Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells

Mutations in Wiskott-Aldrich syndrome (WAS) protein (WASp), a regulator of actin dynamics in hematopoietic cells, cause WAS, an X-linked primary immunodeficiency characterized by recurrent infections and a marked predisposition to develop autoimmune disorders. The mechanisms that link actin alterations to the autoimmune phenotype are still poorly understood. We show that chronic activation of plasmacytoid dendritic cells (pDCs) and elevated type-I interferon (IFN) levels play a role in WAS autoimmunity. WAS patients display increased expression of type-I IFN genes and their inducible targets, alteration in pD

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

textabstractThe classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research

Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond.

International audienceABSTRACT: The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories - the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells - plus the detailed description of the main B-cell regulator, FcγRIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express "Pathogen Recognition Receptors" such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology

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

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