TY - JOUR A1 - Traub, Jan A1 - Husseini, Leila A1 - Weber, Martin S. T1 - B cells and antibodies as targets of therapeutic intervention in neuromyelitis optica spectrum disorders JF - Pharmaceuticals N2 - The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD. KW - neuromyelitis optica spectrum disorders KW - B cells KW - antibodies KW - eculizumab KW - ravulizumab KW - inebilizumab KW - tocilizumab KW - satralizumab KW - ublituximab Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222957 SN - 1424-8247 VL - 14 IS - 1 ER - TY - JOUR A1 - Kader, Hidaya A. A1 - Azeem, Muhammad A1 - Jwayed, Suhib A. A1 - Al-Shehhi, Aaesha A1 - Tabassum, Attia A1 - Ayoub, Mohammed Akli A1 - Hetta, Helal F. A1 - Waheed, Yasir A1 - Iratni, Rabah A1 - Al-Dhaheri, Ahmed A1 - Muhammad, Khalid T1 - Current insights into immunology and novel therapeutics of atopic dermatitis JF - Cells N2 - Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes. KW - atopic dermatitis KW - immune system KW - T cells KW - B cells KW - keratinocytes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241008 SN - 2073-4409 VL - 10 IS - 6 ER - TY - JOUR A1 - Sánchez-Maldonado, Jose Manuel A1 - Moñiz-Díez, Ana A1 - ter Horst, Rob A1 - Campa, Daniele A1 - Cabrera-Serrano, Antonio José A1 - Martínez-Bueno, Manuel A1 - Garrido-Collado, María del Pilar A1 - Hernández-Mohedo, Francisca A1 - Fernández-Puerta, Laura A1 - López-Nevot, Miguel Ángel A1 - Cunha, Cristina A1 - González-Sierra, Pedro Antonio A1 - Springer, Jan A1 - Lackner, Michaela A1 - Alcazar-Fuoli, Laura A1 - Fianchi, Luana A1 - Aguado, José María A1 - Pagano, Livio A1 - López-Fernández, Elisa A1 - Clavero, Esther A1 - Potenza, Leonardo A1 - Luppi, Mario A1 - Moratalla, Lucia A1 - Solano, Carlos A1 - Sampedro, Antonio A1 - Cuenca-Estrella, Manuel A1 - Lass-Flörl, Cornelia A1 - Canzian, Federico A1 - Loeffler, Juergen A1 - Li, Yang A1 - Einsele, Hermann A1 - Netea, Mihai G. A1 - Vázquez, Lourdes A1 - Carvalho, Agostinho A1 - Jurado, Manuel A1 - Sainz, Juan T1 - Polymorphisms within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis: a two-stage case control study in the context of the aspBIOmics consortium JF - Journal of Fungi N2 - Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4\(_{rs7526628T/T}\) genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4\(_{rs7526628T}\) allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2\(_{rs12137965G}\) allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2\(_{rs17013271T}\) allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2\(_{rs12137965G}\) allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2\(_{rs17013271T}\) allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk. KW - invasive aspergillosis KW - TNFSF4 KW - MAPKAPK2 KW - genetic susceptibility KW - B cells KW - monocytes KW - serum biomarkers KW - TSLP KW - TNFSF14 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220107 SN - 2309-608X VL - 7 IS - 1 ER - TY - JOUR A1 - Dirks, Johannes A1 - Fischer, Jonas A1 - Haase, Gabriele A1 - Holl-Wieden, Annette A1 - Hofmann, Christine A1 - Girschick, Hermann A1 - Morbach, Henner T1 - CD21\(^{lo/−}\)CD27\(^−\)IgM\(^−\) Double-Negative B Cells Accumulate in the Joints of Patients With Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis JF - Frontiers in Pediatrics N2 - 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 CD21\(^{lo/−}\)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. KW - juvenile idiopathic arthritis KW - B cells KW - antinuclear antibodies KW - synovial fluid KW - double negative B cells Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236286 SN - 2296-2360 VL - 9 ER - TY - JOUR A1 - Prelog, Martina T1 - Differential Approaches for Vaccination from Childhood to Old Age JF - Gerontology N2 - Primary prevention strategies, such as vaccinations at the age extremes, in neonates and elderly individuals, demonstrate a challenge to health professionals and public health specialists. The aspects of the differentiation and maturation of the adaptive immune system, the functional implications of immunological immaturity or immunosenescence and its impact on vaccine immunogenicity and efficacy will be highlighted in this review. Several approaches have been undertaken to promote Th1 responses in neonates and to enhance immune functions in elderly, such as conjugation to carrier proteins, addition of adjuvants, concomitant vaccination with other vaccines, change in antigen concentrations or dose intervals or use of different administration routes. Also, early protection by maternal vaccination seems to be beneficial in neonates. However, it also appears necessary to think of other end points than antibody concentrations to assess vaccine efficacy in neonates or elderly, as also the cellular immune response may be impaired by the mechanisms of immaturity, underlying health conditions, immunosuppressive treatments or immunosenescence. Thus, lifespan vaccine programs should be implemented to all individuals on a population level not only to improve herd protection and to maintain protective antibody levels and immune memory, but also to cover all age groups, to protect unvaccinated elderly persons and to provide indirect protection for neonates and small infants. KW - immunosenescence KW - aging KW - T cells KW - B cells KW - immunization KW - vaccination KW - thymus KW - influenza KW - neonates KW - antibody Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196602 SN - 0304-324X SN - 1423-0003 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 59 IS - 3 ER - TY - JOUR A1 - Gernert, Michael A1 - Tony, Hans-Peter A1 - Schwaneck, Eva Christina A1 - Fröhlich, Matthias A1 - Schmalzing, Marc T1 - Low B cell counts as risk factor for infectious complications in systemic sclerosis after autologous hematopoietic stem cell transplantation JF - Arthritis Research & Therapy N2 - Background Autologous hematopoietic stem cell transplantation (aHSCT) is a treatment option for a selected group of systemic sclerosis (SSc) patients with good available evidence but can be associated with considerable morbidity and mortality. The aim of this study was to describe infectious complications and distinct immune reconstitution patterns after aHSCT and to detect risk factors in lymphocyte subsets, which are associated with an elevated rate of infections after aHSCT. Methods Seventeen patients with SSc were included in this single-center retrospective cohort study. Clinical and laboratory data was collected before and for 12 months after aHSCT, including immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting. Results Cytomegalovirus (CMV) reactivations were common in CMV-IgG-positive patients (50%) and needed treatment. Mycotic infections occurred in 17.6%. One patient died (resulting in a mortality of 5.9%) due to pneumonia with consecutive sepsis. All patients showed decreased T helper cells (CD3\(^+\)/CD4\(^+\)) and within the B cell compartment decreased post-switched memory B cells (CD19\(^+\)/CD27\(^+\)/IgD\(^-\)) and elevated naive B cells (CD19\(^+\)/CD27\(^-\)/IgD\(^+\)) until 12 months after aHSCT. Patients who developed infections had significantly lower B cells before aHSCT than patients who did not develop infections. Conclusion After aHSCT, monitoring for infectious complications, especially for CMV reactivations, is crucial as the reconstitution of the immune system takes longer than 12 months. Low peripheral B cells might be a risk factor for an elevated infection rate. KW - Systemic sclerosis KW - Autologous hematopoietic stem cell transplantation KW - Infectious complications KW - CMV reactivation KW - B cells Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229962 VL - 22 ER - TY - JOUR A1 - Alrefai, Hani A1 - Muhammad, Khalid A1 - Rudolf, Ronald A1 - Pham, Duong Anh Thuy A1 - Klein-Hessling, Stefan A1 - Patra, Amiya K. A1 - Avots, Andris A1 - Bukur, Valesca A1 - Sahin,, Ugur A1 - Tenzer, Stefan A1 - Goebeler, Matthias A1 - Kerstan, Andreas A1 - Serfling, Edgar T1 - NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells JF - Nature Communications N2 - Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis. KW - B cells KW - psoriasis KW - interleukins KW - inflammation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173053 VL - 7 ER - TY - JOUR A1 - Mahmood, Zafar A1 - Schmalzing, Marc A1 - Dörner, Thomas A1 - Tony, Hans-Peter A1 - Muhammad, Khalid T1 - Therapeutic Cytokine Inhibition Modulates Activation and Homing Receptors of Peripheral Memory B Cell Subsets in Rheumatoid Arthritis Patients JF - Frontiers in Immunology N2 - Memory B cells have known to play an important role in the pathogenesis of rheumatoid arthritis (RA). With the emergence of B cell-targeted therapies, the modulation of memory B cells appears to be a key therapeutic target. Human peripheral memory B cells can be distinguished based on the phenotypic expression of CD27 and IgD, characterizing the three major B cell subpopulations: CD27+IgD+ pre-switch, CD27+IgD- post-switch, and CD27-IgD- double-negative memory B cells. We evaluated different memory cell populations for activation markers (CD95 and Ki-67) and chemokine receptors (CXCR3 and 4) expressing B cells in active RA, as well as under IL6-R blockade by tocilizumab (TCZ) and TNF-α blockade by adalimumab (ADA). Memory B cells were phenotypically analyzed from RA patients at baseline, week 12, and week 24 under TCZ or ADA treatment, respectively. Using flow cytometry, surface expression of CD95, intracellular Ki-67, and surface expressions of CXCR3 and CXCR4 were determined. Compared with healthy donors (n = 40), the phenotypic analysis of RA patients (n = 80) demonstrated that all three types of memory B cells were activated in RA patients. Surface and intracellular staining of B cells showed a significantly higher percentage of CD95+ (p < 0.0001) and Ki-67+ (p < 0.0001) cells, with numerically altered CXCR3+ and CXCR4+ cells in RA. CD95 and Ki-67 expressions were highest in post-switch memory B cells, whereas CD19+CXCR3+ and CD19+CXCR4+ expressing cells were substantially higher in the pre-switch compartment. In all subsets of the memory B cells, in vivo IL-6R, and TNF-α blockade significantly reduced the enhanced expressions of CD95 and Ki-67. Based on our findings, we conclude that the three major peripheral memory B cell populations, pre-, post-switch, and double-negative B cells, are activated in RA, demonstrating enhanced CD95 and Ki-67 expressions, and varied expression of CXCR3 and CXCR4 chemokine receptors when compared with healthy individuals. This activation can be efficaciously modulated under cytokine inhibition in vivo. KW - B cells KW - inflammation KW - adalimumab KW - tocilizumab (IL-6 inhibitor) KW - memory B cells KW - rheumatoid arhritis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212380 SN - 1664-3224 VL - 11 ER - TY - JOUR A1 - Muhammad, Khalid A1 - Rudolf, Ronald A1 - Pham, Duong Anh Thuy A1 - Klein-Hessling, Stefan A1 - Takata, Katsuyoshi A1 - Matsushita, Nobuko A1 - Ellenrieder, Volker A1 - Kondo, Eisaku A1 -  Serfling, Edgar T1 - Induction of Short NFATc1/αA Isoform Interferes with Peripheral B Cell Differentiation JF - Frontiers in Immunology N2 - In lymphocytes, immune receptor signals induce the rapid nuclear translocation of preformed cytosolic NFAT proteins. Along with co-stimulatory signals, persistent immune receptor signals lead to high levels of NFATc1/αA, a short NFATc1 isoform, in effector lymphocytes. Whereas NFATc1 is not expressed in plasma cells, in germinal centers numerous centrocytic B cells express nuclear NFATc1/αA. When overexpressed in chicken DT40 B cells or murine WEHI 231 B cells, NFATc1/αA suppressed their cell death induced by B cell receptor signals and affected the expression of genes controlling the germinal center reaction and plasma cell formation. Among those is the Prdm1 gene encoding Blimp-1, a key factor of plasma cell formation. By binding to a regulatory DNA element within exon 1 of the Prdm1 gene, NFATc1/αA suppresses Blimp-1 expression. Since expression of a constitutive active version of NFATc1/αA interfered with Prdm1 RNA expression, LPS-mediated differentiation of splenic B cells to plasmablasts in vitro and reduced immunoglobulin production in vivo, one may conclude that NFATc1/αA plays an important role in controlling plasmablast/plasma cell formation. KW - B cells KW - DT40 cells KW - germinal center KW - NFATc1 KW - plasmablasts KW - plasma cells Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197501 SN - 1664-3224 VL - 9 IS - 32 ER - TY - JOUR A1 - Gernert, Michael A1 - Tony, Hans-Peter A1 - Schwaneck, Eva Christina A1 - Gadeholt, Ottar A1 - Schmalzing, Marc T1 - Autologous hematopoietic stem cell transplantation in systemic sclerosis induces long-lasting changes in B cell homeostasis toward an anti-inflammatory B cell cytokine pattern JF - Arthritis Research & Therapy N2 - Background Autologous hematopoietic stem cell transplantation (aHSCT) is performed in patients with aggressive forms of systemic sclerosis (SSc). The profile of B cell reconstitution after aHSCT is not fully understood. The aim of this study was to investigate changes of B cell subsets and cytokine production of B cells in patients with SSc after aHSCT. Methods Peripheral blood of six patients with SSc was collected at defined intervals up to 16 months after aHSCT. Immunophenotyping was performed, and B cell function was determined by measuring cytokine secretion in supernatants of stimulated B cell cultures. Results Within 1 month after aHSCT, a peak in the percentage of CD38\(^{++}\)/CD10\(^+\)/IgD\(^+\) transitional B cells and CD38\(^{++}\)/CD27\(^{++}\)/IgD\(^−\) plasmablasts was detected. Long-term changes persisted up to 14 months after aHSCT and showed an increased percentage of total B cells; the absolute B cell number did not change significantly. Within the B cell compartment, an increased CD27/IgD\(^+\) naïve B cell percentage was found whereas decreased percentages of CD27\(^+\)/IgD\(^+\) pre-switched memory, CD27\(^+\)/IgD\(^−\) post-switched memory, and CD27\(^−\) /IgD\(^−\) double-negative B cells were seen after aHSCT. Cytokine secretion in B cell cultures showed significantly increased IL-10 concentrations 13 to 16 months after aHSCT. Conclusion A changed composition of the B cell compartment is present for up to 14 months after aHSCT indicating positive persisting effects of aHSCT on B cell homeostasis. The cytokine secretion profile of B cells changes in the long term and shows an increased production of the immune regulatory cytokine IL-10 after aHSCT. These findings might promote the clinical improvements after aHSCT in SSc patients. KW - Systemic sclerosis KW - B cells KW - Memory B cells KW - naïve B cells KW - Autologous hematopoietic stem cell transplantation KW - Interleukin-10 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201004 VL - 21 ER -