title: Age-Related Decline in Natural IgM Function: Diversification and Selection of the B-1a Cell Pool with Age.
abstract: Streptococcus pneumoniae is the most common cause of pneumonia, which claims the lives of people over the age of 65 y seven times more frequently than those aged 5-49 y. B-1a cells provide immediate and essential protection from S. pneumoniae through production of natural Ig, which has minimal insertion of N-region additions added by the enzyme TdT. In experiments with SCID mice infected with S. pneumoniae, we found passive transfer of IgG-depleted serum from aged (18-24 mo old) mice had no effect whereas IgG-depleted serum from young (3 mo old) mice was protective. This suggests protective natural IgM changes with age. Using single cell PCR we found N-region addition, which is initially low in fetal-derived B-1a cell IgM developing in the absence of TdT, increased in 7- to 24-mo-old mice as compared with 3-mo-old mice. To determine the mechanism responsible for the age related change in B-1a cell IgM, we established a mixed chimera system in which mice were reconstituted with allotype-marked mature peritoneal B-1a cells and adult bone marrow cells. We demonstrated even in the presence of mature peritoneal B-1a cells, adult bone marrow contributed to the mature B-1a cell pool. More importantly, using this system we found over a 10-mo-period peritoneal B-1a cell IgM changed, showing the number of cells lacking N-region additions at both junctions fell from 49 to 29% of sequences. These results strongly suggest selection-induced skewing alters B-1a cell-derived natural Ab, which may in turn be responsible for the loss of natural IgM-mediated protection against pneumococcal infection.
authors.affiliation: Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, Manhasset, NY 11030; nholodic@gmail.com.
authors.forename: Nichol E
authors.identifier: 0000-0002-2671-6918
authors.initials: NE
authors.lastname: Holodick
authors.affiliation: Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, Manhasset, NY 11030;
authors.forename: Teresa
authors.identifier: 0000-0003-1822-9383
authors.initials: T
authors.lastname: Vizconde
authors.affiliation: Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, Manhasset, NY 11030;
authors.forename: Thomas J
authors.identifier: 0000-0002-0670-4872
authors.initials: TJ
authors.lastname: Hopkins
authors.affiliation: Center for Oncology and Cell Biology, Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, Manhasset, NY 11030; Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, NY 11030; and Department of Molecular Medicine, Hofstra Northwell School of Medicine, Manhasset, NY 11030.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Rothstein
mesh_terms: D019264:Adoptive Transfer; D000375:Aging; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D005434:Flow Cytometry; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology*; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011008:Pneumococcal Infections / Q000276:immunology*; D013296:Streptococcus pneumoniae
chemical_list: D000907:Antibodies, Bacterial; D007075:Immunoglobulin M