Therapy with anti-CD20 monoclonal antibodies is highly efficacious in various autoimmune diseases including multiple sclerosis (MS), a prototypic autoimmune inflammatory disease of the central nervous system (CNS). However, which B cell subsets and altered B cell-regulating factors mediate the clinical efficacy of anti-CD20 treatment is unclear. To address this gap in knowledge, we performed longitudinal high-dimensional single-cell transcriptomic and proteomic profiling of blood, cerebrospinal fluid (CSF), and intestinal samples from people with MS (pwMS), combined with immune profiling in a preclinical autoimmune encephalomyelitis model during anti-CD20 therapy. CSF analyses were performed using previously published datasets. Multisite intestinal profiling was conducted in one anti-CD20-treated patient with MS and one control participant. By applying algorithm-guided analyses of flow cytometry, single-cell transcriptomic, and immune receptor repertoire data, we found that anti-CD20 B cell depletion was associated with increased frequencies of regulatory mucosal-derived IgA-producing B cells in the periphery and CSF, together with increased B cell receptor clonal overlap between mucosal and systemic compartments, indicating enhanced trafficking of IgA B cells from gut mucosal tissues to the systemic circulation and the CNS. Moreover, we demonstrated that higher levels of B cell-activating factor and a proliferation-inducing ligand were related to favorable outcomes in pwMS during anti-CD20 treatment. Together, our findings suggest that mucosal immune regulatory mechanisms may be harnessed by anti-CD20 B cell depletion, opening previously unknown therapeutic avenues for MS.
T. Neziraj, Elisabeth Pössnecker, Angela A. Wang et al.· Science Translational Medici...· 0 citations
BackgroundBlood-based biomarkers (BBM) are promising to help diagnose Alzheimer's disease (AD) and are on the verge of implementation in diagnostic dementia workups. However, evaluating BBM performance in peripheral memory clinics is essential to establish their real-world clinical utility.ObjectiveTo evaluate the diagnostic concordance of BBMs with clinically established diagnoses in an unselected peripheral memory clinic population using predefined, validated thresholds.MethodsIn a peripheral memory clinic, plasma levels of phosphorylated Tau217 (pTau217), amyloid-β 42/40 ratio (Aβ42/Aβ40), glial fibrillary acidic protein, and neurofilament light (NfL) were measured in patients (mean age 75.2 ± 8.8 years, 48.3% female) clinically diagnosed with subjective cognitive decline (SCD; n = 108), mild cognitive impairment (MCI; n = 55), AD dementia (n = 132), or non-AD dementia (non-AD; n = 28). BBM levels were compared across diagnostic groups and concordance between clinical diagnoses and BBM test results, based on thresholds developed in an academic memory clinic, were analyzed.ResultsThe levels of all four BBMs differed between SCD and AD dementia (p < 0.001). Between AD dementia and non-AD dementia, only PTau217 levels differed (p = 0.03). In SCD participants, 50% (pTau217) to 79% (NfL) showed abnormality in at least one BBM. In AD dementia patients, this ranged from 83% (pTau217) to 97% (NfL); all had at least one abnormal BBM, and 68% had abnormalities in all four BBMs.ConclusionsIn a peripheral real-world memory clinic setting the BBMs demonstrated high concordance with clinically diagnosed dementia due to AD. Our findings suggest utility of BBMs in peripheral memory clinic practice, in patients with suspected dementia.
Marleen Kloppenburg-Lagendijk, Claire Van Nyendaal, Inge M. W. Verberk et al.· Journal of Alzheimer's Disea...· 0 citations
Grey matter network topology is altered in Alzheimer’s disease and these alterations are related to cognitive decline, which suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to tau.
Diederick M. de Leeuw, F. Duits, E. Dicks et al.· Brain Communications· 0 citations
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