Long-lived plasma cells in the bone marrow produce memory antibodies that provide immune protection persisting for decades after infection or vaccination but can also contribute to autoimmune and allergic diseases. However, the composition of the microenvironmental niches that are important for the generation and maintenance of these cells is only poorly understood. Here, we demonstrate that, within the bone marrow, plasma cells interact with the platelet precursors (megakaryocytes), which produce the prominent plasma cell survival factors APRIL (a proliferation-inducing ligand) and IL-6 (interleukin-6). Accordingly, reduced numbers of immature and mature plasma cells are found in the bone marrow of mice deficient for the thrombopoietin receptor ( IntroductionAntibody-secreting plasma cells are found in many tissues. However, the plasma cells that provide antigen-specific systemic antibodies for up to decades after immunization or infection predominantly reside in the bone marrow. [1][2][3] There are multiple lines of evidence that individual plasma cells can survive in humans and mice for many months at the least. [4][5][6][7] These long-lived plasma cells are important for maintaining protective antibody memory. However, autoantibody-secreting long-lived plasma cells are refractory to conventional immunosuppressive therapy and therefore represent a therapeutic challenge in autoimmune diseases. [8][9][10] Plasma cell survival is not cell-autonomous but depends on signals provided by their environment. The most potent plasma cell survival factors identified so far are a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), tumor necrosis factor-␣ (TNF-␣), stromal-derived factor-1␣, and signals transduced via CD44. [11][12][13][14] The bone marrow contains multiple microenvironmental niches that stimulate cellular proliferation, differentiation, and survival. [15][16][17][18][19][20] Each niche seems to support specifically one or a few particular hematopoietic stem or precursor cells. In this way, the sizes of these populations are limited by the number of available niches. 16,21 Similarly, competition for a limited number of survival niches may also control the turnover rate within the bone marrow plasma cell compartment. 12,[22][23][24] One or multiple niches may exist that have the capability to support the terminal differentiation and survival of bone marrow plasma cells. 25 As indicated by strong colocalization between a particular subtype of stromal-derived factor-1␣ ϩ reticular stromal cells and immunoglobulin G ϩ (IgG ϩ ) bone marrow plasma cells, the former seems to be an important element of plasma cell niches in that tissue. 26 However, in culture, bone marrow stromal cells support plasma cell survival only for a limited time, 13 suggesting that additional cell types contribute to the formation of plasma cell niches.In addition, it has been shown that macrophage-derived APRIL is required to support differentiation/survival of bone marrow plasma cells during early life, suggesting that factors ...

Emergency mobilization of neutrophil granulocytes (neutrophils) from the bone marrow (BM) is a key event of early cellular immunity. The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) stimulates this process, but it is unknown how individual neutrophils respond in situ. We show by intravital 2-photon microscopy that a systemic dose of human clinical-grade G-CSF rapidly induces the motility and entry of neutrophils into blood vessels within the tibial BM of mice. Simultaneously, the neutrophil-attracting chemokine KC (Cxcl1) spikes in the blood. In mice lacking the KC receptor Cxcr2, G-CSF fails to mobilize neutrophils and antibody blockade of Cxcr2 inhibits the mobilization and induction of neutrophil motility in the BM. KC is expressed by megakaryocytes and endothelial cells in situ and is released in vitro by megakaryocytes isolated directly from BM. This production of KC is strongly increased by thrombopoietin (TPO). Systemic G-CSF rapidly induces the increased production of TPO in BM. Accordingly, a single injection of TPO mobilizes neutrophils with kinetics similar to G-CSF, and mice lacking the TPO receptor show impaired neutrophil mobilization after short-term G-CSF administration. Thus, a network of signaling molecules, chemokines, and cells controls neutrophil release from the BM, and their mobilization involves rapidly induced Cxcr2-mediated motility controlled by TPO as a pacemaker. IntroductionNeutrophils are the most abundant and, arguably, the most important leukocyte in the vertebrate immune system. Under normal conditions, human bone marrow (BM) produces ϳ 10 11 neutrophils per day. 1 In "danger situations" such as peripheral infections, the constant release of neutrophils can be dramatically increased within hours, a process termed danger or stress mobilization. 2 The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) is central to the danger mobilization of neutrophils in both humans and mice. 3 However, although recombinant G-CSF has been used in clinical hematology for 20 years, the molecular mechanisms by which it mobilizes neutrophils are still not well understood.Neutrophils are restrained in the BM by the binding of their chemokine receptor Cxcr4 to the chemokine Cxcl12, which is expressed in a membrane-associated fashion by BM stromal cells. 4 There is evidence that G-CSF breaks the Cxcr4-Cxcl12 bond by activating neutrophil proteases, 5 thereby releasing neutrophils from the BM into the bloodstream. 3,6 However, several findings cannot be explained by the Cxcr4-Cxcl12 breakage concept alone. First, G-CSF can mobilize neutrophils in protease-deficient mice, arguing against the need for protease activation for this process. 7,8 Second, because neutrophil-specific deletion of Cxcr4 in mice results in much higher numbers of circulating neutrophils compared with wild-type animals, factors other than Cxcr4 must be involved in steering neutrophils into the BM blood sinuses (unless the process is passive). Finally, the specific Cxcr4-antagonist AMD3100 a...

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Long-lived plasma cells survive in a protected microenvironment for years or even a lifetime and provide humoral memory by establishing persistent Ab titers. Long-lived autoreactive, malignant, and allergen-specific plasma cells are likewise protected in their survival niche and are refractory to immunosuppression, B cell depletion, and irradiation. Their elimination remains an essential therapeutic challenge. Recent data indicate that long-lived plasma cells reside in a multicomponent plasma cell niche with a stable mesenchymal and a dynamic hematopoietic component, both providing essential soluble and membrane-bound survival factors. Alternative niches with different hematopoietic cell components compensate fluctuations of single cell types but may also harbor distinct plasma cell subsets. In this Brief Review, we discuss conventional therapies in autoimmunity and multiple myeloma in comparison with novel drugs that target plasma cells and their niches. In the future, such strategies may enable the specific depletion of pathogenic plasma cells while leaving the protective humoral memory intact.

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Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315.BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315.BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient ΔdblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma.

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