BLyS Levels Research Articles

Definition of follicular helper T cell and cytokines expression in synovial fluid of rheumatoid arthritis.

This study aimed to assess the role of synovial fluid (SF) CD4+T, CD19+B, follicular helper cells (Tfh), and cytokines in the pathogenesis of rheumatoid arthritis (RA). This study enrolled 16 patients with RA and 8 patients with osteoarthritis (OA). The frequencies of the SF CD4+ T, CD19+ B, Tfh cells, and Tfh subsets were assessed using flow cytometry. The medical condition in patients with RA was evaluated using The Disease Activity Score 28 (DAS28), the Clinical Disease Activity Index (CDAI), and the Simplified Disease Activity Index (SDAI). Levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF) were measured. The cytokines IL-4, IL-13, IL-21, and BLyS were measured by ELISA test. The percentages of SF CD4+T, CD19+B, and PD-1+CXCR5+ Tfh in RA patients were higher than those in OA patients. And the Tfh2 was the main subset among Tfh subsets. In addition, levels of IL-21 and BLyS were higher in patients with RA compared to patients with OA. Furthermore, the treatment of TNF-α inhibitors may be associated with decreased levels of SF Tfh. Elevated SF Tfh, B cell, and cytokines expression profiles were observed in RA patients. Tfh2 was the major subset of the Tfh, and IL-21 and BLyS were significantly enhanced. Additionally, TNF-α inhibitors reduced Tfh in SF. Therefore, Tfh, B, and Tfh2 cells could play a significant role in the progression of RA. Key Points •Tfh cells in the synovial fluid are significantly higher in RA patients and are dominated by the Tfh2 subpopulation. •Synovial fluid Tfh cells decrease in RA patients after anti-TNF-α treatment.

Berberine might block colorectal carcinogenesis by inhibiting the regulation of B-cell function by Veillonella parvula.

Colorectal carcinogenesis and progression are related to the gut microbiota and the tumor immune microenvironment. Our previous clinical trial demonstrated that berberine (BBR) hydrochloride might reduce the recurrence and canceration of colorectal adenoma (CRA). The present study aimed to further explore the mechanism of BBR in preventing colorectal cancer (CRC). We performed metagenomics sequencing on fecal specimens obtained from the BBR intervention trial, and the differential bacteria before and after medication were validated using quantitative polymerase chain reaction. We further performed ApcMin/+ animal intervention tests, RNA sequencing, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assays. The abundance of fecal Veillonella parvula ( V . parvula ) decreased significantly after BBR administration ( P = 0.0016) and increased through the development from CRA to CRC. Patients with CRC with a higher V. parvula abundance had worse tumor staging and a higher lymph node metastasis rate. The intestinal immune pathway of Immunoglobulin A production was activated, and the expression of TNFSF13B (Tumor necrosis factor superfamily 13b, encoding B lymphocyte stimulator [BLyS]), the representative gene of this pathway, and the genes encoding its receptors (interleukin-10 and transforming growth factor beta) were significantly upregulated. Animal experiments revealed that V. parvula promoted colorectal carcinogenesis and increased BLyS levels, while BBR reversed this effect. BBR might inhibit V. parvula and further weaken the immunomodulatory effect of B cells induced by V. parvula , thereby blocking the development of colorectal tumors. ClinicalTrials.gov, No. NCT02226185.

Pre-Clinical Autoimmunity in Lupus Relatives: Self-Reported Questionnaires and Immune Dysregulation Distinguish Relatives Who Develop Incomplete or Classified Lupus From Clinically Unaffected Relatives and Unaffected, Unrelated Individuals.

Systemic lupus erythematosus (SLE) is propelled by pathogenic autoantibody (AutoAb) and immune pathway dysregulation. Identifying populations at risk of reaching classified SLE is essential to curtail inflammatory damage. Lupus blood relatives (Rel) have an increased risk of developing SLE. We tested factors to identify Rel at risk of developing incomplete lupus (ILE) or classified SLE vs. clinically unaffected Rel and healthy controls (HC), drawing from two unique, well characterized lupus cohorts, the lupus autoimmunity in relatives (LAUREL) follow-up cohort, consisting of Rel meeting <4 ACR criteria at baseline, and the Lupus Family Registry and Repository (LFRR), made up of SLE patients, lupus Rel, and HC. Medical record review determined ACR SLE classification criteria; study participants completed the SLE portion of the connective tissue disease questionnaire (SLE-CSQ), type 2 symptom questions, and provided samples for assessment of serum SLE-associated AutoAb specificities and 52 plasma immune mediators. Elevated SLE-CSQ scores were associated with type 2 symptoms, ACR scores, and serology in both cohorts. Fatigue at BL was associated with transition to classified SLE in the LAUREL cohort (p≤0.01). Increased levels of BLyS and decreased levels of IL-10 were associated with type 2 symptoms (p<0.05). SLE-CSQ scores, ACR scores, and accumulated AutoAb specificities correlated with levels of multiple inflammatory immune mediators (p<0.05), including BLyS, IL-2Rα, stem cell factor (SCF), soluble TNF receptors, and Th-1 type mediators and chemokines. Transition to SLE was associated with increased levels of SCF (p<0.05). ILE Rel also had increased levels of TNF-α and IFN-γ, offset by increased levels of regulatory IL-10 and TGF-β (p<0.05). Clinically unaffected Rel (vs. HC) had higher SLE-CSQ scores (p<0.001), increased serology (p<0.05), and increased inflammatory mediator levels, offset by increased IL-10 and TGF-β (p<0.01). These findings suggest that Rel at highest risk of transitioning to classified SLE have increased inflammation coupled with decreased regulatory mediators. In contrast, clinically unaffected Rel and Rel with ILE demonstrate increased inflammation offset with increased immune regulation, intimating a window of opportunity for early intervention and enrollment in prevention trials.

The potential use of serum interleukin-21 as biomarker for lupus nephritis activity compared to cytokines of the tumor necrosis factor (TNF) family.

Lupus nephritis (LN) is a significant consequence of systemic lupus erythematosus (SLE). To the best of our knowledge, this is the first work that focuses on evaluation of serum interleukin (IL-) 21 as a diagnostic biomarker of LN activity, compared to B lymphocyte stimulator (BlyS), tumor necrosis factor ligand superfamily member 13 (TNF-SF13), and traditional techniques of active LN attempting to compare their diagnostic usefulness. Serum levels of IL-21, BlyS, and TNF-SF13 during LN were investigated. Twenty-five biopsy-proven, active LN female patients and 15 SLE patients without active LN and 20 healthy controls (HCs) joined this work. Serum IL-21 level was significantly higher in active LN group than in inactive LN group. Correlation analysis showed that serum IL-21 levels were significantly correlated with total SLEDAI (r = 0.41, p = 0.03), renal-SLEDAI (r = 0.48, p = 0.04), renal activity index (AI) (r = 0.93; p < 0.001), and 24-h proteinuria (r = 0.51; p > 0.008). Receiver operating characteristic curve (ROC) revealed the ability of serum IL-21 to discriminate between active and inactive LN with 70% sensitivity at >240pg/ml cutoff point (AUC 0.809). For Egyptian SLE patients, serum levels of IL-21 were superior to TNF-SF13 and BlyS and correlated significantly with the activity indexes of LN, indicating a promising role as a potential biomarker of active LN.

Associations Between Smoking and Systemic Lupus Erythematosus-Related Cytokines and Chemokines Among US Female Nurses.

Smoking has been associated with increased systemic lupus erythematosus (SLE) risk, but the biologic basis for this association is unknown. Our objective was to investigate whether women's smoking was positively associated with SLE-associated proinflammatory chemokines/cytokines (stem cell factor [SCF], B lymphocyte stimulator [BLyS], interferon-γ-inducible 10-kd protein [IP-10], and interferon-α); or negatively associated with antiinflammatory cytokine interleukin-10 (IL-10); and whether associations were modified by SLE-related autoantibody status. The Nurses' Health Study (NHS, n = 121,700) and NHSII (n = 116,429) cohorts were begun in 1976 and 1989. In 1988-1990 (NHS) and 1996-1999 (NHSII), ~25% of participants donated blood samples. We identified 1,177 women without SLE with banked samples, and we tested by enzyme-linked immunoassay (ELISA) for chemokines/cytokines as well as anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP. Antinuclear antibodies (ANAs) were detected by HEp-2 cell indirect immunofluorescence, and anti-double-stranded DNA antibodies and were assayed by ELISA. Smoking was assessed until blood draw. Separate tobit and linear regression analyses, adjusted for potential confounders, modeled associations between smoking and log-transformed chemokine/cytokine concentrations. Analyses were stratified by autoantibody status. Effect estimates were calculated as ratios of geometric means expressed as percentage differences. Among the 15% of current/recent versus 85% of past/never smokers, BLyS levels were 8.7% higher (P < 0.01) and were 24% higher (P < 0.0001) among those who were ANA positive. Current/recent smokers had IL-10 concentrations 46% lower (P < 0.01) than past/never smokers; each 10 pack-years of smoking was associated with a 17% decrease in IL-10 level (P < 0.001). Smoking was not associated with IP-10 or SCF. Elevated BLyS and lower IL-10 levels among current smokers, particularly among ANA-positive women, may be involved in SLE pathogenesis.

Caffeine intake influences disease activity and clinical phenotype in systemic lupus erythematosus patients.

Caffeine, one of the most widely consumed products in the world, seems to interact with multiple components of the immune system by acting as a non-specific phosphodiesterase inhibitor. In vitro dose-dependent treatment with caffeine down-regulates mRNA levels of key inflammation-related genes in peripheral blood mononuclear cells. So far, no robust data are available about the possible contribution of caffeine in systemic lupus erythematosus (SLE). The aim of this study was to evaluate the impact of caffeine consumption on SLE-related disease phenotype and activity, in terms of clinimetric assessment and cytokine serum levels. We performed a cross-sectional study, enrolling consecutive patients and reporting their clinical and laboratory data. Disease activity was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K). Caffeine intake was evaluated by a 7-day food frequency questionnaire, including all the main sources of caffeine. As previously reported, patients were divided into four groups according to the daily caffeine intake: <29.1 mg/day (group 1), 29.2-153.7 mg/day (group 2), 153.8-376.5 mg/day (group 3) and >376.6 mg/day (group 4). At the end of questionnaire filling, blood samples were collected from each patient to assess cytokine levels. These were assessed by using a panel by Bio-Plex assays to measure the levels of IL-6, IL-10, IL-17, IL-27, IFNγ, IFNα and BLyS. We enrolled 89 consecutive SLE patients. We observed a negative correlation between caffeine consumption and disease activity, measured with SLEDAI-2K. A significantly higher prevalence of lupus nephritis, neuropsychiatric involvement, haematological manifestations, hypocomplementaemia and anti-dsDNA positivity was observed in patients with a low intake of caffeine. Furthermore, patients with a low intake of caffeine were more frequently treated with glucocorticoids. Regarding cytokine analysis, a negative correlation between daily caffeine consumption and serum level of IFNγ was found (p = 0.03, r = -0.2); furthermore, patients with a high intake of caffeine showed lower serum levels of IFNα (p = 0.02), IL-17 (p = 0.01) and IL-6 (p = 0.003). In this report we demonstrated the impact of caffeine on SLE disease activity status, as confirmed by the inverse correlation between its intake and both SLEDAI-2K values and cytokine levels. Moreover, patients with a low caffeine consumption seem to have a more severe disease phenotype.

MO039THE 24-WEEK INTERIM ANALYSIS RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II STUDY OF ATACICEPT IN PATIENTS WITH IGA NEPHROPATHY AND PERSISTENT PROTEINURIA

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Despite being described over 50 years ago, there remains no approved therapy for this common global cause of kidney failure. The central pathogenic feature in IgAN is the formation of circulating IgA containing immune complexes which have the propensity to deposit in the kidneys and trigger glomerular inflammation and tubulointerstitial scarring. The primary substrate for immune complex formation is an excess of poorly O-galactosylated polymeric IgA1 (Gd-IgA1) in the circulation. These IgA1 O-glycoforms are thought to trigger the formation of IgA and IgG autoantibodies. Atacicept is a human TACI-Ig fusion protein that inhibits B cell-stimulating factors, BLyS and APRIL, and has been associated with reductions in levels of serum IgA and IgG, as well as reductions in mature B cells and plasma cells. A number of studies have shown elevated levels of BLyS, APRIL and Gd-IgA1 in IgAN patients which have been linked to worse clinical outcomes. IgAN patients with persistent proteinuria &amp;gt;1 g/day are at increased risk of progression to end-stage renal disease. This Phase II study examines the safety and efficacy of atacicept in reducing pathogenic Gd-IgA1 levels and measures of renal activity in IgAN. Method This Phase II study (NCT02808429) enrolled patients with IgAN and proteinuria ≥1 g/day or 0.75 mg/mg on 24-hour urine protein-creatinine ratio (UPCR) despite maximal standard of care therapy (angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker). Enrolled patients were randomized 1:1:1 to receive placebo or atacicept 25mg or 75mg once weekly by subcutaneous injection. The primary endpoint was a change in proteinuria by 24-hour UPCR at Week 48; key secondary endpoints included change in eGFR, serum immunoglobulin and Gd-IgA1 levels. Results Data from the 24-week interim analysis are reported here for enrolled patients (placebo=5; atacicept 25mg=6; atacicept 75mg=5). A consistent, dose-dependent reduction in serum immunoglobulins (IgA, IgG and IgM) and, in particular, Gd-IgA1 (Figure) were observed through Week 24. In parallel, proteinuria (24-hour UPCR) showed a higher median % reduction from baseline with atacicept at Week 24: -18.67% and -25.34% with atacicept 25 mg and 75 mg, respectively, vs +0.098% with placebo (Figure). eGFR remained stable over time. TEAEs were reported by 81% of the subjects. TEAEs were mild or moderate in severity, with no severe TEAEs reported. No serious related events, events with severe hypogammaglobulinemia or fatal outcome were reported. Conclusion These 24-week interim analysis results provide early proof of concept for the potential treatment of atacicept in patients with IgAN and persistent proteinuria.

Increased interferon-1α, interleukin-10 and BLyS concentrations as clinical activity biomarkers in systemic lupus erythematosus

Background and objectiveTo analyse the association between interferon-1α (INF1α), interleukin-10 (IL-10) and BLyS concentrations and clinical activity in systemic lupus erythematosus (SLE). Patients and methodsA cross-sectional, observational study of 142 SLE patients and 34 healthy controls was performed, through a complete blood and urine test and review of their medical history. Serum concentration of INF1α, IL-10 and BLyS was determined by colorimetric methods. A biostatistical analysis was performed with R (3.3.2). Results69% of our SLE patients showed at least one cytokine increased. INF1α, IL-10 and BLyS are higher in SLE patients than in healthy controls (p<0.001, p=0.005 and p=.043, respectively), being INF1α the most frequent. Patients were categorised according to low or high concentrations of the three cytokines. We found a significant association between increased IL-10/INF1α concentrations and a higher clinical activity measured by SELENA-SLEDAI (p<0.0001) and, to a lesser extent, an association with increased INF1α/IL-10/BLyS concentrations. Elevated levels of IL-10/INF1α and INF1α/IL-10/BLyS related to increased C3-C4 consumption (p<0.001 and p=0.001, respectively) and anti-dsDNA titres (p=0.001 and p=0.002, respectively). Elevated INF1α/BLyS related to higher anti-dsDNA titres (p=0.004) and ENA positivity (p<0.001). Increased levels of INF1α/IL-10/BLyS related to positivity of ANAs (p<0.001) and APL (p=0.004). ConclusionsINF1α, IL-10 and BLyS are higher in SLE patients than in healthy controls. Increased IL-10 levels, regardless of whether or not there were also increased levels of BLyS and/or INF1α, was the cytokine that best fit with clinical activity in SLE measured with classic methods.

Association Between Changes in BLyS Levels and the Composition of B and T Cell Compartments in Patients With Refractory Systemic Lupus Erythematosus Treated With Belimumab.

Introduction: Belimumab is a monoclonal antibody against soluble BLyS used for treatment of refractory Systemic Lupus Erythematosus (SLE). Although B cells are the main target of this therapy, a BLyS-dependent T cell activation pathway has also been demonstrated. The aim of the study is to analyze B and T cells phenotype modifications in a cohort of SLE patients treated with belimumab in correlation with serum BLyS levels.Materials and Methods: Fourteen SLE patients were enrolled in the study. Lymphocyte immunophenotyping by flow cytometry and determination of serum BLyS levels by high sensitivity ELISA were performed before the first infusion of belimumab, after 6 and 12 months of treatment. Sex and age-matched healthy controls were enrolled for the comparisons.Results: Baseline number of total B cells, especially switched memory B cells, were lower in SLE patients compared to control subjects. After 6 months of treatment, the total number of B cells, particularly, naive and transitional B cells, was significantly reduced in correlation with the reduction of BLyS levels. No significant association was found between baseline counts of B cells and reduction of SLEDAI-2K over time. In terms of response prediction, a significant association between SLEDAI-2K improvement at 12 months and the decrease of total number of B cells within the first 6 months of therapy was observed. Concerning the T cell compartment, the baseline percentage number of CD8+ effector memory was associated with SLEDAI-2K at baseline and with its improvement after 12 months of therapy. Furthermore, T cell lymphopenia and low number of circulating recent thymic emigrants were also observed compared to control subjects measured at baseline.Discussion: The effects of belimumab on B cell subpopulations could be explained by the direct blockage of soluble BLyS, while the mild effects on T cells might be explained indirectly by the reduction of disease activity by means of therapy. B cell immunophenotyping during belimumab might be useful for monitoring the response to treatment.

Aumento de las concentraciones de interferón-1α, interleucina-10 y BLyS como biomarcadores de actividad clínica en el lupus eritematoso sistémico

Background and objectiveto analyse the association between interferon-1α (INF1α), interleukin-10 (IL-10) and BLyS concentrations and clinical activity in systemic lupus erythematosus (SLE). Patients and methodsA cross-sectional, observational study of 142 SLE patients and 34 healthy controls was performed, through a complete blood and urine test and review of their medical history. Serum concentration of INF1α, IL-10 and BLyS was determined by colorimetric methods. A biostatistical analysis was performed with R (3.3.2.). Results69% of our SLE patients showed at least one cytokine increased. INF1α, IL-10 and BLyS are higher in SLE patients than in healthy controls (P<.001, P=.005 and P=.043, respectively), being INF1α the most frequent. Patients were categorised according to low or high concentrations of the three cytokines. We found a significant association between increased IL-10/INF1α concentrations and a higher clinical activity measured by SELENA-SLEDAI (P<.0001) and, to a lesser extent, an association with increased INF1α/IL-10/BLyS concentrations. Elevated levels of IL-10/INF1α and INF1α/IL-10/BLyS related to increased C3-C4 consumption (P<.001 and P=.001 respectively) and anti-dsDNA titres (P=.001 and P=.002 respectively). Elevated INF1α/BLyS related to higher anti-dsDNA titres (P=.004) and ENA positivity (P<.001). Increased levels of INF1α/IL-10/BLyS related to positivity of ANAs (P<.001) and APL (P=.004). ConclusionsINF1α, IL-10 and BLyS are higher in SLE patients than in healthy controls. Increased IL-10 levels, regardless of whether or not there were also increased levels of BLyS and/or INF1α, was the cytokine that best fit with clinical activity in SLE measured with classic methods.

The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus

ObjectiveIn systemic lupus erythematosus (SLE) patients, excessive formation of neutrophil extracellular traps (NETs) is observed and their degradation is impaired. In vitro, immune complexes (ICx) trigger NET formation while NET-derived DNA is a postulated autoantigen for anti-nuclear autoantibodies (ANAs), found in SLE. Based on these self-perpetuating mechanisms in SLE, this study investigates whether interfering with ICx formation using a combination of rituximab (RTX) and belimumab (BLM) could decrease NET formation and ameliorate disease. MethodsA phase 2A, open-label, single arm proof-of-concept study was performed wherein 16 SLE patients with severe, refractory disease were treated with a combination of CD20-mediated B-cell depletion with rituximab and sustained inhibition of B-cell activating factor BlyS with belimumab. Besides safety, the study's endpoints were chosen to address the concept of autoantibodies in relation to excessive NET formation. ResultsWe demonstrated a surge of BlyS levels upon RTX-mediated B-cell depletion which was abrogated by subsequent BLM treatment. As such, therapeutic intervention with RTX + BLM led to specific reductions in ANAs and regression of excessive NET formation. RTX + BLM appeared to be safe and achieved clinically significant responses: low lupus disease activity state was achieved in 10 patients, renal responses in 11 patients and concomitant immunosuppressive medication was tapered in 14 out of the 16 patients. ConclusionsThis study provides novel insights into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX + BLM. Altogether putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology. Trial registrationClinicalTrials.gov NCT02284984.

B-lymphocyte stimulator: can we consider it a marker for severity of hepatitis C virus-induced B-cell non-Hodgkin lymphoma?

ObjectiveB-lymphocyte stimulator (BLyS) is a member of tumor necrosis factor family. BLyS is essential for the survival of normal and malignant B lymphocyte. Hepatitis C virus (HCV) infection likely represents the early event leading to BLyS upregulation. The aim of this study was to determine the relation between serum BLyS levels and the severity of HCV-related B-cell non-Hodgkin lymphoma (B-NHL).Patients and methodsSeventy-eight B-NHL patients both HCV-positive and HCV-negative and 20 patients with HCV infection without lymphoproliferative disorders, in addition to 20 age-matched and sex-matched controls, were included in the study. PCR for HCV, evaluation of levels of soluble BLyS protein in blood, bone marrow aspirate and biopsy with flow cytometry, and lymph node biopsy with immunophenotyping for CD5, CD23, CD10, CD20, and cyclinD1 were performed.ResultsThe serum BLyS levels were significantly higher in B-NHL patients and HCV patients without lymphoproliferative disorders compared with the control group. The serum BLyS levels were statistically significantly higher in aggressive lymphoma patients with HCV-positive infection compared with aggressive lymphoma patients with HCV-negative infection, but there was no statistically significant difference between BLyS levels in indolent B-NHL patients with or without HCV infections. Moreover, there was no statistically significant difference between BLyS levels in aggressive and indolent lymphoma patients with HCV-positive infection.ConclusionBLyS levels are increased in HCV-induced B-NHL but it cannot be considered as a marker for severity of the disease (indolent or aggressive). More studies are needed.

Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis

BackgroundThe aim was to investigate CD4+T-cell subsets, immune cells and their cytokine profiles in blood and synovial compartments in rheumatoid arthritis (RA) and inflammatory osteoarthritis (OA) to define specific immune signatures.MethodsPeripheral blood, synovial fluid (SF) and synovial membranes (SM) of RA and OA patients were analyzed. CD4+T-cell subset frequencies were determined by flow cytometry, and cytokine concentrations in serum and SF were measured by ELISA.ResultsIn peripheral blood, OA patients had altered frequencies of regulatory T-cell subsets, and higher frequencies of Th17 and of Th1/17 cells than RA patients. In the synovial compartment of OA patients, conventional Th17 cells were largely excluded, while Th1/17 cells were enriched and more frequent than in RA patients. Conversely, in the synovial compartment of RA patients, regulatory T cells and Tfh cells were enriched and more frequent then in OA patients. IL-17 and Blys were increased both in serum and SF of RA patients, and correlated with autoantibodies and disease activity. Notably, Blys levels were already significantly elevated in RA patients with low disease activity score in 28 joints (DAS28) and without autoantibody positivity.ConclusionsAlthough patients with inflammatory OA have immune activation in the synovial compartment, they display different T-cell subset frequencies and cytokine profiles. Soluble mediators such as Blys might help to discriminate mild clinical forms of RA from inflammatory OA particularly at the onset of the disease.

Abnormal Expression and Clinical Significance of B Lymphocyte Stimulating Factor in B Cell-derived Malignant Hematologic Diseases

To explore the expression and clinical significance of B cell lymphocyte stimulating factor (BLyS) in B cell-derived malignant hematological diseases. Fifty-seven cases of newly diagnosed B cell-derived hematologic malignancies were admitted and treated in our hospital from March 2015 to 2016 July. including 17 cases of multiple myeloma(MM) (A group) and 40 cases of B cell non-Hodgkin's lymphoma(B-NHL) (B group), 30 healthy volunteers were enrolled in control group(C group). The BLyS level in peripheral blood of A,B and C groups was detected by ELISA kit; for patient with hematologic malignancies, the BLyS level was detected again after chemotherapy and was compared with level before chemotherapy. The BLyS level in patients with B cell-derived hematologic malignancies significantly increased, as compared with healthy volanteers(P<0.05). After chemotherapy, the BLyS level in patients all significantly dicreased (P<0.05); the BLyS level in peripheral blood of DLBCL and FL patients was significantly higher than that in patients with B-NHL of other types(P<0.05); the BLyS level in peripheral blood of patients at III-IV stage was significantly higher than that in patients at I-II stage. The BLyS expression in B cell derived hematologic malignancies significantly increases, moreover the its expression level in B-NHL patients at different stages and histologic types is different, suggesting that detection of BLyS expression level in patients in vivo possesses a certain guiding role for diagnosis, staging and treatment of B cell-derived hematologic malignancies.

Blood relatives with incomplete lupus are distinguished from unaffected relatives and relatives with classified disease by altered autoantibodies, soluble inflammatory and regulatory mediators, and clinical features

Abstract Blood relatives (Rel) of lupus patients have increased risk of systemic lupus erythematosus (SLE). Some have autoantibodies and clinical features, but do not meet ≥ 4 ACR criteria needed to reach SLE classification (incomplete lupus, ILE). This study examined individuals enrolled in the Lupus Family Registry and Repository who only met 3 ACR classification criteria during medical record review. ILE patients (n=77) were matched to unaffected Rel and unrelated controls (Ctls), with a subset of ILE patients (n=55) matched to medical record-confirmed SLE patients. ILE patients had significantly higher SLE-specific screening questionnaire (CSQ) scores than unaffected Rel and Ctls (p≤0.0001). A number of soluble mediators that positively correlated with CSQ scores were highest in ILE patients, including SCF (p=0.0001), BLyS (p=0.0018), MCP-3 (p=0.0167), and TNFRI (p=0.0196), as well as ANA titer (p&amp;lt;0.01) and number of lupus-associated autoantibodies (p&amp;lt;0.01). Comparing ILE vs. SLE patients, SLE patients had higher rates of arthritis, serositis, and renal disease (p≤0.004), number of autoantibody specificities (p&amp;lt;0.004), and levels of BLyS (p=0.0138), IL-2Rα (p=0.0201), IP-10 (p=0.0269), and TNFRII (p=0.0309). Yet, ILE patients had higher levels of the regulatory mediator TGF-β (p=0.0454). Identification of factors which discern relatives at increased risk of transitioning to classified SLE may be beneficial to curtail inflammatory damage.

Dysregulation of T helper-type cytokines appears prior to and concurrent with appearance of autoantibody specificities during early SLE pathogenesis and contributes to prognosis of transition to classified disease

Abstract Autoantibodies and immune dysregulation are associated with systemic lupus erythematosus (SLE), but how these factors influence disease development is unknown. This study evaluates timing and changes in SLE-linked autoantibodies and soluble mediator pathways in the years preceding SLE classification. Serial sera from 84 SLE cases spanning pre- and post-SLE classification (average time = 5.98 years) and matched healthy controls (HC) were obtained from the Department of Defense Serum Repository. Adjusting for multiple comparison, a number of soluble mediators, including IL-5 (q=4.35×10−6), IL-6 (q=8.26×10−6), and IFN-γ (q=0.037), were significantly elevated in cases vs. HC &amp;gt;3.5 years pre-classification, prior to (IL-5 and IL-6) and concurrent with (IFN-γ) the earliest SLE-specific autoantibody specificity, anti-Ro/SSA. Th1-type, Th17-type, and TNF superfamily soluble mediators increased longitudinally in cases approaching SLE classification, but not in HC (q&amp;lt;0.05). In particular, serum levels of BLyS and APRIL were comparable in cases and HC until &amp;lt;10 months pre-classification (q=0.003 and q=0.019, respectively). Random forest models incorporating IL-5, IL-6, and IFN-γ levels (79–82% accuracy) distinguished future SLE patients better than models with ANA alone (58% accuracy) &amp;gt;3.5 years before classification. These data indicate that pre-clinical immune system perturbations allow for the accumulation of autoantibodies preceding clinical symptoms and SLE classification.

P-B26 Changes in plasma BLyS levels in patients with HCV mixed cryoglobulinemic vasculitis during treatment with Rituximab

P-B26 Changes in plasma BLyS levels in patients with HCV mixed cryoglobulinemic vasculitis during treatment with Rituximab

B cell non-Hodgkin's lymphoma in chronic hepatitis C virus patients: An interesting relationship.

An association exists between hepatitis C virus (HCV) infection and non-Hodgkin's lymphoma (NHL), but a causal relationship is not fully established. HCV is a lymphotropic virus that represents a major etiologic agent of mixed cryoglobulinemia (MC) type II which is characterized by a low-grade B cell clonal lymphoproliferative disorder that usually progresses to a more aggressive malignant lymphoma. This study assessed the role of cryoglobulin and B lymphocyte stimulator (BLys) in the pathogenesis of NHL in chronic HCV patients. Sixty HCV patients, 30 free of B cell NHL (group I) and 30 with B cell NHL (group II), and 30 healthy controls (group III) were studied. Qualitative cryoglobulin assessment and a quantitative assay for BLys were done. In group II, BLyS positivity rate was 1.5-fold higher than of group I (p ≤ 0.01). A positive association was found between positivity rate of MC and the level of BLyS (p ≤ 0.01). High BLyS levels were associated with HCV-associated lymphoproliferative disorder coupled with positive MC.

FRI0391 The Association between Type I Interferon Response, Complement Activation and Clinical Findings in Systemic Lupus Erythematosus

BackgroundThe complement system plays an important role in systemic lupus erythematosus (SLE) and it might be a therapeutic target for therapy. Type I interferon (IFN) response and type I IFN-induced...

AB0084 Serum Levels of Syndecan-1 and Organ Involvement in Systemic Lupus Erythematosus

BackgroundSyndecan-1 is expressed on plasma cells surface and serum levels as reflect an activation of these cells. To date, a significant association between serum levels of syndecan-1with disease activity has...