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Plasma cell homeostasis: the effects of chronic antigen stimulation and inflammation.

ABSTRACT: Long-lived plasma cells (LLPCs) that maintain humoral immunity to previously encountered Ags occupy a compartment in the bone marrow (BM). The rules and mechanisms by which cells enter (and leave) this compartment are poorly understood. We looked at what happens to the LLPC compartment and to plasma cell lifespan in general, in situations in which Ag stimulation and/or inflammation persist. We find that chronic Ag supply causes the generation of short-lived plasma cells in the local lymphoid organ, at the expense of any LLPC production. Furthermore, we find that inflammation caused by infection (mediated via TNF-?) causes a dramatic mobilization of LLPCs from the BM, with a concomitant reduction in circulating Ab levels against previously immunized Ags. These data are discussed in the context of the capacity of the BM LLPC compartment and competition for entry to it.

SUBMITTER: Slocombe T

PROVIDER: S-EPMC3836257 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Plasma cell homeostasis: the effects of chronic antigen stimulation and inflammation.

Slocombe Tom T Brown Sheila S Miles Katherine K Gray Mohini M Barr Tom A TA Gray David D

Journal of immunology (Baltimore, Md. : 1950) 20130809 6

Long-lived plasma cells (LLPCs) that maintain humoral immunity to previously encountered Ags occupy a compartment in the bone marrow (BM). The rules and mechanisms by which cells enter (and leave) this compartment are poorly understood. We looked at what happens to the LLPC compartment and to plasma cell lifespan in general, in situations in which Ag stimulation and/or inflammation persist. We find that chronic Ag supply causes the generation of short-lived plasma cells in the local lymphoid org ...[more]

PMID: 23935195

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Project description:Upon reactivation of quiescent neurotropic viruses antigen (Ag)-specific brain resident-memory CD8+ T-cells (bTRM) may respond to de novo-produced viral Ag through the rapid release of IFN-γ, which drives subsequent interferon-stimulated gene expression in surrounding microglia. Through this mechanism, a small number of adaptive bTRM may amplify responses to viral reactivation leading to an organ-wide innate protective state. Over time, this brain-wide innate immune activation likely has cumulative neurotoxic and neurocognitive consequences. We have previously shown that HIV-1 p24 Ag-specific bTRM persist within the murine brain using a heterologous prime-CNS boost strategy. In response to Ag restimulation, these bTRM display rapid and robust recall responses, which subsequently activate glial cells. In this study, we hypothesized that repeated challenges to viral antigen (Ag) (modeling repeated episodes of viral reactivation) culminate in prolonged reactive gliosis and exacerbated neurotoxicity. To address this question, mice were first immunized with adenovirus vectors expressing the HIV p24 capsid protein, followed by a CNS-boost using Pr55Gag/Env virus-like particles (HIV-VLPs). Following the establishment of the bTRM population [>30 days (d)], prime-CNS boost animals were then subjected to in vivo challenge, as well as re-challenge (at 14 d post-challenge), using the immunodominant HIV-1 AI9 CD8+ T-cell epitope peptide. In these studies, Ag re-challenge resulted in prolonged expression of microglial activation markers and an increased proliferative response, longer than the challenge group. This continued expression of MHCII and PD-L1 (activation markers), as well as Ki67 (proliferative marker), was observed at 7, 14, and 30 days post-AI9 re-challenge. Additionally, in vivo re-challenge resulted in continued production of inducible nitric oxide synthase (iNOS) with elevated levels observed at 7, 14 and 30 days post re-challenge. Interestingly, iNOS expression was significantly lower among challenged animals when compared to re-challenged groups. Furthermore, in vivo specific Ag re-challenge produced lower levels of arginase (Arg)-1 when compared with the challenged group. Taken together, these results indicate that repeated Ag-specific stimulation of adaptive immune responses leads to cumulative dysregulated microglial cell activation.

Dataset Information

Plasma cell homeostasis: the effects of chronic antigen stimulation and inflammation.

Publications

Plasma cell homeostasis: the effects of chronic antigen stimulation and inflammation.

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