Bone marrow fat and the decline of B lymphopoiesis in rabbits

Abstract

B lymphopoiesis is necessary to generate a diverse pool of naïve B cells that are able to respond to a broad spectrum of antigens during immune responses to pathogens and to vaccination. Rabbits have been utilized for many years to generate high affinity monoclonal and polyclonal antibodies. Specific antibodies generated in rabbits have greatly advanced scientific discoveries, but the unique qualities of rabbit B cell development have been underappreciated. Unlike in humans and mice, where B lymphopoiesis declines in mid to late life, B lymphopoiesis in rabbits arrests early in life, between 2–4 months of age. This review focuses on the early loss of B cell development in rabbits and the contribution of the bone marrow microenvironment to this process. We also propose directions for future research in this area, and discuss how the rabbit can be used as a model to understand the decline of B lymphopoiesis that occurs in humans late in life. Such studies will be important for developing therapeutics targeted to prevent and/or reverse declining B lymphopoiesis in the elderly, as well as boosting immunity and antibody responses after infection or vaccination.

Inflammatory Changes in Bone Marrow Microenvironment Associated with Declining B Lymphopoiesis

“…Rabbit B lymphopoiesis declines at an accelerated rate compared to that of elderly humans and aged mice (29, 49–56). In this study, we found that the arrest of B lymphopoiesis in young rabbits is associated with increased fat, myeloid cells, and inflammatory molecules, conditions similar to those seen in BM of aged humans and mice (4, 10–15, 19, 21, 57–59).…”

“…Increased levels of inflammatory cytokines, including IL-1, IL-6, and TNFα, are found in aged BM, and all of these are known to negatively regulate B lymphopoiesis, and enhance myelopoiesis (22–28). We previously showed that adipocytes inhibit B lymphopoiesis in vitro , and that this inhibition is mediated in part, by IL-1 (23, 29). Adipocytes also express other inflammatory molecules, such as S100A8 and S100A9 (30, 31), and their expression is increased in multiple tissues during aging in mice and humans (32).…”

Immunomodulatory Function of Myeloid-Derived Suppressor Cells during B Cell-Mediated Immune Responses

“…In addition, although MDSCs usually suppress proliferation of T cells by secreting inducible nitric oxide synthase (iNOS) and arginase, these mechanisms do not play a role in B lymphopoiesis [ 29 ]. Treatment with IL-1 also increases the number of CD11b + Gr1 + myeloid cells in culture by promoting myelopoiesis at the multipotent progenitor stage [ 29 , 32 ].…”

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…In the mouse retrovirus immunodeficiency system, ex vivo derived M-MDSCs from LP-BM5-infected mice also induced a moderate expansion of Tregs in vitro, but concurrently suppressed their IL-10 production (114 (44,162). More recent study showed that MDSCs in the bone marrow of aged mice suppressed B cell lymphopoiesis in an IL-1-dependent manner (74,75). B cells play crucial roles in cancer as sources of malignant cells in several lymphomas (136) and as sources of tumor-specific antibodies (144).…”