scholarly journals SIAE Rare Variants in Juvenile Idiopathic Arthritis and Primary Antibody Deficiencies

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Eirini Sevdali ◽  
Elena Tsitsami ◽  
Maria Tsinti ◽  
Evangelia Farmaki ◽  
Efimia Papadopoulou-Alataki ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Sialic Acid ◽  
Cell Activation ◽  
Rare Variants ◽  
Primary Antibody ◽  
Healthy Children ◽  
B Cell Activation ◽  
Loss Of Function ◽  
Primary Antibody Deficiencies ◽  
Sialic Acid Binding

Sialic acid acetylesterase (SIAE) deficiency was suggested to lower the levels of ligands for sialic acid-binding immunoglobulin-like receptors, decreasing the threshold for B-cell activation. In humans, studies of rare heterozygous loss-of-function mutations in SIAE gene in common autoimmune diseases, including juvenile idiopathic arthritis (JIA), yielded inconsistent results. Considering the distinct pathogenesis of the two main subtypes of JIA, autoinflammatory systemic (sJIA) and autoimmune oligo/polyarticular (aJIA), and a predisposition to autoimmunity displayed by patients and families with primary antibody deficiencies (PADs), the aim of our study was to analyze whether SIAE rare variants are associated with both the phenotype of JIA and the autoimmunity risk in families with PADs. A cohort of 69 patients with JIA, 117 healthy children, 54 patients, and family members with PADs were enrolled in the study. Three novel SIAE variants (p.Q343P, p.Y495X, and c.1320+33T>C) were found only in patients with aJIA but interestingly also in their healthy relatives without autoimmunity, while none of PAD patients or their relatives carried SIAE defects. Our results show that SIAE rare variants are not causative of autoimmunity as single defects.

scholarly journals Persistent Activation of Innate Immunity in Patients with Primary Antibody Deficiencies

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Gerasimina Tsinti ◽  
Demosthenes Makris ◽  
Anastasios E. Germenis ◽  
Matthaios Speletas
Keyword(s):  
Innate Immunity ◽  
Cell Activation ◽  
Immune Cell ◽  
Primary Antibody ◽  
Favorable Effect ◽  
Polymorphonuclear Cells ◽  
Replacement Treatment ◽  
Primary Antibody Deficiencies ◽  
Immunoglobulin Replacement ◽  
Clinical Conditions

Primary antibody deficiencies (PAD) represent a heterogeneous group of disorders, with common variable immunodeficiency being the most common with clinical significance. The main phenotypic defect resides in the inability of B cells to produce antibodies, and the cornerstone of therapy is immunoglobulin replacement treatment in order to fight infections. However, the management of the other inflammatory manifestations is inadequate, reinforcing the hypothesis that a complex genetic background affecting additional cell populations, such as polymorphonuclear cells (PMN) and monocytes, influences the expression of the clinical phenotype of the disease. In this study, we investigated by flow cytometry in different conditions (resting state, and after isolation and incubation, with and without stimuli) the expression pattern of several markers on PMN and monocytes, indicative of their maturation, capacity for chemotaxis, adhesion, opsonization, migration, and phagocytosis in 25 PAD patients, 12 healthy blood donors, and 4 septic patients. In this context, we also analyzed patients before and after the initiation of replacement treatment, as well as an untreated patient in different clinical conditions. Interestingly, we observed that PAD patients exhibit a chronic activation status of the innate immunity compartment, along with several differences in the expression of activation, maturation, and adhesion markers, with respect to different clinical conditions. Moreover, immunoglobulin replacement treatment had a favorable effect on PMN, as it was expressed by a more mature and less activated phenotype on basal state cells, and an enhanced activation capacity after LPS exposure. Thus, we conclude that PAD patients display a persistent innate immune cell activation, which is probably associated with the chronic inflammatory stress, usually observed in these disorders.

STAT3 phosphorylation mediates the stimulatory effects of interferon alpha on B cell differentiation and activation in SLE

Rheumatology ◽  
2019 ◽  
Author(s):  
Aurélie De Groof ◽  
Julie Ducreux ◽  
Floor Aleva ◽  
Andrew J Long ◽  
Alina Ferster ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Type I ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Loss Of Function ◽  
Stat3 Phosphorylation

Abstract Objective Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. Methods Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. Results Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. Conclusion IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.

scholarly journals AB0036 CHILDREN WITH EXTENDED OLIGOARTICULAR AND POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS HAVE A CYTOKINE PATTERN FAVOURING B CELL ACTIVATION IN CIRCULATION

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1321.3-1321
Author(s):  
R. A. Moura ◽  
F. Oliveira-Ramos ◽  
C. Marques ◽  
A. Brito ◽  
R. L. Teixeira ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
B Cell ◽  
Cell Activation ◽  
Large Fraction ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
B Cell Activation ◽  
Serum Samples ◽  
Early Ra ◽  
Cytokine Pattern

Background:Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. The majority of polyarticular JIA (pJIA) and a large fraction of extended oligoarticular JIA (oJIA) patients fulfil classification criteria for rheumatoid arthritis (RA) in adulthood. B-cells play several important roles in RA pathogenesis, but it is still unclear if the pattern of B-cell involvement in pJIA and extended oJIA follows what has been described for adults with RA.Objectives:The main goal of this study was to determine the concentration of cytokines potentially relevant for B-cell activation in serum from children with pJIA and extended oJIA when compared to children with persistent oJIA, adult JIA, early and established RA.Methods:Serum samples were collected from children with extended oJIA (n=8), persistent oJIA (n=6), pJIA (n=6), adult JIA (n=8), untreated early RA (<1 year of disease duration, n=12), established RA patients treated with synthetic disease-modifying anti-rheumatic drugs (DMARDs) (n=10) and two groups of age- and sex-matched healthy donors (children, n=6 and adults, n=10). A proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF), interleukin (IL)-6 and IL-21 serum levels were measured by enzyme-linked immunosorbent assay (ELISA).Results:Children with extended oJIA, early and established RA patients had significantly higher BAFF serum levels when compared to controls, but no significant differences were observed in children with persistent oJIA, pJIA and adult JIA when compared to all groups included. APRIL serum levels were significantly increased in early and established RA patients when compared to both controls and children with persistent oJIA. No significant differences were found in APRIL concentrations between children with JIA, adult JIA and controls. IL-6 serum levels were significantly increased in children with extended oJIA, pJIA, early and established RA when compared to controls, but no significant differences were found in children with persistent oJIA and adult JIA patients. IL-21 serum levels were significantly increased in early RA when compared to controls, but no significant differences were observed between any of the other groups included.Conclusion:The similarity in B-cell cytokine pattern found between extended oJIA, pJIA, early and established RA patients, contrarily to what was observed in persistent oJIA, suggests an early B-cell involvement in the pathogenesis of extended oJIA and pJIA as described for RA.Disclosure of Interests:None declared

scholarly journals Decreased Levels of CD54 (ICAM-1)-Positive Lymphocytes in the Peripheral Blood in Untreated Patients with Active Juvenile Dermatomyositis

2000 ◽  
Vol 7 (4) ◽  
pp. 693-697 ◽  
Author(s):  
Maurice R. G. O'Gorman ◽  
Laura Bianchi ◽  
David Zaas ◽  
Virginia Corrochano ◽  
Lauren M. Pachman
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
B Lymphocytes ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Juvenile Dermatomyositis ◽  
Healthy Children ◽  
B Cell Activation ◽  
Activation Markers

ABSTRACT Significant abnormalities are observed in the peripheral blood of juvenile dermatomyositis (JDM) patients with active disease. In this study, we confirm that there is a significant increase in the relative percentage of B lymphocytes in the peripheral blood of a group of untreated children with newly diagnosed active JDM compared to healthy children (P < 0.0001). In order to investigate if properties intrinsic to B cells contributed to their relative increase in JDM, the percentage of B cells expressing activation markers (CD23, CD25, CD54, and CD69) was measured and compared to pediatric controls. Compared to healthy children less than 10 years of age (not significantly different from the JDM group), the JDM patients had an increase in the proportion of lymphocytes expressing CD19 (B cells;P = 0.0017) and decreases in the percentage of lymphocytes that were CD3− CD16+ and/or CD56+ (NK cells; P = 0.01) and CD3+ CD8+ (T suppressor/cytotoxic cells;P = 0.02). There were no significant differences in any of the B-cell activation markers assessed. Of note, the percentage of CD54+ non-B lymphocytes (i.e., T cells and NK cells expressing CD54) was significantly lower in the JDM patients (25% ± 5%) than in the “age-related” healthy control group (43% ± 4%;P = 0.013). These results suggest the following for untreated children with active JDM: (i) the increase in the percentage of peripheral blood B cells is not due to intrinsic B-cell activation, and (ii) CD54/ICAM-1+ non-B cells, CD8+ T cells, and NK cells are being removed from circulation and may be participating in the pathophysiology of the disease.

scholarly journals Germinal Center Marker GL7 Probes Activation-Dependent Repression of N-Glycolylneuraminic Acid, a Sialic Acid Species Involved in the Negative Modulation of B-Cell Activation

2007 ◽  
Vol 27 (8) ◽  
pp. 3008-3022 ◽  
Author(s):  
Yuko Naito ◽  
Hiromu Takematsu ◽  
Susumu Koyama ◽  
Shizu Miyake ◽  
Harumi Yamamoto ◽  
...  
Keyword(s):  
Sialic Acid ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
Germinal Centers ◽  
Negative Regulator ◽  
B Cell Activation ◽  
Germinal Center B Cells

ABSTRACT Sialic acid (Sia) is a family of acidic nine-carbon sugars that occupies the nonreducing terminus of glycan chains. Diversity of Sia is achieved by variation in the linkage to the underlying sugar and modification of the Sia molecule. Here we identified Sia-dependent epitope specificity for GL7, a rat monoclonal antibody, to probe germinal centers upon T cell-dependent immunity. GL7 recognizes sialylated glycan(s), the α2,6-linked N-acetylneuraminic acid (Neu5Ac) on a lactosamine glycan chain(s), in both Sia modification- and Sia linkage-dependent manners. In mouse germinal center B cells, the expression of the GL7 epitope was upregulated due to the in situ repression of CMP-Neu5Ac hydroxylase (Cmah), the enzyme responsible for Sia modification of Neu5Ac to Neu5Gc. Such Cmah repression caused activation-dependent dynamic reduction of CD22 ligand expression without losing α2,6-linked sialylation in germinal centers. The in vivo function of Cmah was analyzed using gene-disrupted mice. Phenotypic analyses showed that Neu5Gc glycan functions as a negative regulator for B-cell activation in assays of T-cell-independent immunization response and splenic B-cell proliferation. Thus, Neu5Gc is required for optimal negative regulation, and the reaction is specifically suppressed in activated B cells, i.e., germinal center B cells.

scholarly journals Primary Antibody Deficiencies: Scientific Discoveries Leading to Challenging Paradigms in a Complex Disease Landscape

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-28-SCI-28
Author(s):  
Anne Durandy ◽  
Sven Kracker ◽  
Marina Cavazzana
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Cell Function ◽  
B Cell Activation ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Phosphoinositide 3 Kinase ◽  
Cell Defect ◽  
Increased Susceptibility

Abstract Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies in humans that affect both children and adults. The patients display a decrease in IgG and/or IgA serum levels associated with lower, normal or higher IgM levels, which cause an increased susceptibility to bacterial but also viral infections. Main other complications are auto-immunity, lymphoproliferation and increased susceptibility to various types of cancers. PADs can be caused by B intrinsic and/or extrinsic defects leading to impaired early B cell development, B cell migration, B cell survival, B cell activation or defects in Immunoglobulin class switch recombination (CSR). Among the latter (B cell activation- and CSR-deficiencies), some PADs are linked to unbalanced signaling pathways, in which both gain of function and loss of function variations lead to different immune defects, pinpointing the requirement of a tightly controlled activity for proper immune response. 1) Activated PI3K-d Syndromes (APDS) are due to dominant mutations in either the PIK3CD gene encoding the p110d protein, the catalytic subunit of phosphoinositide 3 kinase d (PI3Kd) or the PIK3R1 gene encoding the regulatory subunit of phosphoinositide 3 kinase p85a. Both gene defects lead to hyperactivation of PI3K through an increased p110δ function. A frequent hyper-IgM phenotype is observed, likely due to both a T and a B cell defect. Of note, impaired or loss of function of p110δ or p85α subunit of PI3K leads to a completely different phenotype characterized by an autosomal recessive agammaglobulinemia. The main life-threatening complication of APDS is B lymphoma occurrence. Targeted therapy aiming to decrease PI3K activation is currently on trial. 2) The importance of the canonical NF-kB signaling for B cell function was firstly highlighted by the description that missense hemizygous mutations in the IKBKG gene, encoding NEMO, the NF-kB essential modulator, cause an X-linked CSR-deficiency associated with hyphohydrotic ectodermal dysplasia. Recently, heterozygous mutations in either the NFKB1 or the NFKB2 genes (encoding respectively for p105 processed to p50 and p100 processed to p52), have been reported to be causative for common variable immunodeficiency (CVID) due to haploinsufficiency of NF-êkB1 (p52) or NF-kB2 (p50), with less nuclear NF-kB accumulation and less transcriptional regulation. Some carriers are asymptomatic, pinpointing to incomplete penetrance, that suggests the role of gene modifyers or environmental factors. Although NF-κB1-deficiency affects mostly B cells, NF-kB2- deficiency combines a T, B and NK cell defect and is frequently associated to pituitary hormone deficiency. CARD11 (caspase recruitment domain containing protein 11)-deficiency (caused by loss of function bi-allelic mutations) also indicated the importance of CARD11 mediated canonical NF-kB1 signaling for B and T cell function since CARD11-deficient patients have a CVID phenotype. Interestingly, heterozygous gain of function mutations in CARD 11 lead to a different phenotype, the so-called BENTA syndrome ("B cell expansion with NF-kB and T cell anergy") characterized by B cell lymphocytosis, lymphoproliferation and immunodeficiency. These examples of PADs show that gain of function, haploinsufficiencies and loss of function mutations can be deleterious by disturbing the delicate balance required for adequate signaling pathways during the immune response. Disclosures No relevant conflicts of interest to declare.

scholarly journals NEU1 and NEU3 enzymes alter CD22 organization on B cells

2021 ◽  
Author(s):  
Hanh-Thuc Ton Tran ◽  
Caishun Li ◽  
Radhika Chakraberty ◽  
Christopher W. Cairo
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Single Particle Tracking ◽  
B Cell Activation ◽  
Sialic Acid Binding ◽  
Receptor Clusters ◽  
And Function ◽  
Cellular Ca

ABSTRACTThe B cell membrane expresses sialic acid binding Immunoglobulin-like lectins, also called Siglecs, that are important for modulating immune response. Siglecs have interactions with sialoglycoproteins found on the same membrane (cis ligands) that result in homotypic and heterotypic receptor clusters. The regulation and organization of these clusters, and their effect on cell activation, is not clearly understood. We investigated the role of human neuraminidase enzymes, NEU1 and NEU3, on the clustering of CD22 on B cells using confocal microscopy. We observed that native NEU1 and NEU3 activity influence the cluster size of CD22. Using single-particle tracking, we observed that NEU3 activity increased the lateral mobility of CD22, which was in contrast to the effect of exogenous bacterial NEU enzymes. Moreover, we show that native NEU1 and NEU3 activity influenced cellular Ca2+levels, supporting a role for these enzymes in regulating B cell activation. Our results establish a role for native NEU activity in modulating CD22 organization and function on B cells.

scholarly journals CD21lo/−CD27−IgM− Double-Negative B Cells Accumulate in the Joints of Patients With Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis

2021 ◽  
Vol 9 ◽  
Author(s):  
Johannes Dirks ◽  
Jonas Fischer ◽  
Gabriele Haase ◽  
Annette Holl-Wieden ◽  
Christine Hofmann ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cross Sectional Study ◽  
Double Negative ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Cross Sectional ◽  
B Cell Subsets

Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases. The appearance of antinuclear antibodies (ANAs) in almost half of the patients suggests B cell dysregulation as a distinct pathomechanism in these patients. Additionally, ANAs were considered potential biomarkers encompassing a clinically homogenous subgroup of JIA patients. However, in ANA+ JIA patients, the site of dysregulated B cell activation as well as the B cell subsets involved in this process is still unknown. Hence, in this cross-sectional study, we aimed in an explorative approach at characterizing potential divergences in B cell differentiation in ANA+ JIA patients by assessing the distribution of peripheral blood (PB) and synovial fluid (SF) B cell subpopulations using flow cytometry. The frequency of transitional as well as switched-memory B cells was higher in PB of JIA patients than in healthy controls. There were no differences in the distribution of B cell subsets between ANA- and ANA+ patients in PB. However, the composition of SF B cells was different between ANA- and ANA+ patients with increased frequencies of CD21lo/−CD27−IgM− “double negative” (DN) B cells in the latter. DN B cells might be a characteristic subset expanding in the joints of ANA+ JIA patients and are potentially involved in the antinuclear immune response in these patients. The results of our explorative study might foster further research dissecting the pathogenesis of ANA+ JIA patients.

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