Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus

Objective To determine the association of plasma B lymphocyte stimulator (BLyS) levels, immunosuppressive therapy, and other clinical parameters with disease activity in systemic lupus erythematosus (SLE). Methods Two hundred forty-five SLE patients were evaluated prospectively over a 2-year period at 4 centers. Assessments were performed every 3–6 months. Univariate analysis was used to determine the association among the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, serum anti–double-stranded DNA (anti-dsDNA), and plasma BLyS levels. A multivariate repeated-measures model incorporating immunosuppressive therapy was utilized. Results Ninety-two percent of the patients were female. Sixty-seven percent were white, 31% African American, and 2% Asian (all of these groups may include Hispanic). Mean values at baseline were as follows: age 41.5 years, disease duration 8.1 years, SELENA–SLEDAI 3.3 (median 2, range 0–18), BLyS 5.57 ng/ml, IgG 1,439 mg/dl, C3 104.4 mg/dl, and C4 21.3 mg/dl; among those positive for anti-dsDNA, the median titer was 1:40 (range 1:10–1:1,280). Univariate analysis showed that plasma BLyS levels were associated with anti-dsDNA titers ( P = 0.0465) and SELENA–SLEDAI scores ( P = 0.0002). In multivariate analyses, a greater increase in the SELENA–SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit ( P = 0.0042) and with a greater increase in the BLyS level from the previous visit ( P = 0.0007). Conclusion The findings of association between a greater increase in the BLyS level from the previous visit and a greater increase in the SELENA–SLEDAI score at the subsequent visit, and between an elevated BLyS level at the previous visit and a greater SELENA–SLEDAI score at the subsequent visit, demonstrate a relationship between circulating BLyS levels and SLE disease activity. These results lend support to the notion that BLyS is a candidate for therapeutic targeting in SLE.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60900/1/23678_ftp.pd

Association of endogenous anti–interferon‐α autoantibodies with decreased interferon‐pathway and disease activity in patients with systemic lupus erythematosus

Objective Numerous observations implicate interferon‐α (IFNα) in the pathophysiology of systemic lupus erythematosus (SLE); however, the potential impact of endogenous anti‐IFNα autoantibodies (AIAAs) on IFN‐pathway and disease activity is unclear. The aim of this study was to characterize IFN‐pathway activity and the serologic and clinical profiles of AIAA‐positive patients with SLE. Methods Sera obtained from patients with SLE (n = 49), patients with rheumatoid arthritis (n = 25), and healthy control subjects (n = 25) were examined for the presence of AIAAs, using a biosensor immunoassay. Serum type I IFN bioactivity and the ability of AIAA‐positive sera to neutralize IFNα activity were determined using U937 cells. Levels of IFN‐regulated gene expression in peripheral blood were determined by microarray, and serum levels of BAFF, IFN‐inducible chemokines, and other autoantibodies were measured using immunoassays. Results AIAAs were detected in 27% of the serum samples from patients with SLE, using a biosensor immunoassay. Unsupervised hierarchical clustering analysis identified 2 subgroups of patients, IFN low and IFN high , that differed in the levels of serum type I IFN bioactivity, IFN‐regulated gene expression, BAFF, anti–ribosomal P, and anti‐chromatin autoantibodies, and in AIAA status. The majority of AIAA‐positive patients had significantly lower levels of serum type I IFN bioactivity, reduced downstream IFN‐pathway activity, and lower disease activity compared with the IFN high patients. AIAA‐positive sera were able to effectively neutralize type I IFN activity in vitro. Conclusion Patients with SLE commonly harbor AIAAs. AIAA‐positive patients have lower levels of serum type I IFN bioactivity and evidence for reduced downstream IFN‐pathway and disease activity. AIAAs may influence the clinical course in SLE by blunting the effects produced by IFNα.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87110/1/30399_ftp.pd

Increased B cell-activating factor (BAFF) level in the sputum of children with asthma

PurposeB cell-activating factor (BAFF) is a tumor-necrosis factor (TNF) superfamily member best known for its role in the survival and maturation of B cells. BAFF activity is observed in naïve cells as well as in effector/memory T cells. We aimed to explore whether BAFF in sputum is expressed at elevated levels in asthmatic airways and associated with eosinophilic inflammation, pulmonary function, and bronchial hyperresponsiveness in children.MethodsOne hundred and fifty-four asthmatic children and 98 healthy children were enrolled in the study. Sputum supernatants were collected and sputum BAFF and eosinophil cationic protein (ECP) levels were measured. We performed pulmonary function tests and methacholine challenge tests, while measuring total eosinophil count, total serum IgE, and serum ECP in all subjects.ResultsAsthmatic children had significantly higher levels of BAFF in induced sputum [26.50 (10.50-100.27) pg/mL] compared to healthy children [18.32 (7.68-44.63) pg/mL; P=0.011]. Sputum BAFF positively correlated with sputum eosinophils (γ=0.406, P<0.001) and sputum ECP (γ=0.789, P<0.001). Significant negative correlations were found between sputum BAFF and FEV1 (γ=-0.291, P<0.001) or post-bronchodilator FEV1 (γ=-0.334, P<0.001), whereas nonsignificant correlations were found between sputum BAFF and bronchial hyperresponsiveness, serum eosinophil count, and serum ECP.ConclusionThese findings suggest that BAFF may play a role in childhood asthma, and BAFF levels in sputum could be a supportive marker that represents airway inflammation, especially eosinophilic inflammation

The Plasma Concentration of the B Cell Activating Factor Is Increased in Children With Acute Malaria

Malaria-specific antibody responses in children often appear to be short-lived but the mechanisms underlying this phenomenon are not well understood. In this study, we investigated the relationship between the B-cell activating factor (BAFF) and its receptors expressed on B cells with antibody responses during and after acute malaria in children. Our results demonstrate that BAFF plasma levels increased during acute malarial disease and reflected disease severity. The expression profiles for BAFF receptors on B cells agreed with rapid activation and differentiation of a proportion of B cells to plasma cells. However, BAFF receptor (BAFF-R) expression was reduced on all peripheral blood B cells during acute infection, but those children with the highest level of BAFF-R expression on B cells maintained schizont-specific immunoglobin G (IgG) over a period of 4 months, indicating that dysregulation of BAFF-R expression on B cells may contribute to short-lived antibody responses to malarial antigens in children. In summary, this study suggests a potential role for BAFF during malaria disease, both as a marker for disease severity and in shaping the differentiation pattern of antigen-specific B cells

УСКОРЕННОЕ ГИПЕРФРАКЦИОНИРОВАНИЕ ДОЗЫ В ЛУЧЕВОМ ЛЕЧЕНИИ НЕОПЕРАБЕЛЬНОГО МЕСТНОРАСПРОСТРАНЕННОГО РАКА ЖЕЛУДКА

Purpose: to compare survival of patients with locally advanced inoperable gastric cancer (LAIGC), receiving accelerated hyperfractionated (AHF) or conventionally fractionated (CF) radiation therapy (RT). Methods and Materials. Between November 1993 and March 2010, 137 patients with LAIGC receiving CF (2 Gy daily) or AHF (1.3 Gy b.i.d.) to total at least 50 Gy RT in combination or without chemotherapy were retrospectively selected from the hospital database of Arkhangelsk clinical oncological dispensary. Overall survival (OS) assessed using actuarial analysis, Kaplan – Meier method and Cox regression. results. The CF and AHF groups were 102 and 35 patients, respectively. Median follow-up time for all patients was 12 years. By the time of analysis 123 (90 %) patients of all cohort died. Median, 7-year survival were 24 (95 % confidence intervals (CI), 17–31) vs 16 (95 % CI, 11–21) months, hazard ratio (HR)=0.71 (95 % CI, 0.46–1.06), р=0.097; and 19 % (95 % CI 8–34 %) vs 6% (95 % CI 2–13 %) in the AHF and CF groups, respectively. In multivariate OS model the difference decreased to HR=0.87 (95 % CI, 0.49–1.55). The location of the tumor in median third (HR=0.60, 95 % CI, 0.37–0.99 in refer to upper third) was the only independent factor influencing survival.  There was no influence of the total dose in chosen level on survival. conclusion. Our retrospective shows trend towards better OS for those LAIGC patients receiving RT in AHF regimen compared to CF. The prospective randomized study with conformal radiation technics is necessary to confirm these findings.Цель исследования – сравнить выживаемость больных местнораспространенным неоперабельным раком желудка (МРНРЖ), получавших лучевую терапию (ЛТ) в режиме ускоренного гиперфракционирования (УГФ) и традиционного фракционирования (ТФ). Материал и методы. Включено 137 больных МРНРЖ из госпитальной базы данных Архангельского клинического онкологического диспансера, получавших ЛТ с химиотерапией (ХТ) и без нее, с ноября 1993 г. по март 2010 г. в режиме ТФ (по 2 Гр ежедневно), либо УГФ (по 1,3 Гр два раза в день, ежедневно) до дозы не менее 50 иГр. Для оценки общей выживаемости (ОВ) использованы актуарный анализ, метод Каплана – Майера и регрессия Кокса. результаты. В группе ТФ оказалось 102 человека, в группу УГФ было отобрано 35. Медиана времени наблюдения всех пациентов составила 12,4 года. К началу анализа погибло 123 (89,8 %) из 137 наблюдаемых больных. Медиана ОВ, 7-летняя ОВ в группе УГФ и ТФ составили 24 (95 % доверительный интервал ДИ 17–31) и 16,0 (95 % ДИ 11–21) мес, ОР=0,71 (95 % ДИ 0,46–1,06), р=0,097; 19 (95 % ДИ 8–34 %) и 6 % (95 % ДИ 2–13 %) соответственно. В многофакторной модели различия между группами сгладились – ОР 0,87 (95 % ДИ 0,49–1,55); единственным независимым фактором благоприятного прогноза была локализация опухоли в теле желудка, ОР 0,60 (95 % ДИ 0,37–0,99). Не выявлено влияния дозы ЛТ в выбранном диапазоне на ОВ. заключение. В ретроспективном анализе выявлено недостоверное преимущество в ОВ больных МРНРЖ, получавших ЛТ в режиме УГФ, по сравнению с режимом ТФ. Эти результаты требуют подтверждения в проспективном рандомизированном исследовании с использованием современных методов облучения

Novel mechanism for the generation of human xeno-autoantibodies against the nonhuman sialic acid N-glycolylneuraminic acid

The nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) is metabolically incorporated into human tissues from certain mammalian-derived foods, and this occurs in the face of an anti-Neu5Gc “xeno-autoantibody” response. Given evidence that this process contributes to chronic inflammation in some diseases, it is important to understand when and how these antibodies are generated in humans. We show here that human anti-Neu5Gc antibodies appear during infancy and correlate with weaning and exposure to dietary Neu5Gc. However, dietary Neu5Gc alone cannot elicit anti-Neu5Gc antibodies in mice with a humanlike Neu5Gc deficiency. Other postnatally appearing anti-carbohydrate antibodies are likely induced by bacteria expressing these epitopes; however, no microbe is known to synthesize Neu5Gc. Here, we show that trace exogenous Neu5Gc can be incorporated into cell surface lipooligosaccharides (LOS) of nontypeable Haemophilus influenzae (NTHi), a human-specific commensal/pathogen. Indeed, infant anti-Neu5Gc antibodies appear coincident with antibodies against NTHi. Furthermore, NTHi that express Neu5Gc-containing LOS induce anti-Neu5Gc antibodies in Neu5Gc-deficient mice, without added adjuvant. Finally, Neu5Gc from baby food is taken up and expressed by NTHi. As the flora residing in the nasopharynx of infants can be in contact with ingested food, we propose a novel model for how NTHi and dietary Neu5Gc cooperate to generate anti-Neu5Gc antibodies in humans

TLR Tolerance Reduces IFN-Alpha Production Despite Plasmacytoid Dendritic Cell Expansion and Anti-Nuclear Antibodies in NZB Bicongenic Mice

Genetic loci on New Zealand Black (NZB) chromosomes 1 and 13 play a significant role in the development of lupus-like autoimmune disease. We have previously shown that C57BL/6 (B6) congenic mice with homozygous NZB chromosome 1 (B6.NZBc1) or 13 (B6.NZBc13) intervals develop anti-nuclear antibodies and mild glomerulonephritis (GN), together with increased T and B cell activation. Here, we produced B6.NZBc1c13 bicongenic mice with both intervals, and demonstrate several novel phenotypes including: marked plasmacytoid and myeloid dendritic cell expansion, and elevated IgA production. Despite these changes, only minor increases in anti-nuclear antibody production were seen, and the severity of GN was reduced as compared to B6.NZBc1 mice. Although bicongenic mice had increased levels of baff and tnf-α mRNA in their spleens, the levels of IFN-α-induced gene expression were reduced. Splenocytes from bicongenic mice also demonstrated reduced secretion of IFN-α following TLR stimulation in vitro. This reduction was not due to inhibition by TNF-α and IL-10, or regulation by other cellular populations. Because pDC in bicongenic mice are chronically exposed to nuclear antigen-containing immune complexes in vivo, we examined whether repeated stimulation of mouse pDC with TLR ligands leads to impaired IFN-α production, a phenomenon termed TLR tolerance. Bone marrow pDC from both B6 and bicongenic mice demonstrated markedly inhibited secretion of IFN-α following repeated stimulation with a TLR9 ligand. Our findings suggest that the expansion of pDC and production of anti-nuclear antibodies need not be associated with increased IFN-α production and severe kidney disease, revealing additional complexity in the regulation of autoimmunity in systemic lupus erythematosus

Reducing LPS content in cockroach allergens increases pulmonary cytokine production without increasing inflammation: A randomized laboratory study

<p>Abstract</p> <p>Background</p> <p>Endotoxins are ubiquitously present in the environment and constitute a significant component of ambient air. These substances have been shown to modulate the allergic response, however a consensus has yet to be reached whether they attenuate or exacerbate asthmatic responses. The current investigation examined whether reducing the concentration of lipopolysaccharide (LPS) in a house dust extract (HDE) containing high concentrations of both cockroach allergens <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> and LPS would attenuate asthma-like pulmonary inflammation.</p> <p>Methods</p> <p>Mice were sensitized with CRA and challenged with the intact HDE, containing 182 ng of LPS, or an LPS-reduced HDE containing 3 ng LPS, but an equivalent amount of CRA. Multiple parameters of asthma-like pulmonary inflammation were measured.</p> <p>Results</p> <p>Compared to HDE challenged mice, the LPS-reduced HDE challenged mice had significantly reduced TNFα levels in the bronchoalveolar lavage fluid. Plasma levels of IgE and IgG1 were significantly reduced, however no change in CRA-specific IgE was detected. In HDE mice, plasma IgG2a levels were similar to naïve mice, while LPS-reduced HDE mice had significantly greater concentrations. Reduced levels of LPS in the HDE did not decrease eosinophil or neutrophil recruitment into the alveolar space. Equivalent inflammatory cell recruitment occurred despite having generally higher pulmonary concentrations of eotaxins and CXC chemokines in the LPS-reduced HDE group. LPS-reduced HDE challenge induced significantly higher concentrations of IFNγ, and IL-5 and IL-13 in the BAL fluid, but did not decrease airways hyperresponsiveness or airway resistance to methacholine challenge. <it>Conclusion: </it>These data show that reduction of LPS levels in the HDE does not significantly protect against the severity of asthma-like pulmonary inflammation.</p