Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function
Sebastian Zeissig, … , Nicholas O. Davidson, Richard S. Blumberg
Sebastian Zeissig, … , Nicholas O. Davidson, Richard S. Blumberg
Published July 1, 2010
Citation Information: J Clin Invest. 2010;120(8):2889-2899. https://doi.org/10.1172/JCI42703.
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Research Article Immunology

Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function

Abstract

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.

Authors

Sebastian Zeissig, Stephanie K. Dougan, Duarte C. Barral, Yvonne Junker, Zhangguo Chen, Arthur Kaser, Madelyn Ho, Hannah Mandel, Adam McIntyre, Susan M. Kennedy, Gavin F. Painter, Natacha Veerapen, Gurdyal S. Besra, Vincenzo Cerundolo, Simon Yue, Sarah Beladi, Samuel M. Behar, Xiuxu Chen, Jenny E. Gumperz, Karine Breckpot, Anna Raper, Amanda Baer, Mark A. Exley, Robert A. Hegele, Marina Cuchel, Daniel J. Rader, Nicholas O. Davidson, Richard S. Blumberg

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Figure 3

Unaltered MHC class I– and class II–restricted antigen presentation in ABL patients.

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Unaltered MHC class I– and class II–restricted antigen presentation in A...
(A) PBMCs (2 ×105) were cultured in the presence or absence of 2 μg/ml CEF peptide mixture on IFN-γ ELISPOT plates. Plates were developed after 20 hours of culture, and the stimulation index (spots in the presence of CEF/spots in the absence of CEF) was calculated. (B) DCs (2 × 104) were cocultured with 1 × 105 tetanus toxin–reactive HLA-DR–restricted SPF3 T cells in the presence or absence of 25 μg/ml tetanus toxin. Cytokine release of T cells was determined after 18–20 hours of coculture by ELISA. Culture of DCs or T cells alone did not lead to detectable cytokine production. One representative experiment is shown. Two additional experiments with cells from independent ABL and control subjects showed comparable results.