@article{HedrichMorbachReiseretal.2020,
  author    = {Hedrich, Christian M. and Morbach, Henner and Reiser, Christiane and Girschick, Hermann J.},
  title     = {New Insights into Adult and Paediatric Chronic Non-bacterial Osteomyelitis CNO},
  series = {Current Rheumatology Reports},
  volume    = {22},
  journal   = {Current Rheumatology Reports},
  issn      = {1523-3774},
  doi       = {10.1007/s11926-020-00928-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232636},
  year      = {2020},
  abstract  = {Purpose of Review To describe in detail the clinical synopsis and pathophysiology of chronic non-bacterial osteomyelitis and SAPHO syndrome. Recent Findings Chronic non-bacterial osteomyelitis (CNO) has been identified as a disease entity for almost 50 years. This inflammatory bone disorder is characterized by osteolytic as well as hyperostotic/osteosclerotic lesions. It is chronic in nature, but it can present with episodic flairs and phases of remission, which have led to the denomination "chronic recurrent osteomyelitis", with its severe multifocal form "chronic recurrent multifocal osteomyelitis" (CRMO). For almost three decades, an infectious aetiology had been considered, since especially Propionibacterium acnes had been isolated from bone lesions of individual patients. However, this concept has been challenged since long-term antibiotic therapy did not alter the course of disease and modern microbiological techniques (including PCR) failed to confirm bone infection as an underlying cause. Over recent years, a profound dysregulation of cytokine expression profiles has been demonstrated in innate immune cells of CNO patients. A hallmark of monocytes from CNO patients is the failure to produce immune regulatory cytokines interleukin-10 (IL-10) and IL-19, which have been linked with genetic and epigenetic alterations. Subsequently, a significant upregulation of pro-inflammatory, NLRP3 inflammasome-dependent cytokines (IL-1β and TNF-α), has been demonstrated. Summary The current knowledge on CNO, the underlying molecular pathophysiology, and modern imaging strategies are summarized; differential diagnoses, treatment options, outcome measures, as well as quality of life studies are discussed.},
  language  = {en}
}
@article{VogtGirschickSchweitzeretal.2020,
  author    = {Vogt, Marius and Girschick, Hermann and Schweitzer, Tilmann and Benoit, Clemens and Holl-Wieden, Annette and Seefried, Lothar and Jakob, Franz and Hofmann, Christine},
  title     = {Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children},
  series = {Orphanet Journal of Rare Diseases},
  volume    = {15},
  journal   = {Orphanet Journal of Rare Diseases},
  doi       = {10.1186/s13023-020-01500-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230505},
  year      = {2020},
  abstract  = {Background Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children's Hospital Wuerzburg, Germany over the last 25 years. Results The cohort comprises 4 (8\%) perinatal, 17 (34\%) infantile and 29 (58\%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88\%), low alkaline phosphatase (AP) activity (in 96\%), accumulating substrates of AP (in 58\%) and X-ray findings (in 48\%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78\%), impairment of mineralization (72\%), premature loss of teeth (64\%), musculoskeletal pain and craniosynostosis (each 64\%) and failure to thrive (62\%). Up to now 20 patients started medical treatment with Asfotase alfa. Conclusions Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.},
  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}
}
@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}
}