A5032400132- Immunodeficiency and Autoimmune Disorders
- T-cell and B-cell Immunology
- Autoimmune Neurological Disorders and Treatments
- Immune Cell Function and Interaction
- Peripheral Neuropathies and Disorders
- Blood disorders and treatments
- Cytomegalovirus and herpesvirus research
- Cystic Fibrosis Research Advances
- Pediatric health and respiratory diseases
- Platelet Disorders and Treatments
- Multiple Sclerosis Research Studies
- Tracheal and airway disorders
- Monoclonal and Polyclonal Antibodies Research
- Blood groups and transfusion
- Histone Deacetylase Inhibitors Research
- Microbial infections and disease research
- Neurological disorders and treatments
- Ion Channels and Receptors
- Immune cells in cancer
- Lymphoma Diagnosis and Treatment
- Polyomavirus and related diseases
- Respiratory viral infections research
- CNS Lymphoma Diagnosis and Treatment
- Single-cell and spatial transcriptomics
- Obsessive-Compulsive Spectrum Disorders
University of Oxford
2014-2025
University Hospital of Zurich
2024
Oxford BioMedica (United Kingdom)
2014-2017
Oxford University Hospitals NHS Trust
2016
John Radcliffe Hospital
2015
University Medical Center Freiburg
2008-2014
MRC Weatherall Institute of Molecular Medicine
2014
University of Freiburg
2013
B-cell survival depends on signals induced by activating factor (BAFF) binding to its receptor (BAFF-R). In mice, mutations in BAFF or BAFF-R cause lymphopenia and antibody deficiency. Analyzing expression BAFF-binding B cells common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion the gene. Removing most of transmembrane part, precludes expression. Without BAFF-R, development is arrested at stage transitional numbers all subsequent stages...
Abstract Autoantibodies against the extracellular domain of N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form encephalitis. To better understand their generation, we aimed to characterize identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from putative site CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA NR1-IgM were detected more...
Introduction N‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of NMDAR. Around 20% patients have an underlying ovarian teratoma, and condition responds to early immunotherapies teratoma removal. However, despite clear therapeutic relevance, mechanisms NR1‐IgG production contribution germinal center B cells levels are unknown. Methods Clinical data longitudinal paired serum NR1‐reactive IgM IgG...
Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs highly variable and a genetic causes have been identified in < 5% patients. Here, we performed whole genome sequencing (WGS) 34 CVID patients (94% sporadic) combined them with transcriptomic profiling (RNA-sequencing B cells) from three healthy controls. We variants disease genes TNFRSF13B, TNFRSF13C, LRBA NLRP12 enrichment known novel pathways. The pathways include B-cell...
Autoantibodies to aquaporin-4 (AQP4) are pathogenic in neuromyelitis optica spectrum disorder (NMOSD). However, it is not known which B cells the major contributors circulating AQP4 antibodies nor conditions promote their generation. Our experiments showed CD19+CD27++CD38++ ex vivo antibody-secreting did produce under several culture conditions. To question whether other circulation were capable of antibody production, differentiated into vitro. Unfractionated peripheral blood mononuclear...
Significance By studying paired blood and deep cervical lymph node samples from patients with neuromyelitis optica spectrum disorders, our data provide evidence for a germinal center–based generation of aquaporin-4 antibodies. Frequent serum immunoglobulin Ms (IgMs) shifts in IgG subclasses were observed alongside preferential synthesis IgGs aquaporin-4–reactive B cells within nodes. Both intranodal antibodies robustly eliminated rituximab administration. This study systematically explores...
In the rapidly evolving field of primary immunodeficiencies (PID), EuroFlow consortium decided to develop a PID orientation and screening tube that facilitates fast, standardized validated immunophenotypic diagnosis lymphoid allows full exchange data between centers. Our aim was tool would be universal for all PIDs offer high sensitivity identify (without need specificity diagnose particular PID) guide prioritize further diagnostic modalities clinical management. The composition has been...
Guidelines for screening primary immunodeficiencies (PID) are well-defined and several consensus diagnostic strategies have been proposed. These proposals only partially implemented due to lack of standardization in laboratory procedures, particularly flowcytometry. The main objectives the EuroFlow Consortium were innovate thoroughly standardize flowcytometric techniques reliable reproducible diagnosis classification PID lymphoid system. proposed antibody panels comprise one orientation tube...
Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand developmental pathway disease-causing B cells and autoantibodies. While such autoreactivities are believed be generated during germinal centre reactions, roles earlier immune checkpoints in autoantigen-specific cell tolerance poorly understood. We address concept patients with CASPR2-autoantibody encephalitis...
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease health, high (~0.5%) frequencies unmutated CASPR2-reactive...
Currently very little is known about the differential expression and function of transcription factor SOX5 during B cell maturation. We identified two new splice variants in human cells, encoding L-SOX5B isoform a shorter L-SOX5F. The transcripts are highly expressed late stages B-cell differentiation, including atypical memory activated CD21low cells germinal center tonsils. In tonsillar sections was predominantly polarized to centrocytes within light zone. After vitro stimulation,...
Introduction Common Variable Immunodeficiency (CVID) is characterized by defective antibody production and hypogammaglobulinemia. Flow cytometry immunophenotyping of blood lymphocytes has become great relevance for the diagnosis classification CVID, due to an impaired differentiation mature post-germinal-center (GC) class-switched memory B-cells (MBC) severely decreased plasmablast/plasma cell (Pb) counts. Here, we investigated in detail pre-GC B-cell maturation compartment CVID patients....
Loss-of-function mutations in DOCK8 are linked to hyper-IgE syndrome. Patients typically present with recurrent sinopulmonary infections, severe cutaneous viral food allergies and elevated serum IgE. Although patients may a spectrum of disease-related symptoms, molecular mechanisms explaining phenotypic variability poorly defined. Here we characterized novel compound heterozygous mutation patient diagnosed primary combined immunodeficiency which was not typical classical deficiency. In...
Mutations in the X-linked inhibitor of apoptosis (XIAP) gene have been associated with XLP-like disease, including recurrent Epstein-Barr virus (EBV)-related haemophagocytic lymphohystiocytosis (HLH), but immunopathogenic bases EBV-related disease XIAP deficiency is unknown. We present first analysis EBV-specific T cell responses functional deficiency. In a family patients novel mutation (G466X) leading to late-truncated protein and varying clinical features, we identified gradual...
Acute myeloid leukemia (AML) is characterized by malignant precursors that span a cellular hierarchy from dedifferentiated leukemic stem cells to mature blasts. While the diagnostic and prognostic importance of AML blast maturation increasingly recognized, personalized therapies are currently not tailored patients individual makeup this hierarchy. In study, we use multiplexed image-based ex vivo drug screening (pharmacoscopy) systematically quantify sensitivity across patients. We analyzed...