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1.
Sci Rep ; 11(1): 15160, 2021 07 26.
Article in English | MEDLINE | ID: mdl-34312421

ABSTRACT

Mosaic loss of chromosome Y (LOY) in immune cells is a male-specific mutation associated with increased risk for morbidity and mortality. The CD99 gene, positioned in the pseudoautosomal regions of chromosomes X and Y, encodes a cell surface protein essential for several key properties of leukocytes and immune system functions. Here we used CITE-seq for simultaneous quantification of CD99 derived mRNA and cell surface CD99 protein abundance in relation to LOY in single cells. The abundance of CD99 molecules was lower on the surfaces of LOY cells compared with cells without this aneuploidy in all six types of leukocytes studied, while the abundance of CD proteins encoded by genes located on autosomal chromosomes were independent from LOY. These results connect LOY in single cells with immune related cellular properties at the protein level, providing mechanistic insight regarding disease vulnerability in men affected with mosaic chromosome Y loss in blood leukocytes.


Subject(s)
12E7 Antigen/blood , Chromosomes, Human, Y/genetics , Leukocytes/immunology , Mosaicism , 12E7 Antigen/deficiency , 12E7 Antigen/genetics , Aged , Aged, 80 and over , Aging/blood , Aging/genetics , Aging/immunology , Alzheimer Disease/blood , Alzheimer Disease/genetics , Alzheimer Disease/immunology , Chromosomes, Human, Y/immunology , Chromosomes, Human, Y/metabolism , Humans , Leukocytes/metabolism , Male , Mutation , RNA, Messenger/blood , RNA, Messenger/genetics , Single-Cell Analysis
2.
J Leukoc Biol ; 104(4): 787-797, 2018 10.
Article in English | MEDLINE | ID: mdl-29791026

ABSTRACT

Leukocyte entry into the CNS is a crucial step in the development of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Adhesion molecules mediating the docking of leukocytes to the endothelium of the blood-brain barrier (BBB) represent valuable targets for interference with the disease. However, little is known about the adhesion and signaling mechanisms in endothelial cells that mediate the diapedesis through the BBB. Here, we show that conditional Tie-2-Cre driven gene inactivation of CD99L2 inhibits leukocyte entry into the CNS during active MOG35-55 -induced EAE and alleviates severity of the disease. No detrimental effect on the immune response was observed. The number of perivascular cuffs around vessels of the CNS was reduced, as was the number of inflammatory foci, sites of demyelination and expression levels of pro-inflammatory cytokines. Three-dimensional analysis of vibratome sections of the CNS revealed an accumulation of leukocytes between endothelial cells and the underlying basement membrane, whereas leukocyte docking to the luminal surface of the endothelium of the BBB was unaffected. Collectively, these results suggest that CD99L2 participates in the development of EAE by supporting diapedesis of leukocytes through the endothelial basement membrane of blood vessels of the BBB in the CNS.


Subject(s)
12E7 Antigen/deficiency , Blood-Brain Barrier , Chemotaxis, Leukocyte/physiology , Encephalomyelitis, Autoimmune, Experimental/immunology , 12E7 Antigen/physiology , Animals , Basement Membrane , Cells, Cultured , Cytokines/biosynthesis , Demyelinating Diseases , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/therapy , Endothelial Cells/pathology , Female , Gene Expression Profiling , Gene Silencing , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myelin-Oligodendrocyte Glycoprotein/immunology , Peptide Fragments/immunology , Radiation Chimera , Transendothelial and Transepithelial Migration
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