Plasma cells (PCs) are the final B-cell differentiation stage. Recent evidence reveals relevant functional differences within the PC compartment. In rodents, early PCs formed in secondary lymphoid tissues show enhanced apoptosis and short life span, whereas PCs present in a final destination organ, such as the bone marrow (BM), have reached a stable prolonged survival state. BM PCs arrive at this organ as a circulating precursor whose cellular nature remains uncertain. An initial aim of this study was to characterize this circulating cell. We hypothesized that antibody-secreting cells detectable in the human blood after immunization might be a candidate precursor. These cells were obtained from the blood of volunteers immunized 6 days earlier with tetanus toxoid (tet), and they were unambiguously identified as PCs, as demonstrated by their expression of the CD38 h phenotype, by morphology, by immunoglobulin (Ig) intracytoplasmic staining, and by IgG-tet-secreting capacity in vitro. In addition, by using the common CD38 h feature, human PCs from tonsil (as a possible source of early PCs), from blood from tet-immunized donors (as the putative precursors of BM PCs), and from BM (as a deposit organ) have been purified and their phenotypes compared. The results show that a variety of differentiation molecules, proteins involved in the control of apoptosis, the B-cell transcription factors, positive regulatory domain I-binding factor 1/B lymphocyteinduced maturation protein 1 and B cellspecific activating protein and, at least partially, the chemokine receptor CXCR4 were expressed by human PCs following a gradient of increasing maturity in the direction: tonsil3blood3BM. However, PCs from these different organs showed a local pattern of adhesion molecule expression. These observations are dis- IntroductionPlasma cells (PCs) are the morphologically well-defined cellular end point of the B-lymphocyte differentiation sequence, and, as such, they exhibit biochemical and structural features indicative of their full commitment to the synthesis and secretion of antibody (Ab). Therefore, PCs are ultimately responsible for the humoral immune response. Experiments in rodents have revealed that, soon after antigen (Ag) entry, PCs are formed in inductive territories of the secondary lymphoid tissue, initially within Ag-activated foci occurring in the T-cell areas of draining lymphoid tissue and, if the Ag persists, they are also generated in germinal centers (GCs). [1][2][3] After this early phase, the number of PCs falls drastically in these areas and they start accumulating in final deposit locations, namely the bone marrow (BM) and the lamina propria (LP), for systemic and mucosal humoral responses, respectively. [4][5][6] PCs present in the deposit organs are not formed in situ, but they derive from close precursors generated in distant lymphoid organs as a result of Ag stimulation, which migrate into these areas through the circulation. 7,8 The nature of this PC precursor has not been fully clarified. It is well established...

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IntroductionSystemic lupus erythematosus (SLE) is characterized by B cell hyper-activation and auto-reactivity resulting in pathogenic auto-antibody generation. The phenotypic analysis of blood B cell subsets can be used to understand these alterations.MethodsThe combined detection of CD19, CD27 and IgD (or IgM) by flow cytometry (FC) analysis delineates five well-defined blood B cell-subsets: naive, switched (S) memory, double negative (DN) memory and CD27 IgD IgM (non-switched memory) B lymphocytes, and plasma cells (PCs). This phenotypic study was performed in 69 consecutive SLE patients and 31 healthy controls.ResultsSLE patients exhibited several abnormalities in the distribution of these B cell subsets, including elevated levels of DN memory B cells and PCs, and decreased CD27 IgD IgM B cells. Active SLE patients also showed decreased presence of S memory B cells and increased proportions of naive B lymphocytes. Nevertheless, when the patients in remission who did not require treatment were studied separately, the only remaining abnormality was a reduction of the CD27 IgD IgM B cell-subset detectable in most of these patients. The level of reduction of CD27 IgD IgM B cells was associated with elevated values of serum SLE auto-antibodies. Further analysis of this latter B cell-subset specifically showed increased expression of CD80, CD86, CD95, 9G4 idiotype and functional CXCR3 and CXCR4.ConclusionsThe presence of a reduced blood CD27 IgD IgM B cell-subset, exhibiting an activated state and enriched for auto-reactivity, is a consistent B cell abnormality in SLE. These findings suggest that CD27 IgD IgM B lymphocytes play a role in the pathogenesis of this disease.

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The present study shows that reimmunization with tetanus toxoid (tet) caused a transient increase of the human blood plasma cell (PC) pool, detectable from 6th to 15th day postboost, as well as the temporal alteration of several PC features. Labeling of specific PC with FITC-tet C fragment (tetC) allowed kinetics analysis of the tetC+ and tetC− PC, and revealed remarkable differences between them: 1) the kinetics of tetC+ PC occurrence was exponential, and most of them appeared in a narrow time frame (5th to 8th day postboost), whereas the tetC− PC increase was lower (three to five times) and more prolonged (4th to 15th day postboost). 2) The tetC+ PC subset contained a fraction of cycling cells, expressed high levels of DR, CD138, and CD126, and responded to IL-6 by improving their survival and Ig secretion; in contrast, the tetC− PC showed higher CXCR4 and lower DR and CD138, did not respond to IL-6, and contained a fraction of apoptotic cells. 3) Sequential phenotypic analysis revealed maturational changes within the tetC+, but not tetC−, PC subset; sequencing of tetC+ PC IgVH genes showed clear features of Ag selection. 4) The tetC+ PC expressed several times more positive regulatory domain I- binding factor 1/B lymphocyte-induced maturation protein 1 transcription factor than the tetC− PC. 5) The tetC− PC and bone marrow resident PC similarly expressed low DR and high CXCR4, but differed in that the latter exhibited higher levels of CD31, CD138, and positive regulatory domain I- binding factor 1/B lymphocyte-induced maturation protein 1. These findings support the view that tetC+ PC contain bone marrow PC precursors, and tetC− PC probably belong to a removable compartment of aged PC.