Survival of Long-Lived Plasma Cells (LLPC): Piecing Together the Puzzle

Abstract

Durable humoral immunity is dependent upon the generation of antigen-specific antibody titers, produced by non-proliferating bone marrow resident long-lived plasma cells (LLPC). Longevity is the hallmark of LLPC, but why and how they survive and function for years after antigen exposure is only beginning to be understood. LLPC are not intrinsically long-lived; they require continuous signals from the LLPC niche to survive. Signals unique to LLPC survival (vs. PC survival in general) most notably include those that upregulate the anti-apoptotic factor Mcl-1 and activation of the CD28 receptor expressed on LLPC. Other potential factors include expression of BCMA, upregulation of the transcription factor ZBTB20, and upregulation of the enzyme ENPP1. Metabolic fitness is another key component of LLPC longevity, facilitating the diversion of glucose to generate pyruvate during times of stress to facilitate long term survival. A third major component of LLPC survival is the microenvironment/LLPC niche itself. Cellular partners such as stromal cells, dendritic cells, and T regulatory cells establish a niche for LLPC and drive survival signaling by expressing ligands such as CD80/CD86 for CD28 and producing soluble and stromal factors that contribute to LLPC longevity. These findings have led to the current paradigm wherein both intrinsic and extrinsic mechanisms are required for the survival of LLPC. Here we outline this diverse network of signals and highlight the mechanisms thought to regulate and promote the survival of LLPC. Understanding this network of signals has direct implications in increasing our basic understanding of plasma cell biology, but also in vaccine and therapeutic drug development to address the pathologies that can arise from this subset.

HPV-Specific Systemic Antibody Responses and Memory B Cells are Independently Maintained up to 6 Years and in a Vaccine-Specific Manner Following Immunization with Cervarix and Gardasil in Adolescent and Young Adult Women in Vaccination Programs in Italy

“…However, recently, it has been proposed that PCs may survive up to 20 years [65]. In addition, PCs and long-lasting serum antibodies have also been shown to persist in the absence of memory B cells [28,64,66,67]. Together, these evidence suggest that circulating antibodies could be detected, regardless of the presence of memory B cells, as observed in our study for some Cervarix vaccinated women.…”

“…However, the two B lymphocyte subsets follow different maintenance kinetics and the correlation is lost over time. The loss of circulating antibodies but not of memory B cells is not uncommon, as also observed for other vaccines, such as against HBV [28,71].…”

“…When naïve B cells are activated after the encounter with their cognate antigen, they become either memory B cells or plasma cells (PCs), which can be short-or long-lived PCs (SLPCs and LLPCs) [63]. While the magnitude of early humoral responses is determined by both types of PCs, the long-term maintenance of antibodies is antigen-independent and could last for life [28,63,64], due to the continuous presence of LLPCs. Whether these are the same PCs generated at priming or are rather derived from the differentiation of memory B cells into "new" LLPCs is not clear yet.…”

“…Different types of humoral immune responses (IgG and nAbs titers, antibody avidity, and memory B cell responses) were analysed after an average of 4-6 years from the third immunization. Indeed, experience with other vaccines indicate that both circulating antibodies and memory B cells may mediate protection and, in some cases, vaccine efficacy has been observed also in the absence of circulating antibodies [28]. As the role of memory B cells is not completely clear in the case of HPV vaccination, we measured their persistence in comparison to antibody levels and properties.…”

Network organization of antibody interactions in sequence and structure space: the RADARS model

“…Both MBC and LLPC may persist for a lifetime (57,63), so the optimal coverage of shape space in balance with affinity requires organization of interaction energy and space. In the case of LLPC we know of no antigen specific deletion mechanism, and competition for niche, which is not antigen specific, might be the only attrition factor (64,65). MBC may undergo further rounds of affinity maturation in GC and can therefore be reorganized (66).…”