psychiatry, King’s College London,
James Black Centre, 125 Coldharbour Lane,
SE5 9NU London, UK
globoid cell leukodystrophy, Niemann-Pick disease type
C1 and juvenile neuronal ceroid lipofuscinosis are LSDs
that are predisposed towards immune system hyperactivity.
Antigen presentation and processing by dedicated antigen
presenting cells (APCs), secretion of pore-forming perforins by cytotoxic-T lymphocytes, and release of pro-inXammatory mediators by mast cells are among the many crucial
immune system functions in which the lysosome plays a
central role. Although the relationship between the modiWcation of the lysosomal compartment in LSDs and modulation of the immune system remains unknown, there is
emerging evidence for early neuroimmune responses in a
variety of LSDs. In this review we bridge biochemical studies on the lysosomal compartment’s role in the immune
system with clinical data on immune system irregularities
in a subset of LSDs.
Introduction
Lysosomal storage disorders (LSDs) are a group of more
than 40 genetically inherited diseases that result from functional defects in at least one of the proteins essential for
normal function of the lysosome [87, 105]. All eukaryotic
cell types contain lysosomes, membrane-bound organelles
that are characterized by an acidic lumen which is rich in
enzymes [78] that are highly eYcient at degrading and sorting their substrates and Wnal products [47, 64]. Proteins,
lipids, nucleic acids, and saccharides are among the cellular
macromolecules that are degraded by a functional lysosomal compartment [87]. These macromolecules may enter
the lysosome from either the intra- or extra-cellular environment [71].
The lysosome is also essential for normal function of the
immune system and the classical view of the lysosomal
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Acta Neuropathol
compartment as a digestive organelle has now expanded,
with the lysosome implicated in the control of cell-surface
receptor-mediated signal transduction [63, 83]. Moreover,
the catabolism of macromolecules in the lysosome is essential for the correct function of several immune system functions including antigen processing and presentation [45,
66], cytokine secretion [101], phagocytosis [109, 110], and
secretion of molecules [12, 44]. Recent studies on the
pathology of a subgroup of LSDs demonstrate that alterations in systemic and neuroimmune responses can be linked
to the pathological manifestations within the CNS. The primary purpose of this review is to describe and analyze the
links between speciWc gene mutations, disease, and the
accompanying altered immune responses.
Lysosomal storage diseases with described immune
system alterations
Globoid cell leukodystrophy
Globoid cell leukodystrophy (GCL), also known as Krabbe disease, is a rare and fatal LSD that is characterized by
marked central nervous system (CNS) pathologies. GCL
patients have mutations in the gene that codes for galactosylceramidase [10]. This enzyme is responsible for the
degradation of galactosylceramide and psychosine, molecules that are highly concentrated in lipid-rich tissues,
including the myelin sheath, kidney, and the epithelial
cells of the intestine and colon [22]. Similar to other LSDs,
the accumulation of cellular macromolecules in the lysosome is a clinical hallmark of this disease. In the case of
GCL, psychosine is the primary component of the storage
material, and accumulation of this molecule is considered
to be a primary cause of subsequent neurodegeneration
[121].
Recent studies suggest that the immune system plays an
important role in the pathogenesis of GCL. For example,
lymphocyte inWltration of the CNS of the twitcher mouse,
the murine model for GCL, has been reported [132]. Following the labeling of blood cells from twitcher mice by
intraperitoneal injection of rhodamine isothiocanate (Rhlc),
a large number of Rhlc-positive cells migrated to the areas
of the brain undergoing the most severe demyelination. A
large number of these Rhlc labeled cells were also positive
for the expression of MAC-1 and MHC-class II molecules,
CD4, CD8 and/or IL-2R, markers of immune system cells.
Moreover, this blood-derived cellular inWltration of the
CNS was correlated with expression of MCP-1 and IL-10,
two molecules which are suggested to be active recruiters
of these cells in twitcher mice.
Conversely, a decrease in cytokine and chemokine
expression as a result of bone marrow transplantation (from
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a wild-type to a twitcher mouse) not only results in
improvements in pathology, but also increased lifespan
[133]. Twitcher mice that received bone marrow from wildtype mice live approximately three times longer and these
transplants also gradually reduced the number of cells
expressing TNF-, MCP-1, and MIP-1 and inWltration of
the brain by Ia+ and CD8+/CD3¡ cells. Taken together the
results of this elegant study demonstrate that cytokine
expression contributes, at least partially, to pathogenesis in
twitcher mice.
Other researchers have focused on determining the
contribution of select cytokines to the pathology of the
twitcher mice. IL-6 and TNF- have been reported to be
upregulated in the CNS of twitcher mice [65]. IL-6 was
predominantly localized to astrocytes, and TNF- was
mainly colocalized with macrophages. With the goal of
determining if these powerful immunomodulatory molecules contribute to the pathology seen in twitcher mice,
double knockout twitcher mice that are deWcient in IL-6
protein or the TNF- receptor-1 (TNFR1) were generated
[93, 94]. Surprisingly, twitcher mice that did not express
IL-6 had a more severe phenotype than IL-6 expressing
twitcher mice. These mice displayed an earlier disease
onset, demonstrated a greater number of Periodic acidSchiV-positive cells within the CNS, were more susceptible to LPS-induced immune reactions, had pronounced
gliosis, and had elevated levels of TNF-[93]. Conversely, twitcher mice that did not express TNFR1 displayed no change in their clinical and pathological course,
as measured by life span, weight loss, and onset day of
twitching [94]. However, these TNFR-1 deWcient twitcher
mice had a longer life span and decreased disruption to
the blood–brain barrier compared to TNFR1-expressingtwitcher mice. As such, removing TNFR1 was not suYcient to inXuence the pathological and/or clinical signs
evident during twitcher mouse pathogenesis. However,
when a secondary insult such as LPS treatment is present,
TNFR1-activation appears to be responsible for amplifying the neuroimmune response to result in exacerbated
CNS pathology.
The accumulation of storage material in GCL may also
contribute to neuroimmune responses in this disorder.
Exposure of peripheral blood mononuclear cells (PBMCs)
derived from GCL patients to psychosine, the primary component of the storage material in GCL, increased the
expression of TNF-, while decreasing the expression of
MCP1 and not changing the expression of IL-8 [35]. After
exposure to psychosine and then LPS, lymphocytes derived
from GCL patients had similar TNF-, MCP-1 and IL-8
expression compared to non-LPS treated GCL lymphocyte
controls. Thus, the peripheral immune cells obtained from
GCL patients demonstrate a constitutive pro-inXammatory
pattern of cytokine expression.
Acta Neuropathol
GM2 gangliosidosis
The normal enzymatic activities of hexosamindase A
(HEXA) and hexosamindase B (HEXB) are required for the
correct catabolism of GM2 ganglioside. HEXA and HEXB
are both isoenzyme complexes that each consists of two
subunits, a -subunit and a -subunit in HEXA and two subunits in HEXB. Mutations in either of these gene-products lead to a group of diseases that are collectively called
the GM2 gangliosidosis [87]. Tay-Sachs disease is caused
by mutations in HEXA, and SandhoV disease is caused by
mutations in HEXB. Tay-Sachs disease patients lack HEXA
isoenzyme, whereas SandhoV patients lack both HEXA and
HEXB hexosaminidase isoenzymes [108]. The resulting
deWciency in these enzymes results in the intralysosomal
accumulation of GM2 ganglioside in these disorders.
Since neurons accumulate a large amount of the GM2
gangliosides relative to other tissues, it is widely thought
that the nervous system is the main pathological target in
the GM2 gangliosidosis. Previous studies in genetically
modiWed mouse models, Hexa-deWcient mice (Hexa¡/¡) for
Tay-Sachs and Hexb-deWcient mice (Hexb¡/¡) for SandhoV, have implicated the accumulation of GM2 ganglioside
or its derivatives with unscheduled neuronal cell death [46].
However, recent studies have provided good evidence that
GM2 ganglioside accumulation cannot account for all of
the nervous system damage in these mice. For example,
neuronal death is decreased and the survival ratios were
enhanced when the bone marrow of Hexb¡/¡ mice is
replaced with bone marrow obtained from wild type mice,
despite not increasing the enzymatic activity of HEX or
decreasing the brain accumulation of GM2 ganglioside [88,
129].
Components of the immune system that are essential for
its eVector functions, such as cytokines and antibodies,
have also been implicated to play a role in the pathology of
the murine models for GM2 gangliosidosis. For instance,
pronounced upregulation of pro-inXammatory gene-transcripts preceding neuronal death has been described in
Hexb-deWcient mice and in SandhoV patients [51, 86, 129].
An upregulation of proinXammatory genes that correlate
with the activation of microglia and increased levels of
TNF- mRNA in autopsied SandhoV human tissue and
Hexb¡/¡ mice has also been reported [129].
The increased expression of MIP1- in astrocytes in
Hexb¡/¡ mice was accompanied by a signiWcant inWltration
of macrophage-like populations into the CNS, and deletion
of the MIP-1 gene signiWcantly ameliorates some of the
prominent pathophysiological phenotypes [134]. Although,
it is still not known why MIP-1 is speciWcally upregulated
in Hexb¡/¡ mice, it is apparent that this upregulation starts
at the presymptomatic stage of the pathogenesis, with
elevated MIP-1 mRNA and protein levels within the
Hexb¡/¡ CNS, but not in other organs of these mice [123].
A parallel relationship was observed between the upregulation of MIP-1 and accumulation of natural substrates of
HexA and HexB. Unexpectedly, the upregulation of MIP1 was closely correlated with microglia, with a marked
accumulation of N-acetylglucosaminyl (GlcNAc)-oligosaccharide, but not with microglia that predominantly accumulated GM2. As such, the accumulation of gangliosides and
GlcNAc-oligosaccharides in sub-populations of glial cells
may cause an uncontrolled MIP-1-speciWc upregulation in
gene expression.
An autoimmune response in Hexb¡/¡ mice has also been
reported with the accompanying pathophysiological phenotypes. It has been suggested that the storage material that
accumulates within lysosomes in cells derived from Hexb¡/¡
mice has the potential to trigger an autoimmune response,
since these aberrantly accumulated substrates are not
degraded and cleared due to altered lysosomal function
[136]. Indeed, Hexb¡/¡ mice not only test positive for antiganglioside autoantibodies, but also demonstrate an agedependent increase in autoantibody titers. IgG deposition
was also observed on the cell surface of neurons in the CNS
of Hexb¡/¡ mice, but not wild type mice. To determine if
these autoantibodies contribute to the pathophysiology of
Hexb¡/¡ mice, a double knockout mouse, in which the gene
coding for the Fc receptor- (FcR) was functionally
deleted from the Hexb¡/¡ mouse was generated. FcR is a
cell-surface protein that is important for the correct eVector
functions of natural killer cells, macrophages, neutrophils,
mast-cells, and microglia [104]. Interestingly, some of
the pronounced clinical pathophysiological symptoms
displayed by Hexb¡/¡ mice were markedly improved in
Hexb¡/¡ FcR¡/¡ mice. Moreover these double-knockout
mice displayed a reduced frequency of apoptotic cell death
within the CNS and a 27% increase in lifespan from 102 to
130 days, strongly suggesting a pathogenic role for the
autoantibodies generated in Hexb-deWcient mice. (Table 1)
Juvenile neuronal ceroid lipofuscinosis (JNCL)
The neuronal ceroid lipofuscinoses (NCLs) are collectively
the most common inherited neurodegenerative storage disorder of childhood [41]. There are at least nine diVerent
forms of NCL which are morphologically deWned by the
accumulation of autoXuorescent storage material in the
lysosome of neurons, leukocytes, and other cell types [42].
Juvenile NCL, or Batten disease, is the most prevalent form
of these disorders and results from mutations in the gene
that codes for CLN3, a lysosomal transmembrane protein of
as yet unknown function [32, 92].
Although studies have implicated CLN3 in lysosomal
amino acid transport and pH regulation [59, 90, 103], the
biochemical and cellular mechanisms that underlie Batten
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Table 1 Reported immune system irregularities in a subset of LSDs
Lysosomal
storage disorder
Gene
Protein
Globoid cell
leukodystrophy
GALC
Galactosylceramidase Blood cells inWltrating CNS; upregulation
of MCP-1 and IL-10 in CNS
GM2 gangliosidosis
Juvenile neuronal ceroid
lipofuscinosis
Gaucher disease
HEXA
HEXB
GM2A
CLN3
GBA
Hexosaminidase A
Hexosaminidase B
GM2 act. protein
CLN3-protein
Glucocerebrosidase
Immune system association
References
[132]
Upregulation of IL-6 and TNF- in CNS
[65]
Psychosine-induced upregulation of TNF-
and down regulation of IL-8, by lymphocytes
[35]
ProinXammatory cell inWltration of CNS
[51]
Astrocyte and microglial activation; complement involvement
[51, 129]
Upregulation of proinXammatory genes
[86]
MIP-1 upregulation and recruitment of blood-borne
cells into the CNS
[134]
Presymptomatic expression of MIP-1
[123]
Age-dependent presence of anti-ganglioside autoantibodies
and their localization in the CNS
[136]
Storage material in leukocytes
[56]
Batten disease patient-derived serum highly reactive
to CNS antigens
[69]
Anti-GAD65 autoantibodies that inhibit catalytic activity
present in patients and Cln3¡/¡ mouse
[21, 102]
IgG entry and deposition within the CNS
[70]
Accumulation of storage material in cells, particularly those
of the macrophage compartment
[114]
Systemic inXammation
[81]
Impaired host-defense
[76]
Bacterial infections
[33]
Dysfunction in monocytes and superoxide generation
[68]
Neutrophil chemotaxis defects
[140]
Lymphoid malignancy
[18]
Polyclonal B cell lymphocytosis and hypergammaglobulinemia
[77]
Chronic stimulation of the immune system
[118]
Systemic AL amyloidosis
[53]
Monoclonal gammopathy
[74]
Autoantibodies present in the serum
[119]
Upregulation of IL-6 and IL-10
[1]
Upregulation of IL-1, IL-1Ra, IL-6, TNF-, sIL-2R; correlation
with clinical symptoms
[7]
Upregulation of IL-1 and TNF-
[67]
Upregulation of TNF-
[81]
Upregulation of CCL18/PARC
[13]
Upregulation of CD163 and correlation with disease severity
[82]
Upregulation of antigen-processing molecules CD1d and
MHC class II molecules
[6]
Upregulation of HLA-DR antigens
[34]
Niemann Pick
disease type C
NPC-1
NPC1
Severe respiratory infections
[84, 97, 111]
NPC-2
NPC2
Depletion of V14-J18; reduction in clearance
of bacterial challenges
[107]
-Mannosidosis
MAN2B2 -D-Mannosidase
Reduced immune system function; recurrent gastro-intestinal
and respiratory tract infections thought to contribute
to premature death
[29]
Reduction in production of speciWc antibodies; humoral and
cellular immunity are compromised
[73]
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Table 1 continued
Lysosomal
storage disorder
Gene
Protein
Mucopolysaccharidosis
VII
GUSB
-Glucuronidase
Immune system association
References
Upper respiratory infections
[125]
Recurrent respiratory and middle ear infections
[135]
Blunted T cell proliferative response; decreased antibody
production; defective antigen processing
[26]
Accumulation of storage material in cells, particularly in the
macrophage compartment
[127]
Each LSD is the result of a mutation in a gene that codes for a lysosomal protein. Each of these proteins is thought to perform a specialized function
in the lysosome. In LSDs, these normal functions of the gene-products are dramatically diminished or absent, which results in cellular and tissue
damage, and eventually death. The immune system displays an altered state in a subset of LSDs
disease pathogenesis and pathology remain essentially
unknown. Several lines of evidence point to an abnormal
neuroimmune response early in JNCL pathogenesis. In common with mouse models of other forms of NCL, localized
glial activation is evident in Cln3 null mutant mice (Cln3¡/¡
mice) several months before the onset of neuron loss and
before these mice become symptomatic [99]. Nevertheless,
both astrocytosis and microglial activation remain at a
low level in Cln3-deWcient mice, with little evidence for
astrocytic hypertrophy or morphological transformation of
microglia to brain macrophages [99, 100]. These data suggest
that reactive cell types may themselves be targeted pathologically and subsequently impact neuron function. Nevertheless
even at early stages in disease progression, microglia in
Cln3¡/¡ mice display immunoreactivity for IL-1 (Lim and
Cooper, unpublished observations), a feature that is also
evident in human JNCL autopsy material (Fig. 1).
In addition to these neuroimmune responses within the
CNS, recent studies suggest that an autoimmune response
is also present early in the pathogenesis of JNCL. Serum
obtained from Batten disease patients has been determined
to include autoantibodies that recognize a variety of CNS
proteins [21, 69]. However, it is not known what precipitates this autoimmune response, and more importantly, it
has not been determined to what extent this altered immune
response contributes to pathology.
One possibility is that lysosomal accumulation of storage material within immune system cells might contribute
to the autoimmune response described in Batten disease.
Lysosomal accumulation of lipophilic and ceroid-like autoXuorescent storage material in a wide variety of cells is the
hallmark of the Batten disease [41, 56]. Before the availability of a genetic diagnosis, the examination of lymphocytes in the peripheral blood for signs of lysosomal
accumulation of storage material was utilized as an easy
method to diagnose NCL patients [30]. However, it remains
unclear to what extent the lysosomal storage material contributes to lysosomal and cellular dysfunction, with no
direct correlation between storage material accumulation
and other neuropathological events.
In the Wrst descriptions of an autoimmune response in
JNCL, the 65 kDa isoform of glutamic acid decarboxylase
(GAD65) was identiWed as an autoantigen in Batten disease
patients [21, 102], with GAD65-speciWc autoantibodies
present in all Batten disease patients tested, as well as in the
Cln3¡/¡ mouse model for this disease. These autoantibodies inhibited the catalytic ability of GAD65, thus blocking
the conversion of glutamate into gamma-aminobutyric acid
(GABA). Since this enzyme is of crucial importance to
GABAergic neurons in the brain, it was hypothesized that
the humoral anti-GAD65 autoimmune response may contribute to the preferential loss of these neurons that occurs
in Batten disease. However, recent studies have indicated
that the anti-GAD65 response is part of a larger autoimmune response in Batten patients, in which multiple brain
regions, cells, and antigens are targeted [69].
Using serum from JNCL patients as primary antisera to
probe Wxed tissues of rat and human CNS revealed that the
immunoreactivity of Batten disease patient serum was not
conWned to GABAergic neurons [69]. Indeed, JNCL serum
recognizes a wide variety of non-GABAergic cell populations in widespread brain regions, including the hippocampus, neocortex, and cerebellum. Moreover, preadsorption
of JNCL serum with recombinant GAD protein did not signiWcantly change the pattern of serum immunoreactivity
[69]. This study provides strong evidence for the notion
that the anti-GAD65 response does not account for the vast
majority of Batten disease patient serum immunoreactivity.
Although it is not known to what extent the altered
immune response in Batten disease patients contributes to
the pathology of this disorder, IgG deposition has been
described in Batten disease brain autopsy material, demonstrating that the brain-reactive autoantibodies may be capable of reacting with their respective autoantigens within the
CNS [70]. Moreover, the same study reported a size-selective breach in blood brain barrier (BBB) integrity in Cln3¡/¡
mice, which suggests that autoantibodies can access the
CNS in Batten disease patients.
If this autoimmune response is determined to contribute
signiWcantly to the pathology of Batten disease, then it will
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Acta Neuropathol
remains unresolved is the impact that this humoral autoimmune response may have outside the CNS. Since Batten
disease is primarily considered to be a neurodegenerative
disease, all studies examining the autoimmune response
have focused on the CNS as the reservoir of autoantigens.
However, since CLN3 appears to be a ubiquitously
expressed protein and other non-CNS organ systems are
aVected in Batten disease patients, the potential adverse
eVects of the autoimmune response on non-CNS organ systems will require further investigation.
Gaucher disease
Fig. 1 Upregulation of the proinXammatory cytokine interleukin 1
(IL-1) in human and murine juvenile neuronal ceroid lipofuscinosis
(JNCL). a–c Immunohistochemical staining for IL-1 reveals the presence of numerous intensely immunoreactive cell types in the neocortex
in human JNCL autopsy material. b, c Increasing magniWcation reveals
IL-1 positive brain macrophages and microglia in various states of
activation. d IL-1 immunoreactive cells with microglial morphology
are also evident in the CNS of presymptomatic Cln3 null mutant mice
(Cln3¡/¡), a mouse model of JNCL, but were not present in agematched control mice (+/+). Colocalization of IL-1 with microglial
markers such as CD68 or F4/80 conWrmed the identity of these IL-1
immunoreactive cells as microglia (data not shown)
be important to determine if immunomodulatory drugs oVer
JNCL patients health beneWts. However, two essential
questions will need to be answered before such a determination is possible: (1) does the autoimmune response alter
crucial cellular processes in Batten patients? and (2) are
these alterations in cellular processes suYcient to contribute to the pathology observed in these patients? The identiWcation of the autoantigens targeted by the humoral
autoimmune response in Batten disease is critical to answer
these questions. Moreover, another important aspect that
123
Gaucher disease is one of the most prevalent lysosomal
storage disorders [98] and results from mutations in GBA,
the gene that encodes glucocerebrosidase [114]. DeWciencies in glucocerebrosidase activity lead to accumulation of
glucosylceramide in the lysosomes of macrophage lineage
cells [114]. Although a number of mutations in the gene
that encodes for glucocerebrosidase have been described,
these mutations have not been reported to accurately predict the severity of clinical manifestations present in these
Gaucher disease patients.
Gaucher disease patients are grouped into three clinical
phenotypes by utilizing a set of criteria ranging from epidemiology, enzyme activity, and CNS clinical manifestations
[8]. Type 1 is characterized to be a non-neuropathic form,
and it is the most common of the three clinical phenotypes,
accounting for roughly 90% of all Gaucher disease patients.
It is characterized by splenohepatomegaly, bone disease,
and hematological abnormalities. Type 2 is the rarest form
of Gaucher disease, and it is characterized by acute neuropathic clinical manifestations and results in death before
2 years of age. The incidence of type 3 Gaucher disease is
roughly intermediate between the incidences of type 1 and
type 2. The clinical manifestations of type 3 vary by subtype and include progressive dementia, bone and visceral
involvement, and typically results in death between the second and fourth decade of life.
Alterations in the function of macrophages found in
Gaucher disease patients, also known as Gaucher cells, are
thought to contribute signiWcantly to Gaucher disease patient
pathology. These cells, which become enlarged as a result of
undegraded glycosylceramide, are found in nearly every organ.
It has been proposed that these cells contain the majority of the
glucosylceramide storage in patient tissues. Moreover, it is
postulated that these cells are closely related to splenohepatomegaly and bone disease, the main clinical manifestations of
Gaucher disease [81]. However, the exact biochemical and
cellular mechanisms by which these altered immune system
cells contribute to pathology are still unknown.
Gaucher disease is one of the LSDs with the most prominent alterations of the immune system. For example, Gaucher
Acta Neuropathol
disease patients display impaired host-defense against
microbial infections [76], and bacterial pathogens that are
benign to healthy individuals can cause signiWcant morbidity in Gaucher disease patients [33]. Although, the exact
mechanisms that lead to increased infection in Gaucher disease patients have not been elucidated, impaired chemotaxis of granulocytes and defective monocyte function in
Gaucher disease patients have been described [68, 140].
Indeed, large amounts of stored glucocerebrosides may
place a burden upon macrophages, directly impairing their
function and attenuating anti-bacterial responses [11].
Interestingly, it has been shown that a deWcit in macrophage
function can be rescued in part by enzyme replacement
therapy, as measured by activities, superoxide anion production along with hematologic and splenohepatic improvements [76].
Gaucher disease patients also have an increase in the
incidence of B cell lymphocytosis and B cell malignancies
[18, 24, 77, 118]. Other B cell dysfunctions such as hypergammaglobulinemia (polyclonal and monoclonal gammopathies) as well as plasmacytosis have been described in
Gaucher disease patients [24, 53, 74, 77, 118]. Although it
is attractive to speculate a direct relationship between the
increased number of B cells and hypergammaglobulinemia,
the relationship between these events has yet to be fully
elucidated. Moreover, it has been reported that a subset of
the immunoglobulins present in Gaucher patient serum are
autoantibodies which recognize several human antigens,
including pyruvate dehydrogenease, rheumatoid factor and
DNA [119]. However, no correlation was found between
the levels of serum immunoglobulins in Gaucher disease
patients and the autoantibody reactivity to these antigens.
Furthermore, immunization of naïve mice with a pool of
anti-DNA autoantibodies that was puriWed from patient
serum did not result in the induction of experimental systemic lupus erythematosus (SLE). From these observations,
it was concluded that the autoantibodies form part of the
non-pathogenic class of naturally occurring autoantibodies
in this disorder [119]. However, it was acknowledged that
the endpoint in assessing autoantibody pathogenicity in this
study was suboptimal, since it did not take into account the
wide array of autoantigens targeted by the complete range
of autoantibodies present in Gaucher disease patients.
Moreover, induction of the SLE disease phenotype might
not be the best determinant of autoantibody-induced pathogenicity, since anti-DNA autoantibodies are a relatively
small component of the Gaucher disease autoantibody repertoire.
Given that cytokines play such a crucial role in the regulation of a wide array of immune system cells, these small
peptides could be one possible link between the functional
alterations of macrophages and B cells reported in Gaucher
disease patients. Cytokines including TNF- and IL-1
have been reported to be increased in Gaucher disease
patients [1, 7, 67, 80]. Moreover, a correlation between the
severity of clinical symptoms and levels of IL-1, IL-1R,
and IL-6 in 24 Gaucher disease patients has been described
[7]. Other soluble immunomodulatory molecules such as
CCL18 and CD163 have also been found to be at a signiWcantly higher concentration in Gaucher disease patients
than control subjects [13, 82]. It is currently thought that
this upregulation of a wide array of immune system molecules leads to a systemic pro-inXammatory response in
Gaucher disease [24]. Recent reports also suggest that these
molecules contribute to the lymphoid cancers found in
Gaucher disease patients by activating and sustaining an
inXammatory environment that can chronically stimulate B
cells [18, 24, 77, 81, 118, 124].
Other evidence for a systemic pro-inXammatory
response in Gaucher disease patients comes from the
higher levels of antigen-presenting molecules in Gaucher
patients. Upregulation of antigen presenting molecules,
including the lipid-binding molecule CD1d and the peptide-binding molecule MHC class II molecule, have been
reported in cells isolated from Gaucher disease patients [6,
34, 118]. It is important to note that the cargo that these
molecules carry to the cell surface is bound in the lysosomes of antigen presenting cells (APC). As such, current
research in the Weld is attempting to determine to what
extent, if at all, the intralysosomal accumulation of glucoceramide impairs the correct processing and loading of the
antigen presenting molecules. An upregulation of CD1d
and MHC-class II molecules could be the result of either
an accelerated transport from the endo-lysosomal compartment to the plasma membrane or from the down regulation
of endocytosis, or possibly from a combination of both
events [6].
Niemann-Pick disease type C (NPC)
Niemann-Pick disease consists of a group of LSDs in which
lipids accumulate in the spleen, liver, lungs, bone marrow,
and the brain. Types A and B are the result of deWciencies
in sphingomyelin phosphodiesterase (SMPD), or sphingomyelinase (ASM), which catalyse the hydrolysis of sphingomyelin into ceramide and phosphorylcholine [112].
Although a handful of reports have documented recurrent
respiratory infections in patients aZicted with NiemannPick type A [78] and type B [3, 9], reports of alterations of
the immune response are more abundant in Niemann-Pick
type C (NPC) disease.
NPC is the result of mutations in either NPC-1 or NPC-2,
resulting in a neurodegenerative disease that is characterized by intracellular accumulation of unesteriWed cholesterol [116]. Cells from Niemann-Pick type C1 patients
characteristically exhibit an accumulation of cholesterol
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Acta Neuropathol
and glycosphingolipids [25]. The NPC1-protein is a membrane glycoprotein that is localized to the endosomal–lysosomal compartment, and it is predicted to have 13
membrane-spanning domains, one of which is hypothesized
to be a sterol-sensing domain [49, 113]. Both NPC1- and
NPC2-proteins appear to be involved in the transport of
several macromolecules, including cholesterol and glycolipids, to the lysosome from the late-endosome, although
the precise function of both proteins remains elusive.
Clinical reports have documented several Niemann-Pick
type C patients to have recurrent and severe respiratory
infections that result in premature death [84, 97, 111].
However, it has not been determined whether NiemannPick type C patients are immunocompromised as a direct
result of mutations in the NPC-1 or NPC-2 genes, or as a
result of downstream pathological events. New insights on
the deleterious eVect that mutations of NPC-1 have on the
natural killer T (NKT) cell population are emerging [107].
NPC-1 deWcient mice were deWcient in V14-J18 NKT
cells, a subpopulation of NKT cells that are evolutionarily
conserved in humans. V14-J18 cells are a specialized
subpopulation of NKT cells that have the ability to recognize the self sphingolipid isoglobotrihexosylceramide
(iGb3) [138] and glycosphingolipids of Gram-negative bacterial origin [61]. Interestingly, mice lacking a functional
NPC-1 were less prone to present antigen to NKT cells and
were signiWcantly less able to clear bacterial challenges in
vivo [107]. It will be important to investigate whether Niemann-Pick disease patients also show NKT cell dysfunction, since this may closely correlate to the suppressed state
of their immune system.
-Mannosidosis
Functional defects in the enzyme -mannosidase result in
the neurodegenerative LSD -mannosidosis. This lysosomal-resident exoglycosidase cleaves a-D-mannosidase
bonds during N-linked oligosaccharide degradation [120].
-Mannosidosis is characterized by the accumulation of oligosaccharides and glycoproteins in various tissues. The
clinical presentation of this disorder includes coarse facial
features, dysostosis multiplex, hearing disabilities, mental
and skeletal abnormalities. Moreover, immunodeWciency is
one of the most prominent clinical manifestations reported
in a subset of -mannosidosis patients [29]. Recurrent
infections of the gastrointestinal and respiratory tracts have
been reported as a signiWcant contributing factor for premature death in this disorder [29].
It is not known how mutations in the gene that codes for
-mannosidase leads to a compromised immune system.
Nevertheless, -mannosidosis patients have a signiWcant
reduction in the production of speciWc antibodies against
immunogens, including poliovirus, diphtheria toxin, and
123
tetanus toxin [73]. Interestingly, polymorphonuclear
neutrophils (PMN) obtained from healthy controls and
exposed to -mannosidosis patient-derived serum displayed a marked decrease in phagocytosis. Moreover, the
density of CD11b and CD16, the complement-binding and
Fc receptors, was signiWcantly enhanced on monocytes
and PMNs. However, the number of circulating leukocytes, serum concentration of immunoglobulins, and
proportion of the IgG subclasses were not signiWcantly
diVerent from controls. It was concluded that -mannosidosis patients are immunocompromised at the humoral and
cellular levels [73].
Mucopolysaccharidosis (MPS) VII
The mucopolysaccharidoses (MPSs) are a group of LSDs
that result from a deWciency of lysosomal enzymes required
for the catabolism of glycosaminoglycans (GAGs), formally
called mucopolysaccharides. The functional deWciency of
these enzymes results in lysosomal accumulation of
glycosaminoglycans in most cells [85]. The disease
progresses to encompass cell, tissue, and organ damage. MPS
VII, also known as Sly disease, results from mutations in
the gene that codes for -glucuronidase, and is characterized by CNS, skeletal, and immune abnormalities [128].
This enzyme deWciency leads to a progressive accumulation of GAGs, dermatan, sulfate, and heparin sulfate in the
tissues of patients [122]. Recurrent upper respiratory infections, pneumonia, bronchitis, and middle ear infections
have been described in human MPS VII patients [125,
135]. However, the extreme rarity of MPS VII, which is
approximately 1:2,111,000 [79], together with the pronounced heterogeneity of the clinical presentation of this
disorder has been a challenge for elucidating disease
pathways.
-Glucuronidase-deWcient mice, the murine model for
MPS VII, have been determined to be immunocompromised [26, 127], with macrophage lineage cells among the
most severely aVected cell types in these mice [127]. Moreover, MPS VII mice showed a decreased T cell proliferative
response and a reduction in antibody production after challenge with speciWc antigens [26]. However, the lymph
nodes of these mice were populated with a composition of
cells that was similar to wild-type mice. It was suggested
that incorrect antigen processing may be a contributing factor for this immune suppression, since a deWciency in antigens processing of proteins can be bypassed by providing
shorter peptides instead of full proteins that need to be processed [26]. Additionally, an exaggerated distortion of
lysosomal morphology was found among the macrophages
of the liver (KupVer cells), peritoneal macrophages, and
reticuloendothelial cells of the spleen. Similar to many
other LSDs, little is known about how these and other
Acta Neuropathol
immune system cells are functionally aVected in MPS VII
and how these eVects may relate to the overall pathology
[117, 135].
Immune system pathways in which the lysosome
plays a central role
The lysosomal compartment plays a central role in a variety
of cellular pathways that are important for normal immune
system function. Three of these functions are of particular
interest to this review since studies on the LSDs have implicated them in one form or another. These three functions
are: (1) protein antigen presentation via major histocompatibility (MHC) molecules; (2) cytotoxic T cell function; and
(3) lipid presentation by CD1d molecules in the context of
NK T cell development.
MHC molecules and antigen presentation
Lysosomal accumulation of storage material has been demonstrated to occur in immune system cells derived from
LSD patients and animal models of LSDs [4, 16, 55, 57].
These cells include PBMCs, monocytes, B cells, natural
killer (NK) cells, and CD4+ and CD8+ lymphocytes.
Before the advent of genetic testing, the examination of
lymphocytes obtained from the peripheral blood was a relatively simple method utilized in the diagnosis of NCLs and
mucopolysaccharidosis, since the morphology of these cells
was drastically altered [16, 30, 75]. Since the normal function of these cells relies upon the correct function of the
lysosomal compartment, it is reasonable to hypothesize that
immune function is altered. The severity of this alteration is
expected to be dependent upon which biochemical pathways are aVected by the loss of a functional lysosomal
protein and/or subsequent intralysosomal accumulation of
storage material.
MHC class I (MHC-I) and MHC class II (MHC-II) proteins have the potential to provide valuable insights into the
alteration of protein processing, sorting, and presentation
that occur in LSDs since these proteins rely upon a functional lysosomal compartment to fulWll their normal roles.
Although it is still not known precisely how the normal
function of these proteins is aVected in the various LSDs,
the expression of MHC molecules is altered in both I cell
disease and Gaucher disease [6, 39]. A confounding variable in the interpretation of these data is that MHC proteins
expression itself is upregulated during disease progression
[31]. However, pathological conditions are not the only
stimuli that alter the expression of MHC proteins because
inhibitors of the normal function of the lysosome, such as
chloroquine and ammonia, also aVect the expression and
presentation of MHC-II molecules [72, 139]. As such, it
would be interesting to determine if the dysfunction of the
lysosomal compartment in LSDs is the direct cause of the
incorrect expression, processing, and loading of MHC-II
molecules.
The majority of the body’s cells present peptides to the
immune system by via MHC proteins [37]. The body’s
CD8+ and CD4+ T cells recognize the antigens for which
they are speciWc via the interaction with its cognate MHC
peptide complex [27]. The presentation of endogenous peptide antigens is largely mediated by MHC-I [39]. These
peptide antigens are generated in the cytosol of the cell,
processed, and loaded on MCH-I for the presentation to
CD8+ T cells. Most nucleated cells express MHC-I, providing the immune system with a powerful surveying tool for
the recognition of virally infected and transformed cells.
Originally, the lysosome was thought play a relatively
minor part in the maturation of antigen-presenting MHC-I
since the bulk of protein degradation is performed in the
cytosol by the proteasome. However, the lysosomal aminopeptidase tripeptidyl peptidase-II (TPP-II) was recently
shown to play a speciWc role in generation of MHC-I epitopes instead of the proteasome [115]. These Wndings suggest that TPP-II can act in combination with or independent
of the proteasome system and can generate epitopes that
evade generation by the proteasome-system.
Nevertheless, the lysosomal compartment clearly plays a
much larger and central role in the antigen presentation
pathway via MHC-II given that protein degradation and
peptide loading onto MHC-II both take place here. MHCII, in turn presents antigen to CD4+ T cells, the main regulators of the immune response. MHC-II has also been
described to present endogenous protein peptides [66], but
the major function of MHC-II, is to present peptide antigens that are derived from extracellular proteins. As such,
the MHC-II pathway is often referred to as the endocytic or
exogenous pathway for antigen presentation. Unlike MHCI, which is ubiquitously expressed, MHC-II is normally
found only on a few speciWc cell types that are specialized
at presenting foreign antigens. For example, dedicated
APCs including macrophages, dendritic cells, activated T
and B lymphocytes all express MHC-II [31].
The lysosomal compartment plays a central role in the
correct function of MHC-II. This molecule consists of an
heterodimer which is assembled in the endoplasmic
reticulum (ER) in conjunction with the chaperone protein
referred to as the invariant chain (li) [66]. This complex is
targeted for delivery to the endosomal/lysosomal compartment, where li undergoes degradation by lysosomal proteases. Previous groups have reported that MHC-II is most
highly abundant in a group of lysosomal-like organelles
that are collectively referred to as MII/MHC class II enrichment compartments. These MII/MHC class II compartments share a number of characteristics with the lysosome,
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Acta Neuropathol
namely the presence of acid hydrolases and lysosomal
membrane proteins, a low pH, and are thought to be positioned relatively late in the endocytic pathway [38, 96,
106]. While MHC-II molecules are assembled and prepared
for peptide loading, the extracellular and intracellular proteins that have arrived in the lysosome are processed into
small peptides that can be loaded onto MHC-II [109]. Proteins enter the acidic endosomal and lysosomal compartments, where they are degraded, denatured, and prepared
for loading onto MHC-II [130]. The acidic environment
within the endosomal and lysosomal compartment is thought
to present a permissive environment for protein denaturation
[50], activation of degradative enzymes [20], and peptides
loaded onto MHC-II [50, 66]. The resulting peptide–MHC-II
complexes are transported to the cell surface [66].
Taken together MHC-I and MHC-II clearly have a
powerful immunomodulatory eVect upon the activation
or suppression of the immune system, but this eVect
depends upon a functioning lysosomal compartment to
correctly process and present speciWc protein antigens.
Although it is still not clear to what extent the presentation of protein antigens is altered in each individual LSD,
biochemical and cellular studies utilizing cells deWcient
in one lysosomal enzyme clearly show alterations in
parameters that are central for the correct function of the
lysosomal compartment. These include alterations in pH
[5, 126, 137], oxidation/reduction states [28], protein
sorting [23], and accumulation of storage material. Any
of these changes by themselves have the potential to
modify the method by which antigens are processed by
the lysosomal compartment.
Cytotoxic T cells
Lymphocytes are constantly surveying the body’s vast
array of MHC–peptide complexes with the purpose of
detecting, and subsequently defending the body from foreign material and transformed cells. As such, it is important
to consider that lymphocytes are among the cell types
where lysosomal storage is most evident in LSDs [16, 55–
58]. A signiWcant proportion of the lymphocyte population
has been reported to have accumulation of storage material
in several LSDs. In late infantile neuronal ceroid lipofuscinosis 12–21% [48], JNCL 20–70% [30, 60], MPS 34–68%
[75] of lymphocytes were reported to be aVected. One vital
question that arises from the presence of storage material
within the lysosomes of lymphocytes is to what extent is
this material alters normal cell function? PBMCs derived
from NCL patients have been used to address this question
[57]. No functional diVerences are apparent between NCL
patient-derived cells and matching controls in the production of reactive oxygen species, cytokine production, or
cell proliferation [58]. However, there was a signiWcant
123
increase of apoptotic cell death with NCL-patient derived
PBMCs compared to controls [57].
Among the repertoire of cells that survey these MHC–
antigen complexes are cytotoxic T cells, also referred to as
CTL or CD8+ T cells. Disease-speciWc lysosomal storage
inclusions can be identiWed in CD8+ cells that are derived
from LSD patients [56]. These CTLs function as one of the
body’s primary defenses and eYciently eliminate target
cells that are recognized as foreign or transformed [91].
CTL accomplish this mission by utilizing their T cell receptors (TcRs) to survey the peptide–MHC-I complexes presented on the cell surface of APCs. Cells that are
recognized as normal do not initiate the activation of CTLs
and are thus ignored, whereas cells that are recognized as
foreign activate the CTL and initiate a series of events to
eliminate the target cell [91].
Among the methods utilized by CTLs to eliminate cells
that are recognized as foreign, are the exposure of membrane proteins such as FAS ligand to initiate death cascades
or the release of soluble secretory proteins from lysosomelike compartments referred to as lytic granules [14, 96].
These granules contain a wide array of cell-killing proteins
such as pore-forming perforin, lysosomal hydrolases, and
granzyme. Lytic granules are considered a special type of
lysosome because they have the ability to perform classical
lysosomal functions, but are also able to secrete their luminal contents [91]. Lytic granules also contain proteins that
are classically considered lysosomal markers, such as
Cathepsin B and D, -glucosidase, lysosomal-associated
membrane protein 1 (LAMP1), and LAMP2 [43]. Moreover, immunoXuorescence and immuno-electron microscopic studies indicate colocalization of lysosomal and lytic
granule proteins in CTL, adding to the evidence that lysosomes and lytic granules are functionally related [17, 96].
Drugs that increase the pH of the lysosomal compartment have also been demonstrated to inhibit the activity of
CTLs [54]. It has been previously reported that lysosomal
pH is altered in a subset of LSDs [5, 126, 137], and as such
it is possible that the normal function of CTLs is aVected in
a subset of LSD patients. It would be interesting to determine if the alterations of lysosomal function that are found
in LSDs also aVect the function of CTLs, since the lysosomal compartment plays such an important role in the
proper function of these cells. Moreover, CTLs could also
be useful in determining the chemical content of the stored
material in LSDs, since these cells have the ability to
secrete the luminal contents of lytic granules. A similar
experiment was conducted utilizing kidney primary cell
cultures from arylsulfatase A-deWcient mice, the murine
model for metachromatic leukodystrophy [61], revealing
the presence of storage material in the extracellular medium
after the induction of calcium-induced lysosomal exocytosis [62]. Furthermore, it was suspected that the secretion of
Acta Neuropathol
lysosomal contents may be a contributing factor for the
presence of sulfatide, a major component of the storage
material in metachromatic leukodystrophy, in the urine of
these patients. It would be informative to determine the
identity of other lysosomal storage components that are
exocytosed, such as proteins, lipids, and metals. Moreover,
it would be valuable to test whether these compounds have
the ability to induce an autoimmune response.
NK T cells
Several valuable clues on how the immune system is
altered in a subgroup of LSDs come from work conducted
on the development and activation of natural killer T cells
(NKT cells). Instead of presenting protein–peptide antigens
like the MHC molecules, the CD1 family of proteins is considered vital for the presentation of self and non-self lipids
and glycolipids as antigens [15]. Similar to MHC-II, the
lysosome is thought to play a crucial role in the loading of
the CD1d molecule. For example, the normal expression of
lysosomal proteases is essential for the correct expression
of lipid antigen on CD1d. Sequentially, the normal development of NKT cells is dependent on normal CD1d antigen
presentation [2]. Saposin C is thought to play a crucial role
in the loading of antigens from the intralysosomal membrane to the CD1d molecule [131].
Isoglobotrihexosylceramide (iGb3) is a lysosomal glycosphingolipid of previously unknown function that has been
shown to be expressed on CD1d cells and it is recognized
both by mouse and human NKT cells [138]. NPC-1 deWcient mice, the mouse model for Niemann Pick disease type
C1, lack V14-J18 NKT cells, which are a major population of CD1d-restricted T cells that are evolutionarily
conserved in mice and humans [107]. As a consequence, NPC1 mutant mice are deWcient in clearing bacterial challenges
[107]. In diverse mouse models of LSDs [Tay-Sachs,
LOTS (late-onset Tay-Sachs), SandhoV, Fabry, GM1 gangliosidosis, and NPC1] there is also a decrease in the total
population of invariant NKT cells (iNKT) cells, and cytokine secretion is abolished [36]. This dramatic reduction in
iNKT function is not due to a decreased expression of
CD1d, but instead correlates with the degree of glycosphingolipid storage in the thymus [26]. Indeed this study
revealed that glycosphingolipid storage in the late endosome and lysosomal compartment impairs the development
of iNKT cells by altering the selection of these cells by the
incorrect processing and presentation of this antigen by
CD1d [36]. Two possible mechanisms for this eVect were
suggested: either the endogenous glycosphingolipids normally presented by CD1d molecules become trapped within
the storage material in the disease cells and consequently
are not loaded onto CD1d; alternatively the high levels of
storage material may out-compete the natural CD1d ligands
in the late endosome and lysosomal compartment [36].
Distinguishing between these two hypotheses is likely to
oVer valuable clues on the biochemical pathways that are
aVected by the presence of storage material in LSDs.
Glycosphingolipid accumulation may not be the only
type of macromolecule that may lead to deWciencies in
NKT cell development. Gaucher disease patients, who
accumulate glucosylceramide and not glycosphingolipids,
have also been reported to have a signiWcant decrease in the
number of NKT cells [19]. NKT cell development is also
dramatically altered by mutations in diverse genes that code
for lysosomal proteins. However, the resultant lack of lysosomal protein function is not the precipitating event in disrupting CD1d antigen presentation, with LSDs in general
appearing to have altered CD1d antigen presentation [40].
It will be interesting to determine the impact that this event
has on the normal development and maturation of the
immune system.
Concluding comments
Lysosomal function is complex and has been shown to be
necessary for many cellular processes. Therefore, it is not
surprising that a variety of genetically distinct defects that
compromise lysosomal function can precipitate a range of
altered immune responses that diVer between LSDs. As we
have discussed, LSDs can largely be divided into two distinct categories, those in which the response is tilted
towards immunosuppression (e.g., Gaucher disease, Niemann-Pick disease, -mannosidosis, and MPS VII) and
those in which an enhanced or autoimmune response may
be evident (e.g., GCL, GM2 gangliosidosis, and JNCL). It
remains to be demonstrated whether such autoimmune
responses simply reXect a physiological activation of diVerent players of the immune system or play a more direct
pathogenic role. Indeed, although the correlates between an
altered immune response and LSDs presented in this review
are compelling, there is still insuYcient evidence to determine whether the altered immune response directly contributes to pathology and/or pathogenesis in each disorder.
Nevertheless, as presented in this review, the lysosome is
clearly strategically placed to inXuence many components
of the immune response. Although the full picture of the
cellular pathways that are aVected by lysosomal function is
now emerging (Fig. 2), a signiWcant challenge will be to
understand how diVerent compartments of the immune system may be aVected in each LSD.
One particularly important consideration, especially in
LSDs with a signiWcant neurological component, will be
to determine the relative contribution of adaptive immune
responses versus the innate neuroimmune or neuroinXammatory responses to result in neurodegenerative changes.
123
Acta Neuropathol
a greater understanding of whether the immune system
should be targeted for treatment strategies for speciWc LSDs
is paramount. Consideration needs to be given to the precise
contribution of the immunological disruption to the pathogenesis of each disease. Moreover, a point during the progression of clinical disease where targeting the immune
system might be beneWcial also needs to be established.
Acknowledgments This study was supported by in part by National
Institutes of Health grants NS044310 and NIEHS Toxicology Training
Grant T32 ES07026-27.
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Fig. 2 InXuence of lysosomal dysfunction upon the immune system in
lysosomal storage disorders (LSDs). Schematic representation of the
multiple ways in which lysosomal dysfunction is recognized to impact
the immune system. These include eVects on antigen presentation via
major histocompatibility (MHC) molecules MHC-I or MHC-II; cytotoxic T cell function; NK/T cell development; and eVects upon innate
immunity via complement activation or the astroglial response
Although the brain has long been considered an immunoprivileged organ, it is now evident that systemic inXammation can have a signiWcant impact upon neuroimmune
responses within the CNS [95]. Moreover, there is also
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