Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function.
Abetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. R...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2010
|
| _version_ | 1797068409306873856 |
|---|---|
| author | Zeissig, S Dougan, S Barral, D Junker, Y Chen, Z Kaser, A Ho, M Mandel, H McIntyre, A Kennedy, S Painter, G Veerapen, N Besra, G Cerundolo, V Yue, S Beladi, S Behar, S Chen, X Gumperz, J Breckpot, K Raper, A Baer, A Exley, M Hegele, R Cuchel, M |
| author_facet | Zeissig, S Dougan, S Barral, D Junker, Y Chen, Z Kaser, A Ho, M Mandel, H McIntyre, A Kennedy, S Painter, G Veerapen, N Besra, G Cerundolo, V Yue, S Beladi, S Behar, S Chen, X Gumperz, J Breckpot, K Raper, A Baer, A Exley, M Hegele, R Cuchel, M |
| author_sort | Zeissig, S |
| collection | OXFORD |
| description | Abetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. Recently, MTP was shown to regulate the CD1 family of lipid antigen-presenting molecules, but little is known about immune function in ABL patients. Here, we have shown that ABL is characterized by immune defects affecting presentation of self and microbial lipid antigens by group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 molecules. In dendritic cells isolated from ABL patients, MTP deficiency was associated with increased proteasomal degradation of group 1 CD1 molecules. Although CD1d escaped degradation, it was unable to load antigens and exhibited functional defects similar to those affecting the group 1 CD1 molecules. The reduction in CD1 function resulted in impaired activation of CD1-restricted T and invariant natural killer T (iNKT) cells and reduced numbers and phenotypic alterations of iNKT cells consistent with central and peripheral CD1 defects in vivo. These data highlight MTP as a unique regulator of human metabolic and immune pathways and reveal that ABL is not only a disorder of lipid metabolism but also an immune disease involving CD1. |
| first_indexed | 2024-03-06T22:10:22Z |
| format | Journal article |
| id | oxford-uuid:5199415b-cc4d-42e6-9410-9c16413ef15d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:10:22Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:5199415b-cc4d-42e6-9410-9c16413ef15d2022-03-26T16:20:34ZPrimary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5199415b-cc4d-42e6-9410-9c16413ef15dEnglishSymplectic Elements at Oxford2010Zeissig, SDougan, SBarral, DJunker, YChen, ZKaser, AHo, MMandel, HMcIntyre, AKennedy, SPainter, GVeerapen, NBesra, GCerundolo, VYue, SBeladi, SBehar, SChen, XGumperz, JBreckpot, KRaper, ABaer, AExley, MHegele, RCuchel, MAbetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. Recently, MTP was shown to regulate the CD1 family of lipid antigen-presenting molecules, but little is known about immune function in ABL patients. Here, we have shown that ABL is characterized by immune defects affecting presentation of self and microbial lipid antigens by group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 molecules. In dendritic cells isolated from ABL patients, MTP deficiency was associated with increased proteasomal degradation of group 1 CD1 molecules. Although CD1d escaped degradation, it was unable to load antigens and exhibited functional defects similar to those affecting the group 1 CD1 molecules. The reduction in CD1 function resulted in impaired activation of CD1-restricted T and invariant natural killer T (iNKT) cells and reduced numbers and phenotypic alterations of iNKT cells consistent with central and peripheral CD1 defects in vivo. These data highlight MTP as a unique regulator of human metabolic and immune pathways and reveal that ABL is not only a disorder of lipid metabolism but also an immune disease involving CD1. |
| spellingShingle | Zeissig, S Dougan, S Barral, D Junker, Y Chen, Z Kaser, A Ho, M Mandel, H McIntyre, A Kennedy, S Painter, G Veerapen, N Besra, G Cerundolo, V Yue, S Beladi, S Behar, S Chen, X Gumperz, J Breckpot, K Raper, A Baer, A Exley, M Hegele, R Cuchel, M Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. |
| title | Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. |
| title_full | Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. |
| title_fullStr | Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. |
| title_full_unstemmed | Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. |
| title_short | Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function. |
| title_sort | primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of cd1 function |
| work_keys_str_mv | AT zeissigs primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT dougans primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT barrald primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT junkery primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT chenz primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT kasera primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT hom primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT mandelh primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT mcintyrea primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT kennedys primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT painterg primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT veerapenn primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT besrag primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT cerundolov primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT yues primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT beladis primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT behars primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT chenx primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT gumperzj primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT breckpotk primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT rapera primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT baera primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT exleym primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT hegeler primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function AT cuchelm primarydeficiencyofmicrosomaltriglyceridetransferproteininhumanabetalipoproteinemiaisassociatedwithlossofcd1function |