Human B-1 Cells and B-1 Cell Antibodies Change With Advancing Age

Age-related deficits in the immune system have been associated with an increased incidence of infections, autoimmune diseases, and cancer. Human B cell populations change quantitatively and qualitatively in the elderly. However, the function of human B-1 cells, which play critical anti-microbial and housekeeping roles, have not been studied in the older age population. In the present work, we analyzed how the frequency, function and repertoire of human peripheral blood B-1 cells (CD19+CD20+CD27+CD38low/intCD43+) change with age. Our results show that not only the percentage of B-1 cells but also their ability to spontaneously secrete IgM decreased with age. Further, expression levels of the transcription factors XBP-1 and Blimp-1 were significantly lower, while PAX-5, characteristic of non-secreting B cells, was significantly higher, in healthy donors over 65 years (old) as compared to healthy donors between 20 and 45 years (young). To further characterize the B-1 cell population in older individuals, we performed single cell sequencing analysis of IgM heavy chains from healthy young and old donors. We found reduced repertoire diversity of IgM antibodies in B-1 cells from older donors as well as differences in usage of certain VH and DH specific genes, as compared to younger. Overall, our results show impairment of the human B-1 cell population with advancing age, which might impact the quality of life and onset of disease within the elderly population

Image_1_Human B-1 cells are important contributors to the naturally-occurring IgM pool against the tumor-associated ganglioside Neu5GcGM3.tif

Only few studies have described the anti-tumor properties of natural antibodies (NAbs). In particular, natural IgM have been linked to cancer immunosurveillance due to its preferential binding to tumor-specific glycolipids and carbohydrate structures. Neu5GcGM3 ganglioside is a sialic acid–containing glycosphingolipid that has been considered an attractive target for cancer immunotherapy, since it is not naturally expressed in healthy human tissues and it is overexpressed in several tumors. Screening of immortalized mouse peritoneal-derived hybridomas showed that peritoneal B-1 cells contain anti-Neu5GcGM3 antibodies on its repertoire, establishing a link between B-1 cells, NAbs and anti-tumor immunity. Previously, we described the existence of naturally-occurring anti-Neu5GcGM3 antibodies with anti-tumor properties in healthy young humans. Interestingly, anti-Neu5GcGM3 antibodies level decreases with age and is almost absent in non-small cell lung cancer patients. Although anti-Neu5GcGM3 antibodies may be clinically relevant, the identity of the human B cells participating in this anti-tumor antibody response is unknown. In this work, we found an increased percentage of circulating human B-1 cells in healthy individuals with anti-Neu5GcGM3 IgM antibodies. Furthermore, anti-Neu5GcGM3 IgMs were generated predominantly by human B-1 cells and the antibodies secreted by these B-1 lymphocytes also recognized Neu5GcGM3-positive tumor cells. These data suggest a protective role for human B-1 cells against malignant transformation through the production of NAbs reactive to tumor-specific antigens such as Neu5GcGM3 ganglioside.</p