Human memory B cells comprise isotype-switched and nonswitched cells with both subsets displaying somatic hypermutation. In addition to somatic hypermutation, CD27 expression has also been considered a universal memory B cell marker. We describe a new population of memory B cells containing isotype-switched (IgG and IgA) and IgM-only cells and lacking expression of CD27 and IgD. These cells are present in peripheral blood and tonsils of healthy subjects and display a degree of hypermutation comparable to CD27+ nonswitched memory cells. As conventional memory cells, they proliferate in response to CpG DNA and fail to extrude rhodamine. In contrast to other recently described CD27-negative (CD27neg) memory B cells, they lack expression of FcRH4 and recirculate in the peripheral blood. Although CD27neg memory cells are relatively scarce in healthy subjects, they are substantially increased in systemic lupus erythematosus (SLE) patients in whom they frequently represent a large fraction of all memory B cells. Yet, their frequency is normal in patients with rheumatoid arthritis or chronic hepatitis C. In SLE, an increased frequency of CD27neg memory cells is significantly associated with higher disease activity index, a history of nephritis, and disease-specific autoantibodies (anti-dsDNA, anti-Smith (Sm), anti-ribonucleoprotein (RNP), and 9G4). These findings enhance our understanding of the B cell diversification pathways and provide mechanistic insight into the immunopathogenesis of SLE.

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The pancreatic islet is necessary for maintaining glucose homeostasis. Within the pancreatic islet, the homeodomain protein Nkx2.2 is essential for the differentiation of all insulin-producing ␤ cells and a subset of glucagon-producing ␣ cells (1). Mice lacking Nkx2.2 have relatively normal sized islets, but a large number of cells within the mutant islet fail to produce any of the four major islet hormones. In this study we demonstrate that Nkx2.2 mutant endocrine cells have been replaced by cells that produce ghrelin, an appetite-promoting peptide predominantly found in the stomach. Intriguingly, normal mouse pancreas also contains a small population of ghrelin-producing cells, defining a new islet '' '' cell population. The expansion of ghrelin-producing cells at the expense of ␤ cells may be a general phenomenon, because we demonstrate that Pax4 mutant mice display a similar phenotype. We propose that insulin and ghrelin cells share a common progenitor and that Nkx2.2 and Pax4 are required to specify or maintain differentiation of the ␤ cell fate. This finding also suggests that there is a genetic component underlying the balance between insulin and ghrelin in regulating glucose metabolism. 2). The mature cell types are defined by their unique hormone expression: glucagon, insulin, somatostatin, and PP, respectively. The ␤ cells are the most abundant cell type, constituting Ͼ75% of the islet, and are centrally located within the islet. ␣, ␦, and PP cells are intermixed at the periphery of the islet, with ␣ cells representing the majority of the remaining cell types. More recently, a fifth peptide hormone has been identified in the human islet. The hormone ghrelin is produced mainly in the stomach and functions to increase secretion of growth hormone and regulate food intake and energy balance (3). Expression of ghrelin in the human islet remains somewhat controversial, because it has variably been reported to be in the ␣ cells (4), ␤ cells (5), or in a unique islet cell type (6). The function of ghrelin within the islet is also unknown, but it may have a paracrine role in regulating insulin secretion.Extensive analyses of the pancreas have led to a tremendous understanding of islet morphology, islet function, and the physiological modulation of islet function and insulin secretion. More recently, there has been increasing interest in understanding the molecular mechanisms underlying embryonic pancreas development as a way to develop therapies to treat diabetes or to discover diagnostic tools for pancreatic cancer. This has led to a surge in the identification of many of the signaling pathways and transcription factors that are critical for the specification, differentiation, and maintenance of the developing pancreas (reviewed in refs. 7 and 8). Although mouse knockout studies have allowed significant progress in identifying many of the intrinsic factors regulating the specification and differentiation of each islet cell type, including Pax4, Pax6, Nkx6.1, Ngn3, Hlxb9, Pdx1, Nkx2.2, and NeuroD, the molecular...