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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 123 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 123 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 123 Acta Neuropathol 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] 123 Acta Neuropathol 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 123 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 123 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, 123 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. References 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 mounting evidence from a number of LSDs that neuroimmune responses begin early in pathogenesis, long before the onset of neuron loss and neurological symptoms [51, 89, 99, 129]. Experimental evidence from mouse models suggests that manipulating diVerent components of the immune system may be of therapeutic beneWt [52, 93, 94, 133, 134]. 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