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Dysregulation of factors vital to the survival B cells and/or plasma cells, such as BAFF and APRIL, could be detrimental to a pregnancy.Serially collected first-, second-, and third-trimester serum samples were measured for BAFF and APRIL by ELISA from 150 pregnant women (71 healthy + 79 with a chronic medical disease) at a single medical center. Postpartum serum samples were also collected from the majority of these women. Matched third-trimester and cord blood samples were collected from 168 women (86 healthy + 82 with a chronic medical disease). Data were analyzed by chi-square statistic, unpaired t-test, paired t-test, Mann-Whitney rank sum test, Wilcoxon signed rank test, Spearman rank order correlation, and receiver operator characteristic (ROC) curve analyses as appropriate.Maternal serum BAFF levels declined as the pregnancies progressed and rebounded postpartum, whereas serum APRIL levels remained relatively flat throughout pregnancy and postpartum. Cord BAFF and APRIL levels correlated positively with gestation age and were considerably greater than the corresponding maternal third-trimester serum BAFF and APRIL levels, respectively. In women who developed preeclampsia, third-trimester BAFF levels were greater, rather than lower, than their corresponding second-trimester BAFF levels. ROC curve analysis suggested a potential role for third-trimester serum BAFF level as a biomarker of preeclampsia.BAFF and APRIL are differentially regulated in the mother during and following pregnancy, whereas each is upregulated in the developing fetus. An increase in third-trimester serum BAFF level may portend development of preeclampsia.

PROBLEM Immunologic, angiogenic, and anti-angiogenic factors are associated with spontaneous abortion (SAB). B cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) may play a role in SAB and may serve singly or in combination as an early biomarker of SAB. METHOD OF STUDY In this prospective observational study, serum sFlt-1, PIGF, BAFF, and APRIL levels were measured in the first trimester of pregnancy in a medically diverse group of women and in non-pregnant controls. Associations and discriminative values of first-trimester sFlt-1, PIGF, BAFF, and APRIL levels and the corresponding APRIL:BAFF, BAFF:sFlt-1, and sFlt-1:PlGF ratios with development of SAB were tested. RESULTS Median serum BAFF level was lower (p = .007) and median serum sFlt-1 level was higher (p

A central proposition of the “business case” for corporate social responsibility (CSR) is that a company's CSR practices are linked to consumer behavior and a firm's financial performance through reputational mechanisms. This study addresses the equivocal support for this proposition through an empirical analysis of the survey items most often used to assess a company's CSR and its stakeholder reputation. This study tests the congruence among nine different measures of environmental, social, and governance dimensions of CSR and a public corporate reputation measure. Two distinct factors are identified—direct CSR impact and assessment/reputation—suggesting that the global corporate reputation does not capture tangible CSR impact (environment and social) and is only congruent with a measure of intangible CSR performance (governance). The study highlights the importance of taking a multidimensional approach. Addressing measurement issues helps unpack the theoretical and practical link between CSR and corporate reputation and provides strategic guidance when planning CSR business and communication strategies.

Objective To investigate the long-term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE. Methods The study was designed as a multicenter, open-label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals). Results Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline. Conclusion This study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long-term disease control.

Dermal blood vessels and regional lymph nodes are innervated by sympathetic nerves and, under stress, sympathetic nerves release norepinephrine (NE). Exposure of primary murine dermal microvascular endothelial cells (pDMECs) to NE followed by co‐culture with Langerhans cells (LCs), responsive CD4(+) T‐cells and antigen resulted in modulation of CD4(+) T‐cell responses. NE‐treatment of pDMECs induced increased production of interleukin (IL)‐6 and IL‐17A while down‐regulating interferon (IFN)‐γ and IL‐22 release. This effect did not require contact between pDMECs and LCs or T‐cells and depended upon pDMEC production of IL‐6. The presence of NE‐treated pDMECs increased the proportion of CD4(+) T‐cells expressing intracellular IL‐17A and increased IL‐17A mRNA while decreasing the proportion of IFN‐γ‐ or IL‐22‐expressing CD4(+) T‐cells and mRNA levels for those cytokines. Retinoic acid receptor‐related orphan receptor gamma (ROR‐ γt) mRNA was significantly increased in CD4(+) T‐cells while T‐box transcription factor (T‐bet) mRNA was decreased. Intradermal administration of NE prior to hapten immunization at the injection site produced a similar bias in draining lymph node CD4(+) T‐cells towards IL‐17A and away from IFN‐γ and IL‐22 production. Under stress, release of NE may have significant regulatory effects on the outcome of antigen presentation through actions on ECs with enhancement of inflammatory skin disorders involving IL‐17/T helper type 17 (Th17) cells.

Clandestine/hidden organizations are composed of groups of people who keep their affiliations secret and conceal internal and external organizational activities. Since the early 2000s, the prominence and notoriety of clandestine organizations have made them the subject of much discussion, debate, and research, although they have existed throughout human history. Three distinct communication characteristics that distinguish clandestine organizations from other types of collective organization create several theoretical, methodological, and ethical challenges for researchers. The increasing development and use of digital information technologies make the study of clandestine organizations both easier and more difficult. Keywords: clandestine organizations; dark web; hidden organizations; secret societies

Objective To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE). Methods Patients with moderate-to-severe SLE (score of ≥8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was the SLE Responder Index (SRI4) at week 52. Secondary end points were reduction in the corticosteroid dosage and time to severe flare. Safety was assessed according to the adverse events (AEs) reported and the laboratory test results. Results Of 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment. A total of 159 patients withdrew before the end of the study. At entry, mean SELENA–SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group. More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25–2.25]; P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35–0.74]; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40–52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95–2.84]; P = 0.0732), compared with placebo. AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo. A worsening of IgG hypoglobulinemia by ≥2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo. Conclusion In patients with moderate-to-severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.

Objective To determine the development of systemic lupus erythematosus (SLE) in NZM 2328 (NZM) mice deficient in 2 BAFF receptors. Methods NZM.BR-3(-/-) .BCMA(-/-) , NZM.BR-3(-/-) .TACI(-/-) , and NZM.BCMA(-/-) .TACI(-/-) mice were evaluated on the clinical, pathologic, serologic, and cellular levels. BAFF receptor expression and lymphocyte phenotype were assessed by flow cytometry, IgG-secreting cells by enzyme-linked immunospot assay, B cell responsiveness to BAFF and generation of Treg cells by in vitro culture, serum BAFF and total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, renal immunopathology by immunofluorescence and histologic analyses, and clinical disease by assessment of proteinuria and mortality. Results Renal immunopathology and clinical disease were attenuated in NZM.BR-3(-/-) .BCMA(-/-) and NZM.BR-3(-/-) .TACI(-/-) mice but were accelerated in NZM.BCMA(-/-) .TACI(-/-) mice. Accelerated disease was associated with increases in B cells, IgG-secreting cells, serum autoantibody levels, and T cells (especially CD4+ activated memory cells), whereas attenuated disease was associated with reductions in many of these parameters. Serum BAFF levels were increased in all double-deficient NZM mice. Exogenous BAFF promoted the in vitro survival of B cells from NZM.BCMA(-/-) .TACI(-/-) or NZM wild-type mice but not those from NZM.BR-3(-/-) .BCMA(-/-) or NZM.BR-3(-/-) .TACI(-/-) mice. In vitro generation of Treg cells was reduced in NZM.BCMA(-/-) .TACI(-/-) mice, but not in NZM.BR-3(-/-) .BCMA(-/-) or NZM.BR-3(-/-) .TACI(-/-) mice. Conclusion Elimination of B lymphocyte stimulator receptor 3 (BR-3) and TACI or BR-3 and BCMA inhibits the development of SLE in NZM mice. Selective targeting of BR-3 plus TACI or BR-3 plus BCMA may be an efficacious therapeutic approach in human SLE.

Objective The diagnosis of Sjogren's syndrome (SS) in routine practice is largely a clinical one and requires a high index of suspicion by the treating physician. This great dependence on clinical judgment frequently leads to delayed diagnosis or misdiagnosis. Tear protein profiles have been proposed as simple and reliable biomarkers for the diagnosis of SS. Given that cathepsin S activity is increased in the lacrimal glands and tears of NOD mice (a murine model of SS), the aim of this study was to explore the clinical utility of using tear cathepsin S (CTSS) activity as a biomarker for SS. Methods A method to measure CTSS activity in tears eluted from Schirmer's test strips was developed and validated. Schirmer's tests were performed and CTSS activity measurements were obtained in 278 female subjects, including 73 with SS, 79 with rheumatoid arthritis, 40 with systemic lupus erythematosus, 10 with blepharitis, 31 with nonspecific dry eye disease, and 12 with other autoimmune diseases, as well as 33 healthy control subjects. Results The median tear CTSS activity in patients with SS was 4.1-fold higher than that in patients with other autoimmune diseases, 2.1-fold higher than that in patients with nonspecific dry eye disease, and 41.1-fold higher than that in healthy control subjects. Tear CTSS levels were equally elevated in patients with primary SS and those with secondary SS, independent of the Schirmer's test strip values or the levels of circulating anti-SSA or anti-SSB antibodies. Conclusion Markedly high levels of tear CTSS activity are suggestive of SS. CTSS activity in tears can be measured in a simple, quick, economical, and noninvasive manner and may serve as a novel biomarker for autoimmune dacryoadenitis during the diagnostic evaluation for SS.

Objective Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. The aim of this study was to characterize B cell immunosuppression mediated by the Fc-engineered antibody, XmAb5871, which coengages FcγRIIb with the B cell antigen receptor (BCR) complex and that is currently in clinical development for the treatment of rheumatoid arthritis (RA). Because rheumatoid factor (RF) might interfere with the binding of XmAb5871 to FcγRIIb, we correlated RF titers with the potency of XmAb5871. Methods We analyzed the expression of CD19, FcγRIIb, and CD86 on naive and memory B cells from 50 patients with RA and 66 healthy donors, quantified XmAb5871-induced promotion of FcγRIIb phosphorylation and suppression of calcium flux in activated B cells, measured CD86 inhibition in whole blood, and correlated RF and anti−citrullinated protein antibody (ACPA) levels with drug potency. We engrafted RA peripheral blood mononuclear cells (PBMCs) into SCID mice, treated them with XmAb5871, and quantified human total IgG, total IgM, and anti-tetanus IgG antibody levels in vivo. Results B cells from all donors expressed CD19 and FcγRIIb, and the expression of FcγRIIb was higher on naive, but not memory, B cells from donors with RA compared with healthy donors. BCR-mediated calcium flux was suppressed by XmAb5871 and was associated with FcγRIIb phosphorylation. XmAb5871 inhibited CD86 induction, and the levels of RF and ACPAs did not affect efficacy. XmAb5871 suppressed B cell activation regardless of disease severity. In SCID mice engrafted with PBMCs from a patient with RA, XmAb5871 suppressed humoral responses. Conclusion Coengagement of the BCR complex and FcγRIIb by XmAb5871 inhibits B cell activation and function. The similar potency in patients with RA and healthy donors and the absence of autoantibody interference suggest that XmAb5871 may represent a new therapeutic strategy to suppress autoreactive B cells in RA.

Alcohol and nicotine are legal, readily available, and commonly used substances that contribute substantially to preventable morbidity and mortality worldwide (1–4). Alcohol and nicotine dependence are common disorders (5, 6) associated with elevated health risks (7, 8). While individuals who use alcohol or nicotine heavily for short periods face some increased risk, individuals with prolonged, heavy use face substantial risk (9, 10). Thus, identifying individuals at risk for persistent alcohol and nicotine dependence among those who experience these disorders has considerable public health importance. Many studies have addressed the course of substance use disorders among patients in treatment (11–17). However, patient studies may be biased by numerous confounds and selection factors (18, 19). To better understand the course of alcohol and nicotine dependence and its predictors, prospective epidemiological studies are useful (18). Researchers studying predictors of persistent substance disorders in large national samples have focused on demographic characteristics (20), psychiatric comorbidity (21, 22), and symptom severity and treatment (23). These all provide important information, but leave many other possible predictors unexplored. Childhood maltreatment is an important factor that may predict the persistence of alcohol and nicotine dependence. Childhood maltreatment refers to harm, neglect, or exploitation of children that may be physical, sexual, or emotional in nature (24). Nationally representative research suggests that nearly one third (30.1%) of the U.S. population is affected by physical, sexual, or emotional abuse, or physical or emotional neglect (25). Researchers have already found that childhood maltreatment predicts increased alcohol and nicotine use (26–29) and dependence symptoms (30, 31), as well as substance use problem severity (32–34). However, whether childhood maltreatment increases the risk for persistence of alcohol and nicotine dependence has not been studied, and chronologically distal risk factors for lifetime occurrence are not necessarily the same factors that predict disorder course once it has begun. One prior study assessed the influence of childhood maltreatment on the course of substance use; this case-control study found that childhood neglect (but not abuse) predicted course of illicit drug use over young and middle adulthood (35). However, no studies have assessed the effect of childhood maltreatment on course of dependence on the most widely used, licit substances: alcohol and nicotine. Given the impairment and consequences associated with longstanding dependence on these substances (6, 36), investigating whether childhood maltreatment predicts the persistence of alcohol and nicotine dependence in a large nationally representative sample of the general population would provide findings with important public health significance. Assessing a range of maltreatment experiences could help determine which specific experiences increase risk; controlling for exposure to other aspects of a difficult childhood (e.g., parental death or divorce) could clarify whether any significant maltreatment effects are simply due to a generally adverse childhood environment. The present study utilizes data from a large, nationally representative US prospective study, in which participants were assessed at two waves, three years apart. First, we provide descriptive information on childhood physical, sexual, and emotional abuse, and physical and emotional neglect, among individuals with baseline alcohol and nicotine dependence, and among those with persistent disorders. Second, we assess the relationship between these five types of childhood maltreatment and the persistence of alcohol and nicotine dependence among those with baseline diagnoses. We conduct these analyses with and without control for other adverse childhood events, to determine whether significant associations are simply the result of a generally difficult childhood. Third, we assess which maltreatment types remain significant when all maltreatment types are considered together, to determine unique effects. Finally, we assess whether experiencing a greater number of types of childhood maltreatment incrementally influences the risk for persistent alcohol and nicotine dependence.

Objective To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE). Methods Bcma-, Taci-, and Br3-null mutations were introgressed into NZM 2328 mice. NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry; for B cell responsiveness to BAFF by in vitro culture; for serum levels of BAFF and total IgG and IgG anti–double-stranded DNA (anti-dsDNA) by enzyme-linked immunosorbent assay; for renal immunopathology by immunofluorescence and histopathology; and for clinical disease. Results BCMA, TACI, and B lymphocyte stimulator receptor 3 (BR3) were not surface-expressed in NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice, respectively. Transitional and follicular B cells from NZM.Br3−/− mice were much less responsive to BAFF than were the corresponding cells from wild-type, NZM.Bcma−/−, or NZM.Taci−/− mice. In comparison with wild-type mice, NZM.Bcma−/− and NZM.Taci−/− mice harbored an increased number of spleen B cells, T cells, and plasma cells, whereas serum levels of total IgG and IgG anti-dsDNA were similar to those in wild-type mice. Despite their paucity of B cells, NZM.Br3−/− mice had an increased number of T cells, and the numbers of plasma cells and levels of IgG anti-dsDNA were similar to those in wild-type mice. Serum levels of BAFF were increased in NZM.Taci−/− and NZM.Br3−/− mice but were decreased in NZM.Bcma−/− mice. Despite their phenotypic differences, NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice had renal immunopathology and clinical disease that were at least as severe as that in wild-type mice. Conclusion Any single BAFF receptor, including BR3, is dispensable for the development of SLE in NZM mice. Development of disease in NZM.Br3−/− mice demonstrates that BAFF–BCMA and/or BAFF–TACI interactions contribute to SLE, and that a profound, life-long reduction in the numbers of B cells does not guarantee protection against SLE.

Objective To assess racial/ethnic differences in the use of biologic disease-modifying antirheumatic drugs (DMARDs) among California Medicaid (Medi-Cal) rheumatoid arthritis (RA) patients. Methods Medi-Cal patient level data for 5,385 DMARD recipients between ages 18 and 100 years with at least 1 diagnosis of RA (International Classification of Disease, Ninth Revision, Clinical Modification code 714.xx) and the use of 1 DMARD between January 1, 1998 and December 31, 2005 were collected. The outcome of interest was the choice of either standard DMARDs (methotrexate, lefluonomide, hydroxychloroquine, and sulfasalazine) or biologic DMARDs (adalimumab, etanercept, anakinra, and infliximab). A univariate analysis and logistic regression model were applied to examine the association of the choice of DMARD among different racial/ethnic groups. Results In the univariate analysis, biologic DMARD use was significantly associated with race/ethnicity (P < 0.001). In the multivariate logistic regression model, after adjusting for age, sex, insurance coverage, 12 comorbid conditions, RA-related drug prescription, RA-related inpatient stay, and rehabilitation visits, African Americans had 53% lower odds of receiving biologic DMARDs as compared to whites, whereas Hispanics had 36% increased odds of receiving biologic DMARDs as compared to whites. Conclusion In this Medi-Cal population, with its racial diversity and relatively homogenous socioeconomic status and health care benefits, racial/ethnic differences were found in RA patients receiving biologic DMARDs.

Isoprenylcysteine (IPC) molecules modulate G-protein-coupled receptor signalling. The archetype of this class is N-acetyl-S-farnesyl-l-cysteine (AFC). Topical application of AFC locally inhibits skin inflammation and elicitation of contact hypersensitivity in vivo. However, the mechanism of these anti-inflammatory effects is not well understood. Dermal microvascular endothelial cells (ECs) are involved in inflammation, in part, by secreting cytokines that recruit inflammatory cells. We have previously shown that the sympathetic nerve cotransmitter adenosine-5'-triphosphate (ATP) and adenosine-5'-O-(3-thio) triphosphate (ATPγS), an ATP analogue that is resistant to hydrolysis, increase secretion of the chemokines CXCL8 (interleukin-8), CCL2 (monocyte chemotactic protein-1) and CXCL1 (growth-regulated oncogene α) by dermal microvascular ECs. Production of these chemokines can also be induced by the exposure to the proinflammatory cytokine TNFα. We have now demonstrated that AFC dose-dependently inhibits ATP-, ATPγS- and TNFα-induced production of CXCL1, CXCL8 and CCL2 by a human dermal microvascular EC line (HMEC-1) in vitro under conditions that do not affect cell viability. Inhibition of ATPγS- or TNFα-stimulated release of these chemokines was associated with reduced mRNA levels. N-acetyl-S-geranyl-l-cysteine, an IPC analogue that is inactive in inhibiting G-protein-coupled signalling, had greatly reduced ability to suppress stimulated chemokine production. AFC may exert its anti-inflammatory effects through the inhibition of chemokine production by stimulated ECs.

SUMMARY In health care, decision makers are generally interested in simultaneous comparisons among multiple treatments or interventions available as treatment choices in real-world clinical setting. The lack of random assignment to treatment in real-world clinical settings leads to selection-bias issues when evaluating the marginal benefits of treatment. The application of instrumental variables (IV) estimation to mitigate selection bias has traditionally been limited to comparing only two treatments/interventions concurrently. Using the case of biologic treatment in rheumatoid arthritis, we describe a generalized method of moments (GMM)–based panel data IV (IV-GMM) framework, to simultaneously estimate multiple treatment effects in the presence of time-varying selection bias and time-invariant heterogeneity. To satisfy the order and rank conditions for identification with multiple endogeneity, we propose lagged values of each treatment as excluded instruments. We evaluate the validity of the IV estimation assumptions on instrument relevance and exogeneity. Results indicate that the IV-GMM model offers enhanced control over selection bias and heterogeneity, and more importantly the panel data framework can provide valid excluded instruments that satisfy the order and rank conditions for identification when dealing with multiple endogenous variables. The approach outlined in this article has broad application for comparative effectiveness and health technology assessment involving multiple treatments/interventions using real-world nonexperimental data. Copyright © 2012 John Wiley & Sons, Ltd.

Objective To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice. Methods Wild-type (WT) NZM 2328, NZM. April–/–, NZM.Baff–/–, and NZM.Baff–/–.April–/– mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, for glomerular deposition of IgG and C3 by immunofluorescence, for renal changes by histopathology, and for clinical disease by laboratory assessment (severe proteinuria). Results In comparison to WT mice, NZM.April–/– mice harbored increased spleen B cells, T cells, and plasma cells (PCs), increased serum levels of IgG antichromatin antibodies, and decreased numbers of bone marrow (BM) PCs. Glomerular deposition of IgG and C3 was similar in NZM.April–/– mice and WT mice, renal changes on histopathology tended to be more severe in NZM.April–/– mice than in WT mice, and development of clinical disease was identical in NZM.April–/– mice and WT mice. BM (but not spleen) PCs and serum IgG antichromatin and anti–double-stranded DNA antibody levels were lower in NZM.Baff–/–.April–/– mice than in NZM.Baff–/– mice, whereas renal immunopathology in each cohort was equally mild. Conclusion APRIL is dispensable for the development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF had no discernible effect on the development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PCs in hosts doubly deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without a concomitant increase in therapeutic efficacy.

Epidermal Langerhans cells (LCs) are dendritic APCs that play an important role in cutaneous immune responses. LCs are associated with epidermal nerves and the neuropeptides vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) inhibit LC Ag presentation for Th1-type immune responses. Here, we examined whether PACAP or VIP modulates LC Ag presentation for induction of IL-17A-producing CD4+ T cells. Treatment with VIP or PACAP prior to in vitro LC Ag presentation to CD4+ T cells enhanced IL-17A, IL-6, and IL-4 production, decreased interferon (IFN)-γ and interleukin (IL)-22 release, and increased RORγt and Gata3 mRNA expression while decreasing T-bet expression. The CD4+ T-cell population was increased in IL-17A- and IL-4-expressing cells and decreased in IFN-γ-expressing cells. Addition of anti-IL-6 mAb blocked the enhanced IL-17A production seen with LC preexposure to VIP or PACAP. Intradermal administration of VIP or PACAP prior to application of a contact sensitizer at the injection site, followed by harvesting of draining lymph node CD4+ T cells and stimulation with anti-CD3/anti-CD28 mAbs, enhanced IL-17A and IL-4 production but reduced production of IL-22 and IFN-γ. PACAP and VIP are endogenous mediators that likely regulate immunity and immune-mediated diseases within the skin.

Neisseria gonorrhoeae is a human-specific organism that is not usually exposed to UV light or chemicals but is likely to encounter reactive oxygen species during infection. Exposure of N. gonorrhoeae to sublethal hydrogen peroxide revealed that the ng1427 gene was upregulated sixfold. N. gonorrhoeae was thought to lack an SOS system, although NG1427 shows amino acid sequence similarity to the SOS response regulator LexA from Escherichia coli. Similar to LexA and other S24 peptidases, NG1427 undergoes autoproteolysis in vitro, which is facilitated by either the gonococcal or E. coli RecA proteins or high pH, and autoproteolysis requires the active and cleavage site residues conserved between LexA and NG1427. NG1427 controls a three gene regulon: itself; ng1428, a Neisseria-specific, putative integral membrane protein; and recN, a DNA repair gene known to be required for oxidative damage survival. Full NG1427 regulon de-repression requires RecA following methyl methanesulphonate or mitomycin C treatment, but is largely RecA-independent following hydrogen peroxide treatment. NG1427 binds specifically to the operator regions of the genes it controls, and DNA binding is abolished by oxidation of the single cysteine residue encoded in NG1427. We propose that NG1427 is inactivated independently of RecA by oxidation.

Summary Neisseria gonorrhoeae (Gc) is an obligate human pathogen and the causative agent of the sexually transmitted infection, gonorrhoea. Despite the fact that the gonococcus is not normally exposed to UV irradiation or visible light, the bacterium expresses a phrB orthologue, which in other organisms encodes a DNA photolyase that repairs UV-induced pyrimidine dimers with energy provided by visible light. We show that a Gc phrB mutant is not more sensitive to UV irradiation, independent of visible light exposure, and that the Gc phrB cannot complement an Escherichia coli phrB mutant strain. The Gc phrB mutant had a reduced colony size that was not a result of a growth defect and the mutant cells exhibited an altered morphology. Although the phrB mutant exhibited increased sensitivity to oxidative killing; it showed increased survival on media containing nalidixic acid or rifampicin, but did not have an increased mutation rate to these antibiotics or spectinomycin and kasugamycin. The Gc phrB mutant showed increased negative DNA supercoiling, but while the protein bound double-stranded DNA, it did not express topoisomerase activity. We conclude that the Gc PhrB has a previously unrecognized role in maintaining DNA supercoiling that is important for normal cell physiology.

Objective To determine whether overexpression of BAFF can promote systemic lupus erythematosus (SLE)–like autoimmunity in mice that are otherwise autoimmune-resistant. Methods We used class II major histocompatibility complex (MHC)–deficient C57BL/6 (B6) mice as a model of resistance to SLE and Sles1-bearing B6 mice as a model of resistance to the autoantibody-promoting capacity of the Sle1 region. We generated BAFF-transgenic (Tg) counterparts to these respective mice and evaluated lymphocyte phenotype, serologic autoimmunity, renal immunopathology, and clinical disease in the BAFF-Tg and non-Tg mouse sets. Results Although constitutive BAFF overexpression did not lead to B cell expansion in class II MHC–deficient B6 mice, it did lead to increased serum IgG autoantibody levels. Nevertheless, renal immunopathology was limited, and clinical disease did not develop. In B6 and B6.Sle1 mice, constitutive BAFF overexpression led to increased numbers of B cells and CD4+ memory cells, as well as increased serum IgG and IgA autoantibody levels. Renal immunopathology was modestly greater in BAFF-Tg mice than in their non-Tg counterparts, but again, clinical disease did not develop. Introduction of the Sles1 region into B6.Sle1.Baff mice abrogated the BAFF-driven increase in CD4+ memory cells and the Sle1-driven, but not the BAFF-driven, increase in serum IgG antichromatin levels. Renal immunopathology was substantially ameliorated. Conclusion Although constitutive BAFF overexpression in otherwise autoimmune-resistant mice led to humoral autoimmunity, meaningful renal immunopathology and clinical disease did not develop. This raises the possibility that BAFF overexpression, even when present, may not necessarily drive disease in some SLE patients. This may help explain the heterogeneity of the clinical response to BAFF antagonists in human SLE.

Objective Despite substantial clinical efficacy of tumor necrosis factor-α (TNF)-antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict response to TNF-antagonist therapy.

Objective To describe a new systemic lupus erythematosus (SLE) Responder Index (SRI) based on the belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials.