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

Published in Volume 120, Issue 8 (August 2, 2010)
J Clin Invest. 2010;120(8):2889–2899. doi:10.1172/JCI42703.
Copyright © 2010, American Society for Clinical Investigation
Research Article
Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function
Sebastian Zeissig1, Stephanie K. Dougan1, Duarte C. Barral2, Yvonne Junker3, Zhangguo Chen1, Arthur Kaser4, Madelyn Ho1, Hannah Mandel1, Adam McIntyre5, Susan M. Kennedy6, Gavin F. Painter7, Natacha Veerapen8, Gurdyal S. Besra8, Vincenzo Cerundolo9, Simon Yue10, Sarah Beladi2, Samuel M. Behar2, Xiuxu Chen11, Jenny E. Gumperz11, Karine Breckpot12, Anna Raper13, Amanda Baer13, Mark A. Exley10, Robert A. Hegele5, Marina Cuchel13, Daniel J. Rader13, Nicholas O. Davidson6 and Richard S. Blumberg1

1Division of Gastroenterology, Hepatology, and Endoscopy and
2Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
4Department of Medicine II, Medical University Innsbruck, Innsbruck, Austria.
5Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
6Gastroenterology Division, Washington University School of Medicine, St. Louis, Missouri, USA.
7Carbohydrate Chemistry Team, Industrial Research Limited, Lower Hutt, New Zealand.
8School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
9MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
10Cancer Biology Program, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
11Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
12Laboratory of Molecular and Cellular Therapy, Department of Physiology-Immunology, Medical School of the Vrije Universiteit Brussel, Brussels, Belgium.
13Cardiovascular Medicine Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Address correspondence to: Richard S. Blumberg, Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. Phone: 617.732.6917; Fax: 617.264.5185; E-mail: rblumberg@partners.org.

Authorship note: Nicholas O. Davidson and Richard S. Blumberg are co–senior authors.


First published July 1, 2010
Received for publication February 17, 2010, and accepted in revised form May 10, 2010.

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.

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