An age-related numerical and functional deficit in CD19⁺CD24^hiCD38^hiB 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+CD24hiCD38hi phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19+CD24hiCD38hi 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+CD24hiCD38hi B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19+CD24hiCD38hi 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+CD24hiCD38hi 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+CD24hiCD38hi 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+CD24hiCD38hi B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19+CD24hiCD38hi B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging.

Autoimmunity in the Elderly: Insights from Basic Science and Clinics - A Mini-Review

“…Further, a reduction in the number and/or an impairment of the function of immature transitional B cells with a CD19+ CD24hi CD38hi phenotype is accompanied by an increased concentration of autoantibodies [29] .…”

Premature B-cell senescence as a consequence of chronic immune activation

“…Though, one study related increased systemic autoimmunity to impaired IL-10 production by immature-transitional B-cells (identified as CD19+CD24 high CD38 high ) in aged individuals. 24 Nonetheless, decreased numbers but not frequencies of spleen IgM+ memory B-cells are observed in elderly as compared with young individuals. 25 Decreased frequencies of peripheral IgM+ memory B-cells have instead been observed in the elderly.…”

Erosive Pustular Dermatosis: A Manifestation of Immunosenescence A Report of 8 Cases

“…This overall change in immunity is termed “immunosenescence.” The process in the elderly is thought to be the opposite of what happens after birth where the inborn or innate immune response is gradually complemented by the learned adaptive immunity. With immunosenescence, the immune system becomes less able to respond to foreign antigens and maintain tolerance to self [13,14,15,16,17]. The term “inflamm-aging” has been coined to describe the phenomenon of chronic low-level innate immune activation leading to increased oxidative stress.…”