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Allergen-specific Abs play a pivotal role in the induction and maintenance of allergic airway inflammation. During secondary immune responses, plasma cell survival and Ab production is mediated by extrinsic factors provided by the local environment (survival niches). It is unknown whether neurotrophins, a characteristic marker of allergic airway inflammation, influence plasma cell survival in the lung. Using a mouse model of allergic asthma, we found that plasma cells from the lung and spleen are distinct subpopulations exhibiting differential expression patterns of neurotrophins and their receptors (Trks). In vitro, the nerve growth factor (NGF) and neurotrophin-3 (NT3) led to a dose-dependent increase in viability of isolated pulmonary plasma cells due to up-regulation of the antiapoptotic Bcl2 pathway. In parallel, the expression of transcription factors that stimulate the production of immunoglobulins (X-box binding protein 1 and NF-B subunit RelA) was enhanced in plasma cells treated with NGF and NT3. These findings were supported in vivo. When the NGF pathway was blocked by intranasal application of a selective TrkA inhibitor, sensitized mice showed reduced numbers of pulmonary plasma cells and developed lower levels of allergen-specific and total serum IgE in response to OVA inhalation. This suggests that in the allergic airway inflammation, NGF/TrkA-mediated pulmonary IgE production contributes significantly to serum-IgE levels. We conclude that the neurotrophins NGF and NT3 act as survival factors for pulmonary plasma cells and thus are important regulators of the local Ab production in the allergic airway disease.

Plasma cells are terminally differentiated B cells that secrete antibodies, important for immune protection, but also contribute to any allergic and autoimmune disease. There is increasing evidence that plasma cell populations exhibit a considerable degree of heterogeneity with respect to their immunophenotype, migration behavior, lifetime, and susceptibility to immunosuppressive drugs. Pathogenic long-lived plasma cells are refractory to existing therapies. In contrast, short-lived plasma cells can be depleted by steroids and cytostatic drugs. Therefore, long-lived plasma cells are responsible for therapy-resistant autoantibodies and resemble a challenge for the therapy of antibody-mediated autoimmune diseases. Both lifetime and therapy resistance of plasma cells are supported by factors produced within their microenviromental niches. Current results suggest that plasma cell differentiation and survival factors such as IL-6 also signal via mammalian miRNAs within the plasma cell to modulate downstream transcription factors. Recent evidence also suggests that plasma cells and/or their immediate precursors (plasmablasts) can produce important cytokines and act as antigen-presenting cells, exhibiting so far underestimated roles in immune regulation and bone homeostasis. Here, we provide an overview on plasma cell biology and discuss exciting, experimental, and potential therapeutic approaches to eliminate pathogenic plasma cells.

Plasma cells can survive for long periods and continuously secrete protective antibodies, but plasma cell production of autoantibodies or transformation to tumor cells is detrimental. Plasma cell survival depends on exogenous factors from the surrounding microenvironment, and largely unknown intracellular mediators that regulate cell homeostasis. Here we investigated the contribution of the microRNA 24-3p (miR-24-3p) to the survival of human plasma cells under the influence of IL-6 and SDF-1α (stromal cell derived factor 1), both of which are bone marrow survival niche mediators. Deep sequencing revealed a strong expression of miR-24-3p in primary B cells, plasma blasts, plasma cells, and in plasmacytoma cells. In vitro studies using primary cells and the plasmacytoma cell line RPMI-8226 revealed that (i) expression of miR-24-3p mediates plasma cell survival, (ii) miR-24-3p is upregulated by IL-6 and SDF-1α, (iii) IL-6 mediates cell survival under ER stress conditions via miR-24-3p expression, and (iv) IL-6-induced miR-24-3p expression depends on the activity of the MAP kinase Erk1/2. These results suggest a direct connection between an external survival signal and an intracellular microRNA in regulating plasma cell survival. miR-24-3p could therefore be a promising target for new therapeutic strategies for autoimmune and allergic diseases and for multiple myeloma.Keywords: Erk1/2 r Interleukin-6 r MicroRNA-24-3p r Plasma cells r Survival Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPlasma cells are key players in the immune system. They represent the terminal stage of B-cell differentiation due to antigendriven activation. The nonproliferating and refractory plasma cells [3]. Long-term survival of plasma cells is a complex process that depends both on external signals, which in sum are referred to as the "survival niche", as well as on the molecular competence to respond to these signals [4]. The bone marrow is the major site for long-term antibody production, but secondary lymphoid organs, the gut, and inflamed tissues could also provide survival niches [5,6]. Reticular bone marrow stromal cells, basophil and eosinophil granulocytes, and others secrete IL-6, APRIL, and SDF-1α (stromal cell derived factor 1) that are able to mediate survival in vitro and in vivo [7,8] Other external factors involved in mediating plasma cell survival are BAFF (B-cell activating factor), TNF, IL-4, . Current research focuses on the intracellular pathway(s) that mediate survival signaling in plasma cells. Functional studies in mice revealed the impact of the transcription factors Blimp1 (B lymphocyte-induced maturation protein-1), Bcl6 (B-cell lymphoma 6 protein), IRF-4 (interferon regulatory factor 4), and XBP1 (X-box binding protein 1) for plasma cell differentiation and survival [10][11][12][13]. Although several factors contributing to the bone marrow survival niche were also identified in humans, little is known about the intracellular mechanisms...

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