Biology subjects

Kaufmann, E.

Publications and source records attributed to Kaufmann, E..

10 recordsLinked to original sources

bioRxiv2026

Development and translational validation of a novel mouse model for allergic rhinitis

Background: Approximately 30% of the North American population are affected by seasonal or perennial rhinitis. Allergens from cats are common triggers of allergic rhinitis. Importantly, cat allergic rhinitis (cat-AR) is a major risk factor for more severe allergic diseases, including asthma. Current therapies rarely achieve full symptom control and development of novel therapeutics is constrained by the lack of physiologically relevant preclinical models. Objective: Establishment of a clinically-informed mouse model of cat allergen exposure in humans. Methods: Controlled human exposure was performed using airborne natural cat dander (CD) in a validated environmental exposure facility. Nasal immune cells and IgE concentrations in serum and nasal samples were assessed. In mice, we established a 14-day intermittent intranasal sensitization and challenge protocol using the same CD allergens. Clinical signs in mice were objectively quantified using AI-based video detection. Cellular changes in the nose were assessed with level-specific, spatial resolution. Lastly, systemic sensitization was confirmed through serum IgE and intradermal ear challenge. Measurements and Main Results: Following CD exposure, cat-allergic participants displayed increased nasal symptoms and eosinophil influx. CD-sensitized mice recapitulated key clinical features, including increased nasal rubbing, elevated nasal immune cell infiltration, and systemic sensitization. Importantly, spatial investigation of the cellular changes revealed major changes in the turbinate and olfactory regions of the nose. Conclusions: This novel mouse model provides a translationally valuable platform for investigating local and systemic mechanisms of cat-AR. It will serve for mechanistic and therapeutic evaluations with the goal of improving clinical translation and therapeutic precision.

immunology↗

bioRxiv2025

Neonatal BCG Vaccination Engages the Vasculature to Elicit γδ T Cell-Mediated Protection against Tuberculosis

The Bacillus Calmette-Guerin (BCG) vaccine remains the only approved vaccine against tuber-culosis (TB). Although its efficacy against pulmonary TB in adults is limited, BCG provides re-markable protection against miliary TB when administered during infancy. Despite more than 100 million infants worldwide receiving BCG annually, the mechanisms underlying its neonatal protective effects remain poorly defined. Here, we demonstrate that subcutaneous neonatal BCG vaccination (BCG-sc) induces a marked expansion of {gamma}{delta} T cells producing IL-17 and IL-22, which mediated protection against subsequent Mycobacterium tuberculosis (Mtb) experimental infection. A similar expansion of {gamma}{delta} T cells was observed in a longitudinal cohort of infants, from birth to three months of infants followed after intradermal BCG vaccination. Mechanistical-ly, BCG-mediated protection in neonates was linked to its early vascular dissemination through the distinct structure of neonatal skin, resembling the protective effects of intravenous BCG in adults. Moreover, neonatal BCG-sc vaccination generated a distinct BCG-induced microbiome signature, characterized by enrichment of Prevotellaceae, Tannerellaceae, and Bifidobacteriaceae, which was associated with protection. Together, these findings identify {gamma}{delta} T cells as key mediators of early-life BCG-induced immunity and highlight the role of the gut-lung axis in long-term protection against TB from infancy into adulthood.

immunology↗

bioRxiv2025

Low-frequency brain oscillations reflect the dynamics of the oculomotor system: a new perspective on subsequent memory effects

Neural activity and eye movements are two well-established predictors of memory performance in humans. Successful memory formation is typically associated with reduced alpha/beta power (i.e., the alpha/beta subsequent memory effect) and an increased number of eye movements. However, the functional relevance of these two memory correlates has primarily been investigated in isolation, leaving their coupling and combined contribution to memory formation largely unknown. Here, we address this gap through four experiments involving simultaneous eye-tracking and scalp or intracranial electroencephalography recordings while participants viewed scenes either freely or under varying levels of visual constraint. Across experiments and cohorts, we identified the degree of visual exploration, rather than subsequent memory performance, as the consistent and robust modulator of alpha/beta power reductions. Going beyond correlations, manipulating eye movements dissociated alpha/beta power reductions from memory. Combined with the finding that saccade parameters predicted the dynamics of alpha/beta activity, our results directly link alpha/beta activity to the oculomotor system. Moreover, we show that the accumulation of saccades over time accounted for the reduced alpha/beta power, resembling the pattern typically observed after stimulus onset. Our work demonstrates that neglecting eye movements results in an incomplete understanding of the alpha/beta subsequent memory effect. Together, the evidence points at alpha/beta activity directly reflecting eye movements, and only indirectly, memory formation. The current study thus bridges two lines of previous research and advocates for new perspectives on the specific interpretation of the alpha/beta subsequent memory effect and on the function of alpha/beta activity in general.

neuroscience↗

bioRxiv2025

CSF single-cell RNA sequencing reveals clonally expanded CD4+ stem cell-like memory T cells in GAD65-antibody associated neurological syndromes

BackgroundGlutamic acid decarboxylase (GAD) antibody-associated autoimmune neurological syndromes (AINS) are a spectrum of autoimmune-mediated CNS disorders. While antibodies targeting the 65 kDa isoform of GAD are of high diagnostic value, T cell mediated cytotoxicity has been identified as a key component of disease pathogenesis. The precise pathophysiological mechanisms by which the disease is triggered and maintained, however, remain incompletely understood. MethodsWe performed single-cell transcriptome and immune repertoire sequencing (sc-seq) in CSF and blood of 8 anti-GAD65 AINS patients compared to 8 non-inflammatory controls. Monoclonal antibodies (mAbs) were synthesized from B cell receptor (BCR) data to evaluate the B cellular immune response. FindingsWe identified an increase and expansion of activated CD4+ stem cell-like memory T cells (TSCM) in the CSF of anti-GAD65 AINS patients. Expanded T cells showed increased expression of proinflammatory genes. The mAb analysis revealed a high frequency of GAD65-reactive BCRs in the CSF of anti-GAD65 AINS patients with increased somatic hypermutations compared to non-GAD-reactive BCRs and BCRs from controls. ConclusionsSc-seq identified clonally expanded CD4+ TSCM in the CSF of anti-GAD65 AINS patients harboring cytotoxic properties likely contributing to disease pathogenesis. GAD-reactive B cells circulate in the CSF of anti-GAD65 AINS patients further supporting the concept of an antigen-specific intrathecal immune response. Future studies need to clarify the actual pathogenicity of these immune cells and the link between T and B cellular immune mechanisms in the pathogenesis of anti-GAD65 AINS. FundingGerman Research Foundation (ERARE18-202 UltraAIE), German Federal Ministry of Education and Research (CONNECT GENERATE (2.0); 01GM1908A and 01GM2208A).

immunology↗

bioRxiv2025

Thalamic oscillations distinguish natural states of consciousness in humans

Natural states of consciousness are thought to be regulated by deep brain structures such as the thalamus. However, very little is known about the underlying electrophysiology in humans. Here, using a rare opportunity to directly record from the human thalamus, we identify a hitherto-unreported brain-state-specific oscillation of approximately 19-45 Hz. This oscillation is present only during Rapid Eye Movement (REM) sleep and wakefulness, while being absent during Non-REM sleep. The 19-45 oscillation further distinguishes REM sleep microstates, co-occurring with bursts of eye movements, and is specific to the Central Thalamus, a structure implicated in causing global brain state transitions. The discovery of a distinct oscillatory signature in the Central Thalamus that distinguishes conscious states opens up avenues to further investigate thalamic contributions to states of consciousness in humans and potentially to refine interventions to treat disorders of consciousness.

neuroscience↗

bioRxiv2024

Cnes2b Regulates Host Resistance, Inflammatory Responses and Tissue Damage Following Cryptococcus deneoformans Infection

The 32.1 Mb Cnes2 chromosome 17 interval was shown to confer resistance to progressive Cryptococcus deneoformans 52D infection. To refine the location of Cnes2 host resistance genes, a subcongenic mouse strain (B6.CBA-Cnes2b) that contains 8.7 Mb from the telomeric region of Cnes2 was created. At 28 days postinfection B6.CBA-Cnes2b mice had a lower lung fungal burden, increased lung injury, as well as mortality compared to C57BL/6N. B6.CBA-Cnes2b mice had increased pulmonary production of pro-inflammatory mediators, chemokines and Th1-type cytokines as well as increased recruitment of monocytes and neutrophils to the lungs. Cnes2b also regulated several elements of the host response to C. deneoformans 52D infection in a sex-dependent manner. Specifically, male B6.CBA-Cnes2b mice had a lower lung fungal burden, increased brain injury and mortality relative to females. Taken together these findings demonstrate that Cnes2b regulates host inflammation in a manner that controls fungal burden and increases tissue damage. Precise identification of the genes encoded by Cnes2b could reveal key mechanisms of cryptococcal host resistance and immune reconstitution or postinfectious inflammatory syndromes. ImportanceThe 32.1 Mb Cnes2 congenic interval from chromosome 17 of resistant CBA/J mice regulates host resistance to C. deneoformans 52D infection. This study characterizes the host response of B6.CBA-Cnes2b mice that carry an 8.7 Mb sub-congenic interval derived from Cnes2 following C. deneoformans 52D infection. B6.CBA-Cnes2b mice had reduced lung fungal burden, increased lung and brain injury, and mortality. The effects of Cnes2b differed between male and female subcongenic mice and are consistent with known sex differences in human cryptococcal disease. The host response of B6.CBA-Cnes2b mice reflects a crucial balance between effective control of fungal burden and potentially deleterious consequences of enhanced inflammation during cryptococcal infection as predicted by the damage response framework. Further analysis of the Cnes2b sub-congenic interval will lead to definitive identification of genes that confer resistance to progressive cryptococcal infection and/or contribute to deleterious inflammatory responses. Defining key mechanisms that regulate the immune response to Cryptococcus sp. is an important step towards the development of host-directed therapeutics that could improve disease outcomes.

immunology↗

bioRxiv2024

BASOPHILS ACTIVATE PRURICEPTOR-LIKE VAGAL SENSORY NEURONS.

Vagal sensory neurons convey sensations from internal organs along the vagus nerve to the brainstem. Pruriceptors are a subtype of neurons that transmit itch and induce pruritus. Despite extensive research on the molecular mechanisms of itch, studies focusing on pruriceptors in the vagal ganglia still need to be explored. In this study, we characterized vagal pruriceptor neurons by their responsiveness to pruritogens such as lysophosphatidic acid, {beta}-alanine, chloroquine, and the cytokine oncostatin M. We discovered that lung-resident basophils produce oncostatin M and that its release can be induced by engagement of Fc{varepsilon}RI. Oncostatin M then sensitizes multiple populations of vagal sensory neurons, including Tac1+ and MrgprA3+ neurons in the jugular ganglia. Finally, we observed an increase in oncostatin M release in mice sensitized to the house dust mite Dermatophagoides pteronyssinus or to the fungal allergen Alternaria alternata, highlighting a novel mechanism through which basophils and vagal sensory neurons may communicate during type I hypersensitivity diseases such as allergic asthma.

neuroscience↗

bioRxiv2023

Memory reactivation of real-world spatial orientation revealed by human electrophysiology.

Memory consolidation relies on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations, spindles and ripples) is thought to coordinate the information flow between relevant brain areas, with ripples mediating memory reactivation. However, in humans empirical evidence for a role of ripples in memory reactivation is lacking. Here, we investigated the relevance of sleep oscillations and specifically ripples for memory reactivation during human sleep using targeted memory reactivation (TMR). Intracranial electrophysiology in epilepsy patients and scalp EEG in healthy participants revealed that elevated levels of SO-spindle activity promoted the read-out of TMR induced memory reactivation. Importantly, spindle-locked ripples recorded intracranially from the medial temporal lobe were found to be instrumental for memory reactivation to unfold during non-rapid eye movement (NREM) sleep. Our findings establish ripples as key-oscillation in human systems consolidation and emphasize the importance of the coordinated interplay of the cardinal sleep oscillations.

neuroscience↗

bioRxiv2023

Electrophysiological signatures of veridical head direction in humans

Information about heading direction is critical for navigation as it provides the means to orient ourselves in space. However, given that veridical head direction signals require physical rotation of the head and most human neuroimaging experiments depend upon fixing the head in position, little is known about how the human brain is tuned to such heading signals. To address this, we asked fifty-two healthy participants undergoing simultaneous EEG and motion tracking recordings (split into two experiments) and ten patients undergoing simultaneous intracranial EEG and motion tracking recordings to complete a series of orientation tasks in which they made physical head rotations to target positions. We then used a series of forward encoding models and linear mixed-effects models to isolate electrophysiological activity that was specifically tuned to heading direction. We identified a robust posterior central signature that predicts changes in veridical head orientation after regressing out confounds including sensory input and muscular activity. Both source localisation and intracranial analysis implicated the medial temporal lobe as the origin of this effect. Subsequent analyses disentangled head direction signatures from signals relating to head rotation and those reflecting location-specific effects. Lastly, when directly comparing head direction and eye gaze-related tuning, we found that the brain maintains both codes while actively navigating, with stronger tuning to head direction in the medial temporal lobe. Together, these results reveal a taxonomy of population-level head direction signals within the human brain that is reminiscent of those reported in the single units of rodents.

neuroscience↗

bioRxiv2021

The human thalamus orchestrates neocortical oscillations during NREM sleep.

A hallmark of non-rapid eye movement sleep is the coordinated interplay of slow oscillations (SOs) and sleep spindles. Traditionally, a cortico-thalamo-cortical loop is suggested to coordinate these rhythms: neocortically-generated SOs trigger spindles in the thalamus that are projected back to neocortex. Here, we used intrathalamic recordings from human epilepsy patients to test this canonical interplay. We show that SOs in the anterior thalamus precede neocortical SOs (peak -50 ms), whereas concurrently-recorded SOs in the mediodorsal thalamus are led by neocortical SOs (peak +50 ms). Sleep spindles, detected in both thalamic nuclei, preceded their neocortical counterparts (peak -100 ms) and were initiated during early phases of thalamic SOs. Our findings indicate an active role of the anterior thalamus in organizing sleep rhythms in the neocortex and highlight the functional diversity of thalamic nuclei in humans. The thalamic coordination of sleep oscillations could have broad implications for the mechanisms underlying memory consolidation.

neuroscience↗