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

Author

Johannes Dirks, Jonas Fischer, Gabriele Haase, Annette Holl-Wieden, Christine Hofmann, Hermann Girschick, and Henner Morbach

Subjects
juvenile idiopathic arthritis, B cells, antinuclear antibodies, synovial fluid, double negative B cells, Pediatrics, RJ1-570
Abstract

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.

Published
2021
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2. The German National Registry of Primary Immunodeficiencies (2012–2017)

Author

Sabine M. El-Helou, Anika-Kerstin Biegner, Sebastian Bode, Stephan R. Ehl, Maximilian Heeg, Maria E. Maccari, Henrike Ritterbusch, Carsten Speckmann, Stephan Rusch, Raphael Scheible, Klaus Warnatz, Faranaz Atschekzei, Renata Beider, Diana Ernst, Stev Gerschmann, Alexandra Jablonka, Gudrun Mielke, Reinhold E. Schmidt, Gesine Schürmann, Georgios Sogkas, Ulrich H. Baumann, Christian Klemann, Dorothee Viemann, Horst von Bernuth, Renate Krüger, Leif G. Hanitsch, Carmen M. Scheibenbogen, Kirsten Wittke, Michael H. Albert, Anna Eichinger, Fabian Hauck, Christoph Klein, Anita Rack-Hoch, Franz M. Sollinger, Anne Avila, Michael Borte, Stephan Borte, Maria Fasshauer, Anja Hauenherm, Nils Kellner, Anna H. Müller, Anett Ülzen, Peter Bader, Shahrzad Bakhtiar, Jae-Yun Lee, Ursula Heß, Ralf Schubert, Sandra Wölke, Stefan Zielen, Sujal Ghosh, Hans-Juergen Laws, Jennifer Neubert, Prasad T. Oommen, Manfred Hönig, Ansgar Schulz, Sandra Steinmann, Klaus Schwarz, Gregor Dückers, Beate Lamers, Vanessa Langemeyer, Tim Niehues, Sonu Shai, Dagmar Graf, Carmen Müglich, Marc T. Schmalzing, Eva C. Schwaneck, Hans-Peter Tony, Johannes Dirks, Gabriele Haase, Johannes G. Liese, Henner Morbach, Dirk Foell, Antje Hellige, Helmut Wittkowski, Katja Masjosthusmann, Michael Mohr, Linda Geberzahn, Christian M. Hedrich, Christiane Müller, Angela Rösen-Wolff, Joachim Roesler, Antje Zimmermann, Uta Behrends, Nikolaus Rieber, Uwe Schauer, Rupert Handgretinger, Ursula Holzer, Jörg Henes, Lothar Kanz, Christoph Boesecke, Jürgen K. Rockstroh, Carolynne Schwarze-Zander, Jan-Christian Wasmuth, Dagmar Dilloo, Brigitte Hülsmann, Stefan Schönberger, Stefan Schreiber, Rainald Zeuner, Tobias Ankermann, Philipp von Bismarck, Hans-Iko Huppertz, Petra Kaiser-Labusch, Johann Greil, Donate Jakoby, Andreas E. Kulozik, Markus Metzler, Nora Naumann-Bartsch, Bettina Sobik, Norbert Graf, Sabine Heine, Robin Kobbe, Kai Lehmberg, Ingo Müller, Friedrich Herrmann, Gerd Horneff, Ariane Klein, Joachim Peitz, Nadine Schmidt, Stefan Bielack, Ute Groß-Wieltsch, Carl F. Classen, Jessica Klasen, Peter Deutz, Dirk Kamitz, Lisa Lassay, Klaus Tenbrock, Norbert Wagner, Benedikt Bernbeck, Bastian Brummel, Eusebia Lara-Villacanas, Esther Münstermann, Dominik T. Schneider, Nadine Tietsch, Marco Westkemper, Michael Weiß, Christof Kramm, Ingrid Kühnle, Silke Kullmann, Hermann Girschick, Christof Specker, Elisabeth Vinnemeier-Laubenthal, Henriette Haenicke, Claudia Schulz, Lothar Schweigerer, Thomas G. Müller, Martina Stiefel, Bernd H. Belohradsky, Veronika Soetedjo, Gerhard Kindle, and Bodo Grimbacher

Subjects
registry for primary immunodeficiency, primary immunodeficiency (PID), German PID-NET registry, PID prevalence, European Society for Immunodeficiencies (ESID), IgG substitution therapy, Immunologic diseases. Allergy, RC581-607
Abstract

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

Published
2019
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3. A Novel AICDA Splice-Site Mutation in Two Siblings with HIGM2 Permits Somatic Hypermutation but Abrogates Mutational Targeting

Author

Johannes Dirks, Gabriele Haase, Tineke Cantaert, Lea Frey, Moritz Klaas, Christian H. Rickert, Hermann Girschick, Eric Meffre, and Henner Morbach

Subjects
Phenotype, Cytidine Deaminase, Siblings, Mutation, Immunology, Humans, Immunology and Allergy, Somatic Hypermutation, Immunoglobulin, Hyper-IgM Immunodeficiency Syndrome, Immunoglobulin Class Switching
Abstract

Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.

Published
2022

4. Effect of Clonally Expanded <scp> PD‐1 high CXCR5 </scp> – <scp>CD4</scp> + Peripheral T Helper Cells on B Cell Differentiation in the Joints of Patients With Antinuclear Antibody–Positive Juvenile Idiopathic Arthritis

Author

Hermann J. Girschick, Henner Morbach, Julia Klaussner, Johannes Dirks, Stephan Hackenberg, Jonas Fischer, Gabriele Haase, Annette Holl-Wieden, and Christine Hofmann

Subjects
musculoskeletal diseases, medicine.medical_treatment, T cell, Cellular differentiation, Immunology, T-cell receptor, CD11c, Biology, Molecular biology, CXCR5, medicine.anatomical_structure, Cytokine, Rheumatology, medicine, Immunology and Allergy, Synovial fluid, B cell
Abstract

Objectives Antinuclear antibody (ANA) positive Juvenile Idiopathic Arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. The objective of this study is to unravel the phenotype and function of synovial CD4+ T cells that promote the aberrant B cell activation in JIA. Methods Flow cytometric analysis was performed to compare the phenotype and cytokine pattern of synovial fluid (SF) PD-1hi CD4+ T cells with tonsil TFH cells. TCRVB next generation sequencing was applied to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was dissected in in vitro co-cultures. Results Multidimensional flow-cytometric analysis revealed the expansion of IL-21 and IFN-γ co-expressing PD-1hi CXCR5- HLA-DR+ CD4+ T cells that accumulate in the joints of ANA+ JIA patients. These T cells exhibited signs of clonal expansion with restricted TCR clonotypes. Phenotypically they resembled peripheral T helper (TPH ) cells with an extrafollicular chemokine receptor pattern and high T-bet and Blimp-1 but low Bcl-6 expression. SF TPH cells particularly skewed B cell differentiation towards a CD21lo/- CD11c+ phenotype by provision of IL-21 and IFN-γ in vitro and correlated with the appearance of SF CD21lo/- CD11c+ CD27- IgM- double-negative B cells (BDN ) in situ. Conclusion Clonally expanded CD4+ TPH cells accumulate in the joints of ANA+ JIA patients and particularly promote CD21lo/- CD11c+ BDN cell differentiation The expansion of TPH and BDN cells might reflect the autoimmune response present in the joints of ANA+ JIA patients.

Published
2021

5. Effect of Clonally Expanded PD-1

Author

Jonas, Fischer, Johannes, Dirks, Julia, Klaussner, Gabriele, Haase, Annette, Holl-Wieden, Christine, Hofmann, Stephan, Hackenberg, Hermann, Girschick, and Henner, Morbach

Subjects
CD4-Positive T-Lymphocytes, Receptors, CXCR5, B-Lymphocytes, Antibodies, Antinuclear, Programmed Cell Death 1 Receptor, Humans, Cell Differentiation, Joints, T-Lymphocytes, Helper-Inducer, Lymphocyte Activation, Arthritis, Juvenile
Abstract

Antinuclear antibody (ANA)-positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA.Flow cytometry was performed to compare the phenotype and cytokine patterns of PD-1Multidimensional flow cytometry revealed the expansion of interleukin-21 (IL-21) and interferon-γ (IFNγ)-coexpressing PD-1Clonally expanded CD4+ Tph cells accumulate in the joints of ANA-positive JIA patients and, in particular, promote CD21

Published
2021

6. IL-21

Author

Jonas, Fischer, Johannes, Dirks, Gabriele, Haase, Annette, Holl-Wieden, Christine, Hofmann, Hermann, Girschick, and Henner, Morbach

Subjects
Male, Interferon-gamma, Tumor Necrosis Factor-alpha, Antibodies, Antinuclear, Child, Preschool, Interleukins, Interleukin-17, Synovial Fluid, Humans, Female, T-Lymphocytes, Helper-Inducer, Child, Arthritis, Juvenile
Abstract

Juvenile Idiopathic Arthritis (JIA) is currently classified into seven subgroups. Recently, antinuclear antibody (ANA) positive JIA patients were suggested to encompass a clinically homogenous new subgroup. CD4

Published
2020

7. IL-21+ CD4+ T helper cells co-expressing IFN-γ and TNF-α accumulate in the joints of antinuclear antibody positive patients with juvenile idiopathic arthritis

Author

Christine Hofmann, Annette Holl-Wieden, Jonas Fischer, Johannes Dirks, Hermann J. Girschick, Henner Morbach, and Gabriele Haase

Subjects
musculoskeletal diseases, 0301 basic medicine, genetic structures, Anti-nuclear antibody, medicine.medical_treatment, Immunology, Cell, Arthritis, Flow cytometry, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, medicine, Immunology and Allergy, Synovial fluid, skin and connective tissue diseases, medicine.diagnostic_test, business.industry, Effector, medicine.disease, eye diseases, 030104 developmental biology, Cytokine, medicine.anatomical_structure, business, 030215 immunology
Abstract

Juvenile Idiopathic Arthritis (JIA) is currently classified into seven subgroups. Recently, antinuclear antibody (ANA) positive JIA patients were suggested to encompass a clinically homogenous new subgroup. CD4+ T helper (Th) cells play an essential role in JIA pathogenesis. Herein, we analyzed cytokine expression in synovial fluid (SF) CD4+ Th cells of JIA patients by using flow cytometry and compared cytokine patterns between JIA subgroups. We could show increased frequencies of IL-21 expressing CD4+ Th cells in the joints of ANA+ Oligo-/Poly-JIA patients, which co-expressed the Th-1 cytokines IFN-γ/TNF-α. In contrast, frequencies of IL-17 expressing cells were lowest in the joints of ANA+ Oligo-/Poly-JIA but enriched in that of ERA-JIA patients. This is the first description of a diverse SF Th cell cytokine pattern in different JIA subgroups. Additionally, we could define IL-21 as an effector cytokine expressed in SF Th cell in a significant proportion of ANA+ JIA patients.

Published
2020

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