Neuroinflammatory diseases . Microbiome . B cells & Antibodies . Immune repertoire . Mucosal immunology . Precision medicine
Decoding functional B cell diversity and mucosal origins in neuroinflammatory diseases: Towards development of cell-type- and microbiota-specific precision therapies
Neuroimmunology: From bedside to bench and back
Fundamental progress has been made in understanding that the "immune privilege" of the brain entails a physiological presence of immune cells in the central nervous system (CNS). Yet, the underlying pathophysiology of immune-mediated diseases of the CNS has not been fully elucidated. In that regard, mounting evidence points towards a pivotal role of microbiota in shaping the immune response during health and disease (Pröbstel & Baranzini. Neurotherapeutics 2018).
Taking cues from opposing clinical trial results with B cell-depleting therapies in multiple sclerosis (MS) (Sabatino*, Pröbstel*, Zamvil. Nature Reviews Neuroscience 2019), we recently discovered a novel subset of gut-originating anti-inflammatory B cells that are trafficking to the brain to counteract neuroinflammation in MS and potentially other neuroinflammatory conditions (Pröbstel et al. Science Immunology 2020, Rojas*, Pröbstel* et al. Cell 2019). Tying these findings to our longstanding interest in autoreactive B cells and antigen discovery (Pröbstel et al. Neurology 2011, Journal of Neuroinflammation 2015, Rheumatology 2016, NEJM 2016), we aim to deconvolute the spatio-temporal cellular and molecular landscape of functionally heterogeneous B cells across compartments and their interaction with gut microbiota in neuroinflammatory diseases with a focus on multiple sclerosis, anti-MOG antibody disease (MOGAD), autoimmune encephalitis, and neurolupus.
We are a highly interdisciplinary, international team pursuing the overall vision of developing novel cell type-specific and microbiome-based strategies to deplete autoreactive, pathogenic B cells and to foster immune regulatory responses through targeted manipulation of the gut microbiome. To that end, we integrate a broad spectrum of methods combining human immunology and immune repertoire analysis, single-cell bioinformatics, microbiota sequencing, and experimental (gnotobiotic) mouse models.
Specifically, research in the Pröbstel lab pursues three main research lines:
Decoding autoreactive immune profiles in MOGAD
We previously identified antibodies against the native conformational myelin protein myelin oligodendrocyte glycoprotein (MOG) in a subgroup of patients with autoimmune neuroinflammation (Pröbstel et al. Neurology 2011) including neurolupus (Pröbstel et al. Rheumatology 2016). Further clinical characterization (Pröbstel et al. Journal of Neuroinflammation 2015) has recently led to the definition of MOGAD as its own disease entity distinct from MS (Marignier*, Hacohen*, Cobo-Calvo*, Pröbstel* et al. Lancet Neurology 2021). Yet, the underlying pathophysiology of MOGAD remains unclear and to date there are no licensed treatments available. Research in the Pröbstel Lab aims to decode autoimmune profiles and microbial triggers in MOGAD synergistically using patient samples and mouse models with the overarching aim to develop personalized treatments strategies.
Deciphering immune cell trafficking and microbiota-immune crosstalk in neuroinflammation in MS
Building on our recent finding of immune cell trafficking from the gut to the inflamed CNS in MS, research in the Pröbstel Lab aims to decipher triggers and profiles of gut-brain trafficking immune cells and to disentangle beneficial from pathogenic immune cell subsets. By leveraging mechanistic insights from patient tissues and microbial transplant models in mice, we strive to develop targeted microbiome therapies to foster immune regulatory responses.
Decrypting mucosal-originating immune cells in neuroinflammation beyond MS
Building on evidence for a role of mucosal originating regulatory B cells in inflammation beyond MS, research in the Pröbstel Lab aims to elucidate the role of mucosal B cells in patients with systemic lupus erythematosus and CNS involvement in close collaboration with the Swiss Lupus Cohort Study and a large European Consortium Study (3TR). Identifying shared pathomechanisms between different neuroinflammatory conditions may pave the way for the development of common immune and microbiota-based therapies for different diseases.
The fundamental impact that the Sars-CoV-2 pandemic has on our immune system and the long-term neurological sequelae of COVID-19 has prompted the Pröbstel Lab to investigate presence of viral transcripts and features of immunopathology in COVID-19 brains (Pröbstel & Schirmer. Trends in Neuroscience 2021) in close collaboration with our neuropathology and neurosurgical colleagues.
Deciphering the immunopathogenesis of Neuro-COVID
Along recent reports, we found an increased level of innate immune activation associated with CNS border areas (Deigendesch et al. Acta Neuropathologica 2020) as well as a compartmentalized cytokine response (Etter et al. medRxiv 2022). Further, we found presence of viral transcripts in the choroid plexus suggesting the choroid plexus as a critical entry point for SARS-CoV-2 (Fuchs et al. Neurology Neuroimmunology Neuroinflammation 2021). Notably, when comparing COVID-19 patients without autoimmune disease to a COVID-19 patient with MS, we found no evidence for MS disease exacerbation. More work is needed to fully elucidate the immunopathology underlying Neuro-COVID to inform rationale treatment decisions.
Collaborations & Research networks
The Pröbstel Lab is part of the Departments of Neurology, Clinical Research (DKF), and the Research Center of Clinical Neurology and Neuroscience Basel (RC2NB). We are closely collaborating with several clinical and experimental research groups locally, nationally, and internationally. A. Pröbstel is a member of the Immunology Community at the University of Basel (uBICo), the Neuroscience Network Basel, and founding member and head of the executive committee of the International Women in Multiple Sclerosis (iWiMS) Network.
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Research in the Pröbstel Lab aims to understand the functional diversity and antigen specificity of B cells and their interaction with gut microbiota that are underlying immune-mediated diseases of the central nervous system with the overall vision of developing strategies to foster immune regulatory responses through targeted manipulation of the gut microbiome.
B cell diversity during autoimmune neuroinflammation. Taking cues from opposing clinical trial results with B cell-depleting therapies in multiple sclerosis (MS), we previously identified proinflammatory memory IgG+ B cell subtypes (Ramesh et al. PNAS 2019) as well as gut originating regulatory IgA+ B cells / plasma cells (Pröbstel et al. Science Immunology 2020). These results highlight the functional diversity and specificity of B cells and identify a pivotal role of gut microbiota and the mucosal compartment in autoimmune neuroinflammatory diseases such as MS.