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.

Abetalipoproteinemia: Three Case Reports, a Novel Microsomal Triglyceride Transfer Protein Gene Mutation and a Literature Review

“…A beta lipoproteinemia (ABL; OMIM#200100) is a rare metabolic autosomal recessive disorder [1][2][3][4][5][6][7][8]. The prevalence is ranging between less than 1 in 100,000 [2,6] and less than 1 in one million [3].…”

“…It is caused by mutations in the microsomal triglyceride transfer protein (MTP) gene [2,9,10]. MTP is the protein responsible for the transfer of triglycerides (TG), cholesteryl ester and phospholipids on to the apolipoprotein B (Apo B) [1]. Apo B promotes the secretion of chylomicrons and very low density lipoproteins (VLDL) from the enterocytes and hepatocytes [1].…”

“…MTP is the protein responsible for the transfer of triglycerides (TG), cholesteryl ester and phospholipids on to the apolipoprotein B (Apo B) [1]. Apo B promotes the secretion of chylomicrons and very low density lipoproteins (VLDL) from the enterocytes and hepatocytes [1]. Deficiency of the MTP genes results in absence of apo B-containing lipoproteins such as low density lipoproteins (LDL), VLDL and chylomicrons [2][3][4][9][10][11].…”

“…They exhibit symptoms of intestinal lipid malabsorption and low plasma lipid levels [1,5,6]. In later childhood, they present with ataxic neuropathy or retinopathy [2,8].…”

“…In later childhood, they present with ataxic neuropathy or retinopathy [2,8]. Loss of fat soluble vitamins due to fat malabsorption might lead to hepatic, neurologic and ophthalmologic symptoms in the form of spinocerebellar degeneration, coagulopathy and pigmented retinopathy [1,3,8,12]. Hepatic steatosis, fibrosis and cirrhosis were also reported in some cases [5].…”