Generation of B and plasma cells involves several organs with a necessary cell trafficking between them. A detailed phenotypic characterization of four circulating B-cell subsets (immature-, naïve-, memory-B-lymphocytes and plasma cells) of 106 healthy adults was realized by multiparametric flow cytometry. We show that CD10, CD27 and CD38 is the minimal combination of subsetting markers allowing unequivocal identification of immature (CD10 IntroductionHuman B-cell biology has been extensively documented. CD38-memory B cells. Very low numbers of plasma cells (2/mL) are found in peripheral blood of healthy donors. Because of their low count, only few studies have been devoted to characterizing their phenotype, most of them dealing with newly generated plasma cells after in vivo immunization.2 Steady-state circulating plasma cells lack CD20, express CD19 and CD38 high . It has been recently reported that steady-state circulating plasma cells are mainly of mucosal origin, the majority of them secreting IgA (84%), expressing CCR10 (56%) and β7 integrin (32%).3 Steady-state circulating plasma cells are generally termed plasmablasts because only half express CD138, a proteoglycan that is a hallmark of plasma cells, 4 while they are CD45 + and HLA-class II + . Plasmablasts are generated in the lymph nodes, and induced to circulate for a short period until they will reach a niche in bone marrow, spleen, mucosa associated lymphoid tissues (MALT) or lymph nodes.5 These niches will provide circulating early plasma cells with those factors required to survive and to further differentiate into long-living mature plasma cells.1 In murine bone marrow, plasma cell niche involves SDF-1 producing cells and is shared with hematopoietic stem cells

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Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.

dSos1 and Sos2 are ubiquitously expressed, universal Ras guanine nucleotide exchange factors (Ras-GEFs) acting in multiple signal transduction pathways activated by upstream cellular kinases. The embryonic lethality of Sos1 null mutants has hampered ascertaining the specific in vivo contributions of Sos1 and Sos2 to processes controlling adult organism survival or development of hematopoietic and nonhematopoietic organs, tissues, and cell lineages. Here, we generated a tamoxifen-inducible Sos1-null mouse strain allowing analysis of the combined disruption of Sos1 and Sos2 (Sos1/2) during adulthood. Sos1/2 double-knockout (DKO) animals died precipitously, whereas individual Sos1 and Sos2 knockout (KO) mice were perfectly viable. A reduced percentage of total bone marrow precursors occurred in single-KO animals, but a dramatic depletion of B-cell progenitors was specifically detected in Sos1/2 DKO mice. We also confirmed a dominant role of Sos1 over Sos2 in early thymocyte maturation, with almost complete thymus disappearance and dramatically higher reduction of absolute thymocyte counts in Sos1/2 DKO animals. Absolute counts of mature B and T cells in spleen and peripheral blood were unchanged in single-KO mutants, while significantly reduced in Sos1/2 DKO mice. Our data demonstrate functional redundancy between Sos1 and Sos2 for homeostasis and survival of the full organism and for development and maturation of T and B lymphocytes.

The immunological bone marrow (BM) microenvironment plays a major role in controlling growth and survival of clonal plasma cells (PC); this might translate into different patterns of expression of molecules involved in immune responses on PC from different types of monoclonal gammopathies (MG). We have studied the expression of a group of nine such molecules on both BMPC and the plasma of 61 newly diagnosed MG patients (30 MG of undetermined significance (MGUS), 27 multiple myeloma (MM) and four plasma cell leukemia (PCL)) and five normal individuals. Clonal PC from all MG displayed significantly increased levels of CD56, CD86 and CD126, and decreased amounts of CD38 (Po0.001). Additionally, HLA-I and b2-microglobulin were abnormally highly expressed in MGUS, while CD40 expression was decreased in MM and PCL (Po0.05). Interestingly, a progressive increase in the soluble levels of b2-microglobulin was found from MGUS to MM and PCL patients (P ¼ 0.03). In contrast, all groups showed similar surface and soluble amounts of CD126, CD130 and CD95, except for increased soluble levels of CD95 observed in PCL. Overall, those phenotypic differences are consistent with increased antigen presentation and costimulatory capacities in MGUS, which progressively deteriorate in malignant MG (MM and PCL).