@article{FischerDirksKlaussneretal.2022,
  author    = {Fischer, Jonas and Dirks, Johannes and Klaussner, Julia and Haase, Gabriele and Holl-Wieden, Annette and Hofmann, Christine and Hackenberg, Stephan and Girschick, Hermann and Morbach, Henner},
  title     = {Effect of clonally expanded PD-1\(^h\)\(^i\)\(^g\)\(^h\) CXCR5-CD4+ peripheral T Helper cells on B cell differentiation in the joints of patients with antinuclear antibody-positive juvenile idiopathic arthritis},
  series = {Arthritis \& Rheumatology},
  volume    = {74},
  journal   = {Arthritis \& Rheumatology},
  number    = {1},
  doi       = {10.1002/art.41913},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256607},
  pages     = {150-162},
  year      = {2022},
  abstract  = {Objective 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. Methods Flow cytometry was performed to compare the phenotype and cytokine patterns of PD-1\(^h\)\(^i\)\(^g\)\(^h\)CD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next-generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro. Results Multidimensional flow cytometry revealed the expansion of interleukin-21 (IL-21) and interferon-γ (IFNγ)-coexpressing PD-1\(^h\)\(^i\)\(^g\)\(^h\)CXCR5-HLA-DR+CD4+ T cells that accumulate in the joints of ANA-positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T-bet and B lymphocyte-induced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL-21 and IFNy, skewed B cell differentiation toward a CD21\(^l\)\(^o\)\(^w\)\(^/\)\(^-\)CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21\(^l\)\(^o\)\(^w\)\(^/\)\(^-\)CD11c+CD27-IgM- double-negative (DN) B cells in situ.},
  language  = {en}
}
@article{DirksFischerHaaseetal.2021,
  author    = {Dirks, Johannes and Fischer, Jonas and Haase, Gabriele and Holl-Wieden, Annette and Hofmann, Christine and Girschick, Hermann and Morbach, Henner},
  title     = {CD21\(^{lo/-}\)CD27\(^-\)IgM\(^-\) Double-Negative B Cells Accumulate in the Joints of Patients With Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis},
  series = {Frontiers in Pediatrics},
  volume    = {9},
  journal   = {Frontiers in Pediatrics},
  issn      = {2296-2360},
  doi       = {10.3389/fped.2021.635815},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236286},
  year      = {2021},
  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 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.},
  language  = {en}
}
@article{DirksHaaseCantaertetal.2022,
  author    = {Dirks, Johannes and Haase, Gabriele and Cantaert, Tineke and Frey, Lea and Klaas, Moritz and Rickert, Christian H. and Girschick, Hermann and Meffre, Eric and Morbach, Henner},
  title     = {A novel AICDA splice-site mutation in two siblings with HIGM2 permits somatic hypermutation but abrogates mutational targeting},
  series = {Journal of Clinical Immunology},
  volume    = {42},
  journal   = {Journal of Clinical Immunology},
  number    = {4},
  doi       = {10.1007/s10875-022-01233-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324253},
  pages     = {771-782},
  year      = {2022},
  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.},
  language  = {en}
}