scholarly journals AB0026 Tlr9 stimulation of anergic hcv-associated atypical memory b cells triggers rheumatoid factor autoimmunity by the tnf-Α pathway

2018 ◽  
Author(s):  
C. Comarmond ◽  
D. Saadoun
Keyword(s):  
B Cells ◽  
Rheumatoid Factor ◽  
Memory B Cells ◽  
Tnf Α ◽  
Stimulation Of

Diverse effects on vaccine-specific serum IgG titres and memory B cells upon methotrexate and anti-TNF-α therapy in children with rheumatic diseases: A cross-sectional study

Vaccine ◽  
2016 ◽  
Vol 34 (10) ◽  
pp. 1304-1311 ◽  
Author(s):  
Hanna M. Ingelman-Sundberg ◽  
Åsa Laestadius ◽  
Cecilia Chrapkowska ◽  
Karina Mördrup ◽  
Bo Magnusson ◽  
...  
Keyword(s):  
B Cells ◽  
Rheumatic Diseases ◽  
Cross Sectional Study ◽  
Memory B Cells ◽  
Sectional Study ◽  
Cross Sectional ◽  
Specific Serum ◽  
Serum Igg ◽  
Tnf Α

Inhibition of Factor VIII-Specific Memory B Cell Responses by Supra-Physiological Concentrations of Factor VIII.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 38-38
Author(s):  
Christina Hausl ◽  
Rafi U. Ahmad ◽  
Maria Sasgary ◽  
Christopher B. Doering ◽  
Pete S. Lollar ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Factor Viii ◽  
B Cell ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Specific Memory ◽  
Stimulation Of

Abstract Inhibitory antibodies against factor VIII (FVIII) are the major complication experienced by hemophilia A patients treated with FVIII products. The most effective therapy to eradicate these antibodies is elevated doses of FVIII over a prolonged period. Despite clinical practice in using such protocols, nothing is known about the immunological mechanisms that cause the down-modulation of FVIII-specific immune responses and the induction of long-lasting immune tolerance against FVIII. Understanding the underlying mechanisms, however, would facilitate designing new therapeutic strategies. The re-stimulation of FVIII-specific memory responses after each dose of FVIII is probably the most important event in the maintenance of FVIII inhibitors in patients. Therefore, the eradication of these memory responses should be an essential step in the down-modulation of inhibitory antibodies and the induction of immune tolerance. We used a murine model of hemophilia A to answer the question whether FVIII-specific memory responses are sensitive to increasing doses of FVIII. In particular, we were interested in the differential effects of FVIII on memory-B-cell and memory-T-cell responses. For the analysis of FVIII-specific memory responses, we re-stimulated FVIII-specific memory B- and T-cells obtained from spleens of hemophilic mice treated with four doses of human FVIII or eight doses of murine FVIII as described (Sasgary et al.: Thromb Haemost2002; 87:266–72; Hausl et al.: Blood2004; 104:115–22). Our results show dose-dependent effects of FVIII on the re-stimulation of FVIII-specific memory B cells in vitro. Physiological concentrations of FVIII below 100 ng/ml re-stimulate memory B cells and induce their differentiation into anti-FVIII antibody-secreting plasma cells. Supra-physiological concentrations above 100 ng/ml, however, inhibit memory-B-cell re-stimulation. The inhibition of memory-B-cell re-stimulation is irreversible and seems to be due to an induction of apoptosis that is at least partly mediated by Fas-dependent mechanisms. Furthermore, the inhibition appears to be initiated by triggering the B-cell receptor (BCR) without the requirement of an excessive cross-linking of the BCR. The activation of FVIII-specific T cells is not affected by increasing doses of FVIII. We conclude that the induction of apoptosis in FVIII-specific memory B cells might be the first step in the induction of immune tolerance in hemophilia A patients with FVIII inhibitors who receive high doses of FVIII. The eradication of memory B cells would prevent their differentiation into antibody-secreting plasma cells and, moreover, might lead to a deficiency of effective antigen-presenting cells required for the re-stimulation of FVIII-specific memory T cells. The induction of regulatory T cells rather than effector T cells could be the consequence of this deficiency.

scholarly journals TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses

2019 ◽  
Vol 71 (5) ◽  
pp. 908-919 ◽  
Author(s):  
Cloé Comarmond ◽  
Valérie Lorin ◽  
Cindy Marques ◽  
Anna Maciejewski-Duval ◽  
Nizar Joher ◽  
...  
Keyword(s):  
B Cells ◽  
Rheumatoid Factor ◽  
Memory B Cells

Toll-Like Receptor Triggering Modulates Factor VIII-Specific Immune Memory in Murine Hemophilia A with Factor VIII Inhibitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 214-214 ◽  
Author(s):  
Peter Allacher ◽  
Christina Hausl ◽  
Rafi U. Ahmad ◽  
Hans Peter Schwarz ◽  
Peter L. Turecek ◽  
...  
Keyword(s):  
B Cells ◽  
Factor Viii ◽  
B Cell ◽  
Hemophilia A ◽  
Memory B Cells ◽  
Immune Memory ◽  
Low Doses ◽  
Specific Memory ◽  
High Doses ◽  
Stimulation Of

Abstract The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in the treatment of hemophilia A patients with FVIII products. Immune Tolerance Induction (ITI) therapy using long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and induce long-lasting immune tolerance. It is a common observation that infections, particularly central venous catheter infections during ITI cause a rise in anti-FVIII antibody titers that can prolong the course of ITI or possibly even lead to failure of ITI. Based on this observation, we asked the question whether microbial components derived from viruses or bacteria modulate the re-stimulation of FVIII-specific immune memory and disturb the recently described inhibition of memory-B-cell-re-stimulation by high doses of FVIII (Hausl et al.: Blood2005; in press). Microbial components are recognized by toll-like receptors (TLRs) that serve as an important link between innate and adaptive immunity. TLRs can discriminate various microbial components such as lipopeptides derived from bacteria or zymosan derived from yeast (recognized by TLR1/2 or TLR2/6), double-stranded RNA derived from viruses (recognized by TLR3), lipopolysaccharide (LPS) derived from gram-negative bacteria (recognized by TLR4), flagellin derived from bacterial flagella (recognized by TLR5), single-stranded RNA derived from viruses (recognized by TLR7/8) or bacterial DNA containing the unmethylated CpG motif (recognized by TLR9). We analyzed the re-stimulation of FVIII-specific memory-B cells using a murine model of hemophilia A as described previously (Hausl et al.: Blood2004; 104:115–22; Hausl et al.: Blood2005, in press). The following TLR ligands were tested: zymosan for TLR2 (0.1–10,000 ng/ml), poly I:C for TLR3 (1.0–50,000 ng/ml), LPS for TLR4 (0.1–10,000 ng/ml), Flagellin for TLR5 (0.01–1,000 ng/ml), Loxoribine for TLR7 (1.0–50,000 ng/ml) and CpG oligonucleotides for TLR9 (0.1–10,000 ng/ml). Our results indicate that none of the TLR ligands at the concentrations tested induced a significant re-stimulation of FVIII-specific memory B cells in the complete absence of either FVIII or T cells. However, ligands for TLR3, TLR4, TLR7 and TLR9 were able to disturb the inhibition of memory-B-cell-re-stimulation by high doses of FVIII and amplified the re-stimulation induced by low doses of FVIII substantially. We conclude that triggering of TLRs by microbial components that are present during infections amplify the re-stimulation of FVIII-specific memory B-cells induced by low doses of FVIII and disturb the inhibition induced by high doses of FVIII.

Genetic Variants of TNFAIP3 in Patients with HCV Related Lymphoma Are Associated with the Presence of Rheumatoid Factor (RF)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1641-1641 ◽  
Author(s):  
Gaetane Nocturne ◽  
Saida Boudaoud ◽  
Caroline Besson ◽  
Frederic Davi ◽  
Danielle Canioni ◽  
...  
Keyword(s):  
B Cells ◽  
Rheumatoid Factor ◽  
Marginal Zone ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Antigenic Stimulation ◽  
Exact Test ◽  
Chronic Antigenic Stimulation ◽  
Sjögren‘S Syndrome ◽  
Stimulation Of

Abstract Background: HCV chronic infection is associated with an increased risk of non-Hodgkin lymphoma (NHL) occurrence. HCV-associated NHL share homologies with primary Sjögren Syndrome (pSS)-associated NHL, and especially an association with chronic antigenic stimulation and with auto-antibody presence, especially rheumatoid factor (RF) and mixed cryoglobulinemia (MC). TNFAIP3 encodes the A20 protein that plays a key role in controlling NF-kB activation. We have previously demonstrated that germline or tumor genetic impairment of A20 plays a role in lymphomagenesis in the context of pSS[1]. The aim of this study was to assess the role of variants of TNFAIP3 in patients with HCV related NHL. Methods: Sixty-one cases of HCV-associated lymphoma with available germline DNA were drawn from the 116 patients included in the LymphoC study. Total exon sequencing of TNFAIP3was performed in a discovery set of 31 cases. Then 30 additional cases and 53 controls (HCV patients without NHL) were used for extension (ie genotyping of the rs2230926 and the TT>A dinucleotide). All our cases and controls were European. Case-only associations were tested with Fischer’s exact test. Differences in lymphoma histologic type and immunological status were assessed using Fisher’s exact test. Results:Among the 61 cases, histology subsets were 23 diffuse large B cell lymphomas (DLBCL), 17 marginal zone lymphomas (MZL), 6 splenic marginal zone lymphoma (SMZL), 5 mantle cell lymphomas, 8 follicular lymphomas, 1 chronic lymphoid leukemia and 1 chronic EBV-related lymphoproliferation. RF and MC were present in 30/61 (49.2%) and 25/43 (58.1%) of the patients respectively. Among the 53 controls, RF and MC were present in 31/53 (58.5%) and 28/53 (52.8%) of the patients respectively. We found the rs2230926G variant in 6/61 (9.8%) patients with NHL and in 7/53 (13.2%) patients without NHL meaning that there was no association between this SNP and HCV-associated NHL (OR=0.72 [95%CI 0.22– 2.28] p=0.77). We did not find any association between the variant and the marginal zone subtype of the lymphoma. However, we found that, among NHL patients, the rs2230926G allele was associated with the positivity of RF (6/30 (20%) in RF+ patients compared to 0/31 (0%) in RF- patients, OR=16.7 [95%CI 0.9 – 311.5], p=0.01). We did not find any association between the rs2230926 variant and the presence of MC patients probably due to the amount of missing data and the variability of the technic of detection. Last, we previously showed that the rs2230926G was functional and able to impair the control of NF-kB activation[1]. Conclusion: This study demonstrates that a germline coding mutation of TNFAIP3leading to a small functional defect of A20 function and of control of activation of NK-kB, plays a key role in lymphomagenesis in the context of chronic antigenic stimulation of RF+ B cells. It extends the scenario already demonstrated in Sjögren’s syndrome-associated lymphomas, a concept which is both novel and paradigm-shifting in the area of lymphomagenesis and autoimmunity. Interestingly, this coding mutation is associated only with HCV-associated lymphoma and presence of RF, which clearly supports different types of lymphomagenesis pathways in patients with HCV, one of them linked to the continuous stimulation of RF+ B cells by the immune complexes between HCV antigens and anti-HCV antibodies. Reference: 1. Nocturne, G., et al., Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome. Blood, 2013 122(25): p. 4068-76. Disclosures No relevant conflicts of interest to declare.

T-Cell-Independent Re-Stimulation of FVIII-Specific Memory B Cells Requires Help from Activated Plasmacytoid Dendritic Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1155-1155 ◽  
Author(s):  
Aniko Ginta Pordes ◽  
Christina Hausl ◽  
Peter Allacher ◽  
Rafi U. Ahmad ◽  
Bernhard Baumgartner ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Hemophilia A ◽  
Plasmacytoid Dendritic Cells ◽  
Memory B Cells ◽  
Specific Memory ◽  
Stimulation Of

Abstract Memory B cells are essential for maintaining FVIII inhibitors in patients with hemophilia A. Using the murine E-17 model of hemophilia A, we showed previously that re-exposure to FVIII re-stimulates memory B cells very rapidly and drives their differentiation into antibody-producing plasma cells. Furthermore, we presented evidence that the re-stimulation of FVIII-specific memory B cells is regulated by the dose of FVIII used. Low doses re-stimulate memory B cells whereas high doses of FVIII inhibit this process and prevent the differentiation into anti-FVIII antibody-producing plasma cells. Both the re-stimulation and the inhibition can be modulated by triggering toll-like receptors (TLR) 7 and 9 with specific ligands that are typically found in microbial components derived from viruses or bacteria. Re-stimulation of FVIII-specific memory B cells in the presence of TLR ligands can even be observed in the absence of CD4+ helper T cells that are otherwise absolutely essential for this process. Based on these previous observations we asked whether the re-stimulation of FVIII-specific memory B cells in the absence of CD4+ helper T cells requires interaction with alternative “helper” cells that provide co-stimulatory signals to memory B cells. To address this question we used spleen cells obtained from hemophilic mice treated with FVIII to generate highly purified populations of memory B cells, CD4+ T cells and dendritic cells. The required purity of the different cell populations was achieved by a combination of magnetic bead separation and multi-color flow cytometric cell sorting. The memory B cell compartment was specified by the expression of CD19 together with surface IgG and the absence of surface IgM and IgD. Memory B cells were single-cell sorted and cultivated in micro-well cultures in the presence of FVIII to stimulate the in vitro differentiation into anti-FVIII antibody- producing plasma cells. Different combinations of CD4+ T cells, ligands for TLR 7 or 9 and dendritic cells were added to the micro-well cultures to find out which of the additives were required for the re-stimulation and differentiation of memory B cells. Neither FVIII alone nor any combination of FVIII and ligands for TLR 7 and 9 were able to re-stimulate highly purified memory B cells to differentiate into anti-FVIII antibody-producing plasma cells. The re-stimulation strictly depended on the presence of additional cells that could provide co-stimulation. These additional cells could be either activated CD4+ T cells or, alternatively, plasmacytoid dendritic cells activated by ligands for TLR 7 or 9. Some re-stimulation in the presence of activated plasmacytoid dendritic cells was even observed in the complete absence of FVIII. Based on our results we conclude that plasmacytoid dendritic cells that are activated by TLR ligands such as those expressed by infectious agents can replace CD4+ T cells in triggering the re-stimulation of memory B cells and their differentiation into antibody-producing plasma cells. Our findings provide important new insights into the regulation of memory-B-cell re-stimulation that need to be considered in the development of new therapeutic strategies for treating patients with FVIII inhibitors. Furthermore, our findings underscore the importance of environmental factors in the regulation of FVIII inhibitor development.

Requirements for Co-Stimulation in T-Cell Dependent and T-Cell Independent Re-Stimulation of FVIII-Specific Memory B Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 238-238 ◽  
Author(s):  
Aniko Ginta Pordes ◽  
Christina Hausl ◽  
Peter Allacher ◽  
Rafi Uddin Ahmad ◽  
Eva M Muchitsch ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Specific Memory ◽  
Stimulation Of

Abstract Memory B cells specific for factor VIII (FVIII) are critical for maintaining FVIII inhibitors in patients with hemophilia A. They are precursors of anti-FVIII antibody-producing plasma cells and are highly efficient antigen-presenting cells for the activation of T cells. The eradication of FVIII-specific memory B cells will be a prerequisite for any successful new approach to induce immune tolerance in patients with FVIII inhibitors. Little is known about the regulation of these cells. Previously we showed that ligands for toll-like receptors (TLR) 7 and 9 are able to re-stimulate FVIII-specific memory B cells in the absence of T-cell help. However, alternative “helper cells” such as dendritic cells are essential for providing help to memory B cells under such conditions. Based on these findings, we asked which co-stimulatory interactions are required for the restimulation of memory B cells in the presence of dendritic cells and ligands for TLR and whether these co-stimulatory interactions are the same as those required for the restimulation of memory B cells in the presence of activated T cells. We used spleen cells from hemophilic mice treated with human FVIII to generate highly purified populations of memory B cells, CD4+ T cells and dendritic cells. The required purity was achieved by a combination of magnetic bead separation and fluorescence-activated cell sorting. The memory B cell compartment was specified by the expression of CD19 together with IgG and the absence of surface IgM and IgD. Memory B cells were cultured in the presence of FVIII to stimulate their differentiation into anti-FVIII antibody-producing plasma cells. Different combinations of CD4+ T cells, ligands for TLR 7 and 9 and dendritic cells were added to the memory-B-cell cultures. Blocking antibodies and competitor proteins were used to specify the co-stimulatory interactions required for the re-stimulation of memory B cells in the presence of either CD4+ T cells or dendritic cells and ligands for TLR 7 and 9. Our results demonstrate that the blockade of B7-1 and B7-2 as well as the blockade of CD40L inhibit the re-stimulation of FVIII-specific memory B cells and their differentiation into anti-FVIII antibody-producing plasma cells in the presence of T-cell help. Similar requirements apply for the re-stimulation of memory B cells in the presence of dendritic cells and ligands for TLR 7 or 9. Dendritic cells in the absence of ligands for TLR are not able to provide help for the re-stimulation of memory B cells, which indicates that dendritic cells need to be activated. Furthermore, ligands for TLR 7 or 9 were not able to re-stimulate memory B cells in the complete absence of dendritic cells. Based on these results we conclude that dendritic cells activated by ligands for TLR 7 or 9 can substitute for activated CD4+ T cells in providing co-stimulatory help for memory-B-cell re-stimulation. CD40-CD40L interactions seem to be the most important co-stimulatory interactions for the re-stimulation of memory B cells, not only in the presence of activated CD4+ T cells but also in the presence of ligands for TLR and dendritic cells.

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