Considerable progress has been made in identifying the transcription factors involved in the early specification of the B-lymphocyte lineage. However, little is known about factors that control the transition of mature activated B cells to antibody-secreting plasma cells. Here we report that the transcription factor XBP-1 is required for the generation of plasma cells. XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma-cell differentiation, and were found at high levels in plasma cells from rheumatoid synovium. When introduced into B-lineage cells, XBP-1 initiated plasma-cell differentiation. Mouse lymphoid chimaeras deficient in XBP-1 possessed normal numbers of activated B lymphocytes that proliferated, secreted cytokines and formed normal germinal centres. However, they secreted very little immunoglobulin of any isotype and failed to control infection with the B-cell-dependent polyoma virus, because plasma cells were markedly absent. XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells.

Purpose To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) with rheumatoid arthritis (RA) and to examine associations of PD and Porphyomonas gingivalis (Pg) with disease features. Methods RA cases (N=287) and controls (N=330) underwent a standardized periodontal examination. HLA-DRB1 status was imputed using SNPs from the extended MHC. Circulating anti-Pg antibody was measured using ELISA and subgingival plaque was assessed for the presence of Pg using PCR. Associations of PD with RA were examined using multivariable regression. Results PD was more common in RA (35%, p = 0.022) and aCCP positive RA (n=240; 37%; p = 0.006) vs. controls (26%). There were no RA-control differences in anti-Pg or the frequency of Pg positivity by PCR. Anti-Pg antibody showed weak but statistically significant associations with both anti-CCP (r=0.14, p=0.022) and RF (r=0.19, p=0.001). PD was associated with increased swollen joint counts (p=0.004), DAS-28-CRP (p=0.045), total Sharp scores (p=0.015), aCCP (p=0.011), and RF (p<0.001). Select anti-citrullinated peptide antibody (ACPA; including antibody to citrullinated filaggrin) were higher in patients with subgingival Pg and higher anti-Pg antibody levels irrespective of smoking. Associations of PD with established seropositive RA were independent of all covariates examined including evidence of Pg infection. Conclusions Both PD and Pg appear to shape RA-related autoreactivity in RA. In addition, PD demonstrates an independent relationship with established seropositive RA.

The tumor necrosis factor alpha (TNF-␣) gene is rapidly activated by lipopolysaccharide (LPS). Here, we show that extracellular signal-regulated kinase (ERK) kinase activity but not calcineurin phosphatase activity is required for LPS-stimulated TNF-␣ gene expression. In LPS-stimulated macrophages, the ERK substrates Ets and Elk-1 bind to the TNF-␣ promoter in vivo. Strikingly, Ets and Elk-1 bind to two TNF-␣ nuclear factor of activated T cells (NFAT)-binding sites, which are required for calcineurin and NFAT-dependent TNF-␣ gene expression in lymphocytes. The transcription factors ATF-2, c-jun, Egr-1, and Sp1 are also inducibly recruited to the TNF-␣ promoter in vivo, and the binding sites for each of these activators are required for LPSstimulated TNF-␣ gene expression. Furthermore, assembly of the LPS-stimulated TNF-␣ enhancer complex is dependent upon the coactivator proteins CREB binding protein and p300. The finding that a distinct set of transcription factors associates with a fixed set of binding sites on the TNF-␣ promoter in response to LPS stimulation lends new insights into the mechanisms by which complex patterns of gene regulation are achieved.Tumor necrosis factor alpha (TNF-␣) is a proinflammatory cytokine that activates multiple-signal transduction pathways and influences a broad range of immunological processes. Multiple extracellular stimuli induce the synthesis of TNF-␣ in a wide variety of cell types, including T and B cells, monocytes and macrophages, mast cells, and fibroblasts (reviewed in reference 1). We have shown that induction of TNF-␣ gene transcription by T or B cell receptor engagement, virus infection, and treatment with a calcium ionophore depends upon the activity of the phosphatase calcineurin (15,18,20). Calcineurin targets the nuclear factor of activated T cells (NFAT) family of proteins (reviewed in references 11 and 38), which are critical for TNF-␣ gene expression by calcineurin-dependent signal transduction pathways (15,48,49).Production of TNF-␣ in response to lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, is of particular clinical importance because TNF-␣ is a mediator of septic shock (reviewed in reference 1). Exposure of monocytes and macrophages to LPS results in activation of the mitogen-activated protein kinase (MAPK) pathway, including the extracellular signal-related kinase (ERK), c-jun NH 2 -terminal kinase (JNK), and p38 cascades (reviewed in reference 12).Here, we show that ERK, but not calcineurin or p38, is required for full transcriptional induction of TNF-␣ gene expression by LPS. We identify TNF-␣ promoter elements critical for LPS induction of the gene and demonstrate that two Sp1 binding sites and three Ets binding sites, in addition to a cyclic AMP response element (CRE)-like site and an Egr site, are critical for LPS induction of the TNF-␣ gene. Consistent with this functional analysis of the TNF-␣ promoter, using chromatin immunoprecipitation and formaldehyde crosslinking (ChIP) assays, we directly detect LPS-induc...