An age-related numerical and functional deficit in CD19+CD24hiCD38hiB cells is associated with an increase in systemic autoimmunity

Niharika A Duggal,Jane Upton,Anna C Phillips,Elizabeth Sapey,Janet M Lord

doi:10.1111/acel.12114

Niharika A Duggal, Jane Upton + Show 3 more

Open Access

https://doi.org/10.1111/acel.12114

Copy DOI

Journal: Aging Cell	Publication Date: Jul 19, 2013
Citations: 89	License type: cc-by

Affiliation: University of Birmingham

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.

Highlights

B cells have been shown to play a pathogenic role in human autoimmune diseases due to their ability to secrete autoantibodies and serve as antigen-presenting cells to T cells (Yanaba et al, 2008b)
Immature transitional CD19 +CD24hiCD38hi B cells have been reported to comprise the highest percentage of IL10-producing B cells upon CD40 stimulation (Blair et al, 2010)
Peripheral blood mononuclear cells (PBMC) isolated from young and older subjects were stimulated for 72 h with anti-CD3 antibody prior to immunostaining for the expression of CD19, CD24, CD38 and IL10 in order to identify B cells with regulatory properties (Blair et al, 2010)

Summary

Introduction

B cells have been shown to play a pathogenic role in human autoimmune diseases due to their ability to secrete autoantibodies and serve as antigen-presenting cells to T cells (Yanaba et al, 2008b). B cells can play both protective and pathogenic roles in the same pathological setting. Since a subset of B cells with immunosuppressive properties have been isolated and shown to suppress inflammation in a number of murine models of chronic inflammation, including collagen-induced arthritis (CIA), experimental autoimmune encephalitis (EAE) and inflammatory bowel disease (Mauri & Bosma, 2012). Two phenotypically distinct subsets of B cells: transitional CD19+CD24hiCD38hi B cells (Blair et al, 2010) and CD19+CD5+CD1dhi ‘B10’ B cells (Yanaba et al, 2008a) have been demonstrated to exert immunosuppressive functions. An additional B-cell subset of CD24hi CD27+ B cells, with 60% of these cells expressing CD38, has been identified with characteristics similar to mouse B10 cells (Iwata et al, 2011)

Results

Discussion

Conclusion