B Cell Functions in the Development of Type I Allergy and Induction of Immune Tolerance

2021 ◽  
pp. 249-264
Author(s):  
Lisa Naomi Pointner ◽  
Fatima Ferreira ◽  
Lorenz Aglas
Keyword(s):  
B Cell ◽  
Immune Tolerance ◽  
Type I ◽  
Cell Functions ◽  
Type I Allergy

Immune Tolerance Induction to Factor IX Through B Cell Gene Transfer – Delineating Between Tolerogenic and Immunogenic B Cells.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3156-3156
Author(s):  
Xiaomei Wang ◽  
Babak Moghimi ◽  
Irene Zolotukhin ◽  
Ou Cao ◽  
Roland W Herzog
Keyword(s):  
B Cells ◽  
Gene Transfer ◽  
B Cell ◽  
Immune Tolerance ◽  
Tolerance Induction ◽  
Factor Ix ◽  
Hemophilia B ◽  
Type I ◽  
Type I Ifn ◽  
Immune Tolerance Induction

Abstract Abstract 3156 At present, the most serious complication in hemophilia therapy is the development of neutralizing antibodies (inhibitors) to intravenous administrated recombinant protein, which compromises therapy, creates immune-toxicity, and increases costs. Although inhibitor formation is less frequent in hemophilia B, it is more prevalent in severe hemophilia B patients, often with additional consequences - up to 50% patients with inhibitors to factor IX (F.IX) develop anaphylactic reactions. These further increase risks of morbidity and mortality. Available bypass therapy is expensive and at risk for thrombosis. Clinical immune tolerance induction (ITI) protocols are lengthy, expensive, and are often terminated in hemophilia B due to anaphylactic reactions or nephrotic syndrome. Therefore, effective protocols to induce immune tolerance to F.IX are urgently needed. B cells have been identified as antigen presenting cells with potentially immune suppressive/regulatory roles. Upon gene transfer, primary B cells were found to induce tolerance to the expressed transgene product. Hence, we use autologous gene-modified primary B cells expressing F.IX antigen fused with immunoglobulin-G heavy chain in a murine model of hemophilia B. Our murine hemophilia B model is unique in both developing high-titer inhibitors and fatal anaphylactic reactions to protein replacement therapy. Retroviral transduced B cells, expressing either full-length or shorter version of F.IX, markedly reduced inhibitor titers up to 30-fold and completely prevented fatal anaphylactic reactions. After 7 weeks of treatment with recombinant human F.IX (IV, 1 IU/mouse, once per week), mice receiving control B cells (n=6) had developed inhibitor titers of 23±8 BU, and 50% died after the last injection. Mice tolerized to F.IX by B cell transplant (n=7) had formed <1 BU, essentially undetectable by this assay, and all survived without anaphylactic reactions. We also tested the B cell-based therapy in already primed mice. Animals receiving B cells expressing the F.IX-IgG fusion successfully reversed the inhibitor and total anti-F.IX IgG titers markedly, whereas animals receiving B cells expressing IgG control had insignificant changes of inhibitor/antibody levels. Our data suggested that B cell-based gene therapy is a promising strategy in not only prevention but also treatment of inhibitors against F.IX. Besides retroviral gene transfer, we tested alternative methods such as DNA nucleofection. Interestingly, although achieving higher gene transfer efficiency, nucleofection of the plasmid encoding the retroviral expression cassette increased rather than decreased immune responses to F.IX. This was likely caused by activation of innate immune mediators and inflammatory cytokine expression as indicated by expression array analysis. Among the 29 genes tested, IL-6 and type I IFN were significantly upregulated in nucleofected B cells compared with retroviral infected B cells, which was further confirmed by ELISA. IL-6 and type I IFN are known to abrogate tolerance such as in transplant rejection and anti-tumor immunity. We suspected that the endosomal DNA sensor TLR9 may induce these cytokines in response to nucleofection. Consistent with this hypothesis, using a TLR9 inhibitory oligodeoxynucleotide (ODN 2088), we significantly reduced nucleofection-associated IL-6 and type I IFN production compared to passive ODN control. These data provide insights into the mechanisms that control the immune phenotype of gene-modified primary B cells, which become tolerogenic under conditions of limited innate responses and immunogenic upon activation of inflammatory and IFN I gene expression. Disclosures: Herzog: Genzyme Corp.: Royalties, AAV-FIX technology, Royalties, AAV-FIX technology Patents & Royalties.

Author response for "Type I interferons provide additive signals for murine regulatory B cell induction by Schistosoma mansoni eggs"

2018 ◽  
Author(s):  
Katja Obieglo ◽  
Alice Costain ◽  
Lauren M. Webb ◽  
Arifa Ozir‐Fazalalikhan ◽  
Shelia L. Brown ◽  
...  
Keyword(s):  
B Cell ◽  
Type I Interferons ◽  
Author Response ◽  
Type I ◽  
Regulatory B Cell ◽  
Cell Induction

Inhibitor treatment by rituximabin congenital haemophilia A

2009 ◽  
Vol 29 (02) ◽  
pp. 151-154 ◽  
Author(s):  
Escuriola Ettingshausen ◽  
R. Linde ◽  
G. Kropshofer ◽  
L.-B. Zimmerhackl ◽  
W. Kreuz ◽  
...  
Keyword(s):  
B Cell ◽  
Immune Tolerance ◽  
High Titre ◽  
Clotting Factor ◽  
Severe Bleeding ◽  
High Morbidity ◽  
Haemophilia A ◽  
Concomitant Treatment ◽  
Bleeding Tendency ◽  
Severe Haemophilia

SummaryThe development of neutralizing alloanti-bodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection. Conclusion: Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.

scholarly journals OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 4-5
Author(s):  
A. Aue ◽  
F. Szelinski ◽  
S. Weißenberg ◽  
A. Wiedemann ◽  
T. Rose ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

Formalin-Fixed Staphylococcus aureus Particles Prevent Allergic Sensitization in a Murine Model of Type I Allergy

2007 ◽  
Vol 144 (3) ◽  
pp. 183-196 ◽  
Author(s):  
Karina Gisch ◽  
Nadine Gehrke ◽  
Matthias Bros ◽  
Christina Priesmeyer ◽  
Jürgen Knop ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Murine Model ◽  
Allergic Sensitization ◽  
Type I ◽  
Type I Allergy ◽  
Formalin Fixed

scholarly journals B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner

2021 ◽  
pp. annrheumdis-2021-220435
Author(s):  
Theresa Graalmann ◽  
Katharina Borst ◽  
Himanshu Manchanda ◽  
Lea Vaas ◽  
Matthias Bruhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
De Novo ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
T Cell Expansion

ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

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