title: An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity.
abstract: Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19(+) CD24(hi) CD38(hi) phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19(+) CD24(hi) CD38(hi) cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19(+) CD24(hi) CD38(hi) B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19(+) CD24(hi) CD38(hi) B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19(+) CD24(hi) CD38(hi) B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19(+) CD24(hi) CD38(hi) cells, suggesting IL10-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19(+) CD24(hi) CD38(hi) B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19(+) CD24(hi) CD38(hi) B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging.
authors.affiliation: MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Immunity and Infection, Birmingham University Medical School, Birmingham, B15 2TT, UK.
authors.forename: Niharika A
authors.initials: NA
authors.lastname: Duggal
authors.forename: Jane
authors.initials: J
authors.lastname: Upton
authors.forename: Anna C
authors.initials: AC
authors.lastname: Phillips
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sapey
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D015703:Antigens, CD
keywords: B cells; autoimmunity; cellular immunology; inflammation; rheumatoid factor