Abstract
BackgroundRecently, using a mouse model of mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease with severe neurological deterioration, we showed that MPS IIIB neuropathology is accompanied by a robust neuroinflammatory response of unknown consequence. This study was to assess whether MPS IIIB lymphocytes are pathogenic.MethodsLymphocytes from MPS IIIB mice were adoptively transferred to naïve wild-type mice. The recipient animals were then evaluated for signs of disease and inflammation in the central nervous system.ResultsOur results show for the first time, that lymphocytes isolated from MPS IIIB mice caused a mild paralytic disease when they were injected systemically into naïve wild-type mice. This disease is characterized by mild tail and lower trunk weakness with delayed weight gain. The MPS IIIB lymphocytes also trigger neuroinflammation within the CNS of recipient mice characterized by an increase in transcripts of IL2, IL4, IL5, IL17, TNFα, IFNα and Ifi30, and intraparenchymal lymphocyte infiltration.ConclusionsOur data suggest that an autoimmune response directed at CNS components contributes to MPS IIIB neuropathology independent of lysosomal storage pathology. Adoptive transfer of purified T-cells will be needed in future studies to identify specific effector T-cells in MPS IIIB neuroimmune pathogenesis.
Highlights
Using a mouse model of mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease with severe neurological deterioration, we showed that MPS IIIB neuropathology is accompanied by a robust neuroinflammatory response of unknown consequence
MPS IIIB causes spontaneous activation of the adaptive immune system To test our hypothesis that MPS IIIB primes an autoimmune response which subsequently provokes the onset or exacerbates MPS IIIB neuropathology, we analyzed the phenotype and functional potential of MPS IIIB mouse lymphocytes
T-cell proliferation assay showed a significant increase in stimulation index of splenic lymphocytes from MPS IIIB mice, compared to wt cells, when stimulated with anti-CD3e ex vivo, suggesting T-cell activation in MPS IIIB mice
Summary
Using a mouse model of mucopolysaccharidosis (MPS) IIIB, a lysosomal storage disease with severe neurological deterioration, we showed that MPS IIIB neuropathology is accompanied by a robust neuroinflammatory response of unknown consequence. This study was to assess whether MPS IIIB lymphocytes are pathogenic. Mucopolysaccharidosis IIIB is a lysosomal storage disease (LSD) with severe neurological manifestations[1]. The primary pathology of MPS IIIB is the accumulation of HS or HS-derived materials in lysosomes in somatic and central nervous system (CNS)[1,2]. The detailed mechanisms of MPS IIIB pathology, especially neuropathology, remain unclear recent studies have implicated aberrant activation of innate and adaptive immunity[2,3,4,5,6,7,8,9].
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