Research Article: Changes in Circulating B Cell Subsets Associated with Aging and Acute SIV Infection in Rhesus Macaques

Date Published: January 17, 2017

Publisher: Public Library of Science

Author(s): W. L. William Chang, Denise F. Gonzalez, Hung T. Kieu, Luis D. Castillo, Ilhem Messaoudi, Xiaoying Shen, Georgia D. Tomaras, Barbara L. Shacklett, Peter A. Barry, Ellen E. Sparger, Aftab A. Ansari.


Aging and certain viral infections can negatively impact humoral responses in humans. To further develop the nonhuman primate (NHP) model for investigating B cell dynamics in human aging and infectious disease, a flow cytometric panel was developed to characterize circulating rhesus B cell subsets. Significant differences between human and macaque B cells included the proportions of cells within IgD+ and switched memory populations and a prominent CD21-CD27+ unswitched memory population detected only in macaques. We then utilized the expanded panel to analyze B cell alterations associated with aging and acute simian immunodeficiency virus (SIV) infection in the NHP model. In the aging study, distinct patterns of B cell subset frequencies were observed for macaques aged one to five years compared to those between ages 5 and 30 years. In the SIV infection study, B cell frequencies and absolute number were dramatically reduced following acute infection, but recovered within four weeks of infection. Thereafter, the frequencies of activated memory B cells progressively increased; these were significantly correlated with the magnitude of SIV-specific IgG responses, and coincided with impaired maturation of anti-SIV antibody avidity, as previously reported for HIV-1 infection. These observations further validate the NHP model for investigation of mechanisms responsible for B cells alterations associated with immunosenescence and infectious disease.

Partial Text

An understanding of B cell biology and development is critical to characterizing the humoral immune response. B cells are lymphocytes derived from bone marrow lymphoid progenitor cells. Mature, naïve B cells migrate to lymphoid tissues, where they may be exposed to antigen and subsequently undergo differentiation and maturation into plasma cells or memory B cells. Plasma cells are long-lived antibody-secreting cells that localize predominantly within the bone marrow, whereas memory and naïve B cells circulate between blood and tissues. As the key component of the humoral immune response, antibodies play a significant role in the control of a wide variety of pathogens, and also contribute to the pathogenesis of certain autoimmune diseases [1]. However, B cell function and the humoral response may become perturbed or dysregulated by certain host conditions including chronic infection with pathogens such as herpes viruses [2–4] that establish lifelong persistence, or agents such as human immunodeficiency virus (HIV)-1 targeting immune response cells (e.g., CD4+ T cells) that directly interact with B cells [5–9]. Another host factor with significant impact on B cell function and the humoral response is deleterious aging of the immune system that is referred to as immunosenescence [10–12]. Investigation of mechanisms by which these various host conditions (e.g., aging, infection) perturb B cell function will require animal models that closely resemble the human host.

A review of reports describing changes in B cell subset distribution in human disease and aging revealed significant variation in the combinations of memory markers including IgD, CD27, CD24, CD38, CD10, and CD21 used for B cell analysis [10, 24, 25, 37, 46, 51]. Reports describing circulating B cell subsets in rhesus macaques have been limited and typically based on a combination of either CD27 and CD21, or CD27 and IgD for characterizing memory B cell populations defined initially by CD20 or occasionally by CD19 staining [17–19, 22]. Accordingly, establishment of a phenotyping panel based on a combination of IgD, CD27, and CD21 as described herein, permitted separation of macaque B cells into SM, UM, and naïve subsets and further separation of the SM subset into AM and RM populations to allow a superior characterization of memory B cell subsets in rhesus macaques. Establishment and use of this expanded staining panel for circulating B cells also revealed a distinctive CD21-CD27+ UM subset that has not been recognized in macaques or reported for circulating human B cells. Future studies are warranted to determine if any functional differences exist between CD21-CD27+ and CD21+CD27+ UM subsets identified by this analysis.




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