TY - JOUR
T1 - Pneumococcal Immunization Reduces Neurological and Hepatic Symptoms in a Mouse Model for Niemann-Pick Type C1 Disease
AU - Houben, Tom
AU - dos Reis, Ines Magro
AU - Oligschlaeger, Yvonne
AU - Steinbusch, Hellen
AU - Gijbels, Marion J. J.
AU - Hendrikx, Tim
AU - Binder, Christoph J.
AU - Cassiman, David
AU - Westerterp, Marit
AU - Prickaerts, Jos
AU - Shiri-Sverdlov, Ronit
N1 - Funding Information:
This research was supported by the Netherlands Organisation for Scientific Research (NWO) (Vidi grant number: 016.126.327; ASPASIA grant number: 015.008.043) and CVON IN-CONTROL (CVON 2012-03). MW is supported by Netherlands Organization of Scientific Research (NWO) VIDI-grant 917.15.350 and a Rosalind Franklin Fellowship from the University Medical Center Groningen.
Funding Information:
This research was supported by the Netherlands Organisation for Scientific Research (NWO) (Vidi grant number: 016.126.327; ASPASIA grant number: 015.008.043) and CVON IN-CONTROL (CVON 2012-03). MW is supported by Netherlands Organization of Scientific Research (NWO) VIDI-grant 917.15.350 and a Rosalind Franklin Fellowship from the University Medical Center Groningen. We would like to thank Prof. Dr. Lieberman, from University of Michigan Medical, for kindly gifting the Npc1nih mice used in this study. We further like to thank Laure Verstraeten and Ilona Cuijpers for their excellent technical support.
Publisher Copyright:
© 2007 - 2019 Frontiers Media S.A. All Rights Reserved.
PY - 2019/1/7
Y1 - 2019/1/7
N2 - Niemann-Pick type C1 (NPC1) disease is caused by a deleterious mutation in the Npc1 gene, causing lysosomal accumulation of unesterified cholesterol and sphingolipids. Consequently, NPC1 disease patients suffer from severe neurovisceral symptoms which, in the absence of effective treatments, result in premature death. NPC1 disease patients display increased plasma levels of cholesterol oxidation products such as those enriched in oxidized low-density lipoprotein (oxLDL), a pro-inflammatory mediator. While it has been shown that inflammation precedes and exacerbates symptom severity in NPC1 disease, it is unclear whether oxLDL contributes to NPC1 disease progression. In this study, we investigated the effects of increasing anti-oxLDL IgM autoantibodies on systemic and neurological symptoms in an NPC1 disease mouse model. For this purpose, Npc1(nih) mice were immunized with heat-inactivated S. pneumoniae, an immunogen which elicits an IgM autoantibody-mediated immune response against oxLDL. Npc1(nih) mice injected with heat-inactivated pneumococci displayed an improved hepatic phenotype, including liver lipid accumulation and inflammation. In addition, regression of motor skills was delayed in immunized Npc1(nih). In line with these results, brain analyses showed an improved cerebellar phenotype and neuroinflammation in comparison with control-treated subjects. This study highlights the potential of the pneumococcal immunization as a novel therapeutical approach in NPC1 disease. Future research should investigate whether implementation of this therapy can improve life span and quality of life of NPC1 disease patients.
AB - Niemann-Pick type C1 (NPC1) disease is caused by a deleterious mutation in the Npc1 gene, causing lysosomal accumulation of unesterified cholesterol and sphingolipids. Consequently, NPC1 disease patients suffer from severe neurovisceral symptoms which, in the absence of effective treatments, result in premature death. NPC1 disease patients display increased plasma levels of cholesterol oxidation products such as those enriched in oxidized low-density lipoprotein (oxLDL), a pro-inflammatory mediator. While it has been shown that inflammation precedes and exacerbates symptom severity in NPC1 disease, it is unclear whether oxLDL contributes to NPC1 disease progression. In this study, we investigated the effects of increasing anti-oxLDL IgM autoantibodies on systemic and neurological symptoms in an NPC1 disease mouse model. For this purpose, Npc1(nih) mice were immunized with heat-inactivated S. pneumoniae, an immunogen which elicits an IgM autoantibody-mediated immune response against oxLDL. Npc1(nih) mice injected with heat-inactivated pneumococci displayed an improved hepatic phenotype, including liver lipid accumulation and inflammation. In addition, regression of motor skills was delayed in immunized Npc1(nih). In line with these results, brain analyses showed an improved cerebellar phenotype and neuroinflammation in comparison with control-treated subjects. This study highlights the potential of the pneumococcal immunization as a novel therapeutical approach in NPC1 disease. Future research should investigate whether implementation of this therapy can improve life span and quality of life of NPC1 disease patients.
KW - Niemann-Pick type C1
KW - oxidized low-density lipoprotein
KW - pneumococcal immunization
KW - inflammation
KW - lipid metabolism
KW - LOW-DENSITY-LIPOPROTEIN
KW - LIPID STORAGE DISORDER
KW - NCTR-BALB/C MICE
KW - BLOOD-BRAIN-BARRIER
KW - NONALCOHOLIC STEATOHEPATITIS
KW - POLYSACCHARIDE VACCINE
KW - OXIDATIVE STRESS
KW - T15 IDIOTYPE
KW - OXIDIZED LDL
KW - ATHEROSCLEROSIS
U2 - 10.3389/fimmu.2018.03089
DO - 10.3389/fimmu.2018.03089
M3 - Article
C2 - 30666257
SN - 1664-3224
VL - 9
SP - 1
EP - 13
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 3089
ER -