Noga Orr (Or-Geva)
Basic Life Res Scientist, Adult Neurology
https://orcid.org/0000-0001-9631-3818All Publications
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Complement As a New Player in the Infectious-Immune-Neuroimmune Axis: The Post-COVID Experience
WILEY-V C H VERLAG GMBH. 2026: 85
View details for Web of Science ID 001882216300048
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C1-esterase Inhibitor Treatment is Associated with Immune and Vascular Pathway Modulation in PASC with Neurological Symptoms: Longitudinal Plasma Proteomics.
Cellular and molecular neurobiology
2026
Abstract
Post-acute sequelae of SARS-CoV-2 infection (PASC), particularly neurological manifestations, remain a significant therapeutic challenge, likely driven by persistent inflammation, immune dysregulation, and endothelial dysfunction. In a randomized, double-blind, placebo-controlled crossover trial, 10 patients with post-COVID-19 neurological symptoms received C1-esterase inhibitor (C1-INH; RUCONEST®) or placebo over two eight-week phases. Longitudinal plasma proteomics (SomaScan®) profiled molecular dynamics during and after C1-INH treatment. C1-INH administration was associated with distinct, phase-specific proteomic signatures, including lower levels of inflammatory-associated proteins such as CRP and IL-6, increased levels of neuroimmune and endothelial repair proteins (Neuropilin-2, CD83, C1QTNF5), and modulation of bradykinin-kinin and extracellular matrix pathways. These molecular shifts were evaluated in relation to clinical change scores during the active treatment windows. Several proteomic changes were observed at timepoint 26 after treatment cessation, describing candidate post-treatment molecular trajectories. In conclusion, these results provide exploratory mechanistic insights and support the need for validation in larger, prospective cohorts. Together, these findings prioritize immune and vascular pathways for further investigation in PASC and may have relevance to other post-infectious neuroimmune conditions.
View details for DOI 10.1007/s10571-026-01736-4
View details for PubMedID 42156560
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Multiple molecular mimics in Epstein Barr Nuclear Antigen-1, and the pathogenesis of multiple sclerosis.
Proceedings of the National Academy of Sciences of the United States of America
2026; 123 (11): e2519445123
Abstract
The Epstein-Barr virus (EBV) infects greater than 95% of humans and is associated with initiating and perpetuating multiple sclerosis (MS). Antibody to Epstein-Barr Nuclear Antigen-1 (EBNA1) is present in nearly 100% of patients with MS before the development of clinical symptoms. Infection with EBV is necessary, but not sufficient, for causation of disease. Within the EBNA1 transcription factor is a stretch of 47 amino acids containing three regions with shared linear sequences of portions of three molecules, Glialcell adhesion molecule (CAM), alpha Crystallin-B, and Anoctamin-2. These cross-reactive linear sequences between EBNA1 and each of these three molecules are termed "molecular mimics." Cross-reactive adaptive immunity to these three molecules mimicking regions of EBNA1 each play distinct roles in the pathogenesis of MS. Antibodies to each of these molecules greatly increase the chance of developing MS. Analysis of the cellular landscape of MS lesions reveals EBNA1 in B cells, glial cells, and neurons. Here, we provide commentary on recent publications on the molecular and cellular landscape of EBV infection in studies on the blood, cerebrospinal fluid, and brain specimens of individuals with MS. The published studies reveal perspectives on the pathology of MS in detail ranging from the atomic level using crystallography to multiplexed anatomical imaging of lesions in the brain.
View details for DOI 10.1073/pnas.2519445123
View details for PubMedID 41790925
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Sex-associated and disease state-dependent monocyte polarization and CNS-trafficking phenotypes in pediatric acute-onset neuropsychiatric syndrome (PANS).
Journal of neuroinflammation
2025; 22 (1): 273
Abstract
Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by the sudden onset of obsessive-compulsive symptoms alongside a constellation of neuropsychiatric and somatic features. Disease progression typically includes flare and recovery states, with some patients exhibiting a persistent disease course (> 12 months of flare). We characterized circulating monocyte subsets during flare and recovery in pediatric patients with PANS, uncovering disease-state-dependent shifts in polarization and trafficking phenotypes. Inflammatory M1-like monocytes and monocyte-derived dendritic cells were elevated during flare, while anti-inflammatory M2-like monocytes were enriched in recovery. We also identified a circulating subset with a surface phenotype consistent with central nervous system (CNS) homing, which was reduced during flare and restored in recovery. These cells were detectable in the cerebrospinal fluid (CSF) of new-onset patients but not in persistent cases, suggesting differential compartmentalization during disease progression. Notably, monocyte phenotypes, including M2 polarization (monocytosis) and circulating CNS-homing profiles, exhibited striking sex-associated differences, particularly during recovery, with several subsets enriched in males but not females. Plasma from flare-phase patients modestly induced CNS-homing markers in monocytes from healthy donors, indicating the presence of circulating modulators. Together, these findings support a model in which distinct myeloid phenotypes-including sex-biased patterns-may contribute to both the pathogenesis and resolution of neuroinflammation in PANS.
View details for DOI 10.1186/s12974-025-03549-6
View details for PubMedID 41254741
View details for PubMedCentralID 4340335
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Does C1 esterase inhibitor play a role in post COVID-19 neurological symptoms? A randomized, double-blind, placebo-controlled, crossover, proof-of-concept study.
Frontiers in neurology
2025; 16: 1523814
Abstract
Many patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience neurologic changes post-infection, which has been hypothesized to be due to dysregulation in the infectious-immune axis that leads to a neuro-immune response. This immune dysfunction has been termed "Alzheimer's of the Immune System" or AIS and there are several immune factors that may play a key role. These include, among others, complement activation due to low levels of C1-esterase inhibitor (C1-INH) and function, and a decrease in signaling of Toll-like receptor (TLR)-3. We propose that C1-INH replacement may upregulate the immune dysfunction, thereby improving neurological symptoms.In this randomized, double-blind, placebo-controlled, crossover, proof-of-concept study, adults experiencing SARS-CoV-2 post-viral fatigue syndrome for >4 weeks post-recovery from coronavirus disease 2019 (COVID-19) infection were randomized 1:1 to two arms: Arm 1 (C1-INH for 8 weeks, then placebo for 8 weeks) or to Arm 2 (placebo for 8 weeks, then C1-INH for 8 weeks). Patients were assessed for adult executive function, abnormal cognitive decline, depression [Beck Depression Inventory-II (BDI-II)], migraine, fatigue [Fatigue Severity Scale (FSS)] and pain (Short-form McGill Pain Questionnaire). Percent change in TLR signaling in response to zymosan was compared with controls at baseline, Week 8 and Week 16. Safety was assessed throughout.At this interim analysis, 36 patients with SARS-CoV-2 post-viral fatigue syndrome had completed the two 8-week treatment periods. In Arm 1, trends toward improvements from baseline at Week 8 of C1-INH therapy were observed in BDI-II score (-8.7 points), mean FSS score (0.6 points), and mean McGill Pain Questionnaire score (-0.4 points). These improvements were either sustained or worsened at Week 16, following crossover to placebo. The outcomes in Arm 2 were compatible with those in Arm 1. Patients with SARS-CoV-2 post-viral fatigue syndrome had low levels of TLR-related signaling biomarkers compared with healthy controls.This proof-of-concept study demonstrates sustained dysregulation of the immune system after COVID-19 infection. Improvements in depression, fatigue, and pain were observed with C1-INH treatment in patients with SARS-CoV-2 post-viral fatigue syndrome, indicating C1-INH may be a potential therapeutic target.The study was registered on September 21, 2024, with the identifier number NCT04705831.
View details for DOI 10.3389/fneur.2025.1523814
View details for PubMedID 41281561
View details for PubMedCentralID PMC12631290
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Epstein-Barr virus and the immune microenvironment in multiple sclerosis: Insights from high-dimensional brain tissue imaging.
Proceedings of the National Academy of Sciences of the United States of America
2025; 122 (11): e2425670122
Abstract
Epstein-Barr virus (EBV) is strongly implicated in the pathogenesis of multiple sclerosis (MS), yet its exact role in disease progression remains unclear. Using high-dimensional CO-detection by indexing, a technology for spatial imaging, this study examines the cellular microenvironment of MS lesions in secondary progressive MS and primary progressive MS. We analyzed immune, glial, neuronal, and endothelial cell interactions within MS lesions and normal-appearing white matter across two independent cohorts. Our findings show the enrichment of EBV markers, particularly EBNA1 and LMP1, within MS lesions. EBV-positive cells interact closely with reactive astrocytes, microglia, and neurons. Image analysis confirmed the presence of EBV-positive staining within neurons and glial cells, suggesting a direct role for EBV in neuronal and glial involvement in MS. Additionally, we observed altered immune cell interactions, including reduced associations with macrophages and memory T cells, and enhanced interactions with glial cells. Disruptions in blood-brain barrier integrity were also noted in regions of the MS brain. These results highlight EBV's contribution to immune modulation, glial dysfunction, and neuronal damage in MS, particularly in progressive subtypes. The analysis of MS brain tissue suggests potential therapeutic targets, including antivirals and brain penetrant immune modulators, to address EBV's impact on MS progression.
View details for DOI 10.1073/pnas.2425670122
View details for PubMedID 40063794
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Hunger guides immunity to friend versus foe.
Nature neuroscience
2024
View details for DOI 10.1038/s41593-024-01590-x
View details for PubMedID 38360948
View details for PubMedCentralID 151888
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Post-infectious inflammation, autoimmunity, and OCD: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS), and Pediatric Acute-onset Neuropsychiatric Disorder (PANS)
DEVELOPMENTAL NEUROSCIENCE
2023
Abstract
Post-infectious neuroinflammation has been implicated in multiple models of acute onset obsessive-compulsive disorder (OCD) including Sydenham's chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by an infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.
View details for DOI 10.1159/000534261
View details for Web of Science ID 001076907900001
View details for PubMedID 37742615
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Metabolomic Characterization of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS).
Frontiers in neuroscience
2021; 15: 645267
Abstract
Introduction: PANS is a controversial clinical entity, consisting of a complex constellation of psychiatric symptoms, adventitious changes, and expression of various serological alterations, likely sustained by an autoimmune/inflammatory disease. Detection of novel biomarkers of PANS is highly desirable for both diagnostic and therapeutic management of affected patients. Analysis of metabolites has proven useful in detecting biomarkers for other neuroimmune-psychiatric diseases. Here, we utilize the metabolomics approach to determine whether it is possible to define a specific metabolic pattern in patients affected by PANS compared to healthy subjects.Design: This observational case-control study tested consecutive patients referred for PANS between June 2019 to May 2020. A PANS diagnosis was confirmed according to the PANS working criteria (National Institute of Mental Health [NIMH], 2010). Healthy age and sex-matched subjects were recruited as controls.Methods: Thirty-four outpatients referred for PANS (mean age 9.5 years; SD 2.9, 71% male) and 25 neurotypical subjects matched for age and gender, were subjected to metabolite analysis. Serum samples were obtained from each participant and were analyzed using Nuclear Magnetic Resonance (NMR) spectroscopy. Subsequently, multivariate and univariate statistical analyses and Receiver Operator Curves (ROC) were performed.Results: Separation of the samples, in line with the presence of PANS diagnosis, was observed by applying a supervised model (R2X = 0.44, R2Y = 0.54, Q2 = 0.44, p-value < 0.0001). The significantly altered variables were 2-Hydroxybutyrate, glycine, glutamine, histidine, tryptophan. Pathway analysis indicated that phenylalanine, tyrosine, and tryptophan metabolism, as well as glutamine and glutamate metabolism, exhibited the largest deviations from neurotypical controls.Conclusion: We found a unique plasma metabolic profile in PANS patients, significantly differing from that of healthy children, that suggests the involvement of specific patterns of neurotransmission (tryptophan, glycine, histamine/histidine) as well as a more general state of neuroinflammation and oxidative stress (glutamine, 2-Hydroxybutyrate, and tryptophan-kynurenine pathway) in the disorder. This metabolomics study offers new insights into biological mechanisms underpinning the disorder and supports research of other potential biomarkers implicated in PANS.
View details for DOI 10.3389/fnins.2021.645267
View details for PubMedID 34121984
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Veto cells for safer nonmyeloablative haploidentical HSCT and CAR T cell therapy.
Seminars in hematology
2019; 56 (3): 173–82
Abstract
Haploidentical donors are a readily available source for mismatched hematopoietic bone marrow transplantation. The application of this regimen is constantly increasing with the advent of methods that overcome T-cell alloreactions that occur due to human-leukocyte-antigen disparity between host and donor. One successful method to overcome both graft rejection and graft-vs-host disease is transplantation of large numbers T-cell-depleted (TCD) haploidentical stem cell grafts (haploSCT), after myeloablative conditioning. The success of stem cell dose escalation is attributed to a unique immunoregulatory cell-property, termed "veto-activity." However, engraftment of mismatched hematopoietic stem cells following reduced-intensity conditioning still represents a major challenge. Here, we describe how the addition of post-transplant high-dose cyclophosphamide can promote immune tolerance induction after megadose TCD haploSCT, following nonmyeloablative conditioning. We also discuss ways of harnessing the immune regulatory properties of adoptively transferred "veto" cells to support mixed chimerism further and confer tolerance to cell-therapies, such as CAR-T cells. These approaches will soon be tested in phase 1-2 clinical studies and may prove to be a safe and efficacious treatment for many disorders such as hemoglobinopathies, autoimmune diseases, and as a prelude for organ tolerance. Moreover, this approach could pave the way for "off-the-shelf" cell-therapy agents, making them cheaper and easily obtainable.
View details for DOI 10.1053/j.seminhematol.2019.03.003
View details for PubMedID 31202427
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Next-generation CD8 memory veto T cells directed against memory antigens.
Leukemia
2019
View details for DOI 10.1038/s41375-019-0501-1
View details for PubMedID 31189891
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Molecular signature of Epstein-Barr virus infection in MS brain lesions.
Neurology(R) neuroimmunology & neuroinflammation
2018; 5 (4): e466
Abstract
Objective: We sought to confirm the presence and frequency of B cells and Epstein-Barr virus (EBV) (latent and lytic phase) antigens in archived MS and non-MS brain tissue by immunohistochemistry.Methods: We quantified the type and location of B-cell subsets within active and chronic MS brain lesions in relation to viral antigen expression. The presence of EBV-infected cells was further confirmed by in situ hybridization to detect the EBV RNA transcript, EBV-encoded RNA-1 (EBER-1).Results: We report the presence of EBV latent membrane protein 1 (LMP-1) in 93% of MS and 78% of control brains, with a greater percentage of MS brains containing CD138+ plasma cells and LMP-1-rich populations. Notably, 78% of chronic MS lesions and 33.3% of non-MS brains contained parenchymal CD138+ plasma cells. EBV early lytic protein, EBV immediate-early lytic gene (BZLF1), was also observed in 46% of MS, primarily in association with chronic lesions and 44% of non-MS brain tissue. Furthermore, 85% of MS brains revealed frequent EBER-positive cells, whereas non-MS brains seldom contained EBER-positive cells. EBV infection was detectable, by immunohistochemistry and by in situ hybridization, in both MS and non-MS brains, although latent virus was more prevalent in MS brains, while lytic virus was restricted to chronic MS lesions.Conclusions: Together, our observations suggest an uncharacterized link between the EBV virus life cycle and MS pathogenesis.
View details for PubMedID 29892607
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Molecular signature of Epstein-Barr virus infection in MS brain lesions
NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION
2018; 5 (4)
View details for DOI 10.1212/NXI.0000000000000466
View details for Web of Science ID 000442610100007
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A new approach for eradication of residual lymphoma cells by host nonreactive anti-third-party central memory CD8 T cells
BLOOD
2013; 121 (15): 3033-3040
Abstract
Generation of T cells endowed with graft-versus-leukemia (GVL) and depleted of graft-versus-host (GVH) activity represents a highly desirable goal in bone marrow transplantation (BMT). Here, we demonstrate that donor anti-third-party CD8 T cells with central memory phenotype (Tcm) exhibit marked GVL reactivity through a unique T-cell receptor-independent mechanism. Thus, in a residual disease mouse model, Tcm therapy following autologous BMT led to significant survival prolongation, with 30% to 40% of the treated mice displaying long-term tumor-free survival. A more impressive finding was that infusion of donor Tcm in an allogeneic model rapidly eliminated residual lymphoma cells and led to long-term survival of 100% in the absence of GVH disease. Collectively, the strong GVL reactivity of anti-third-party Tcm, coupled with their demonstrated enhancement of bone marrow allografting, suggests that the use of Tcm therapy in conjunction with allogeneic T-cell-depleted BMT could be of particular benefit in patients with B-cell malignancies who cannot tolerate intensive myeloablative conditioning.
View details for DOI 10.1182/blood-2012-06-432443
View details for Web of Science ID 000321825700028
View details for PubMedID 23446736
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Murine anti-third-party central-memory CD8(+) T cells promote hematopoietic chimerism under mild conditioning: lymph-node sequestration and deletion of anti-donor T cells
BLOOD
2013; 121 (7): 1220-1228
Abstract
Transplantation of T cell-depleted BM (TDBM) under mild conditioning, associated with minimal toxicity and reduced risk of GVHD, offers an attractive therapeutic option for patients with nonmalignant hematologic disorders and can mediate immune tolerance to subsequent organ transplantation. However, overcoming TDBM rejection after reduced conditioning remains a challenge. Here, we address this barrier using donorderived central memory CD8(+) T cells (Tcms), directed against third-party antigens. Our results show that fully allogeneic or (hostXdonor)F1-Tcm, support donor chimerism (> 6 months) in sublethally irradiated (5.5Gy) mice, without GVHD symptoms. Chimerism under yet lower irradiation (4.5Gy) was achieved by combining Tcm with short-term administration of low-dose Rapamycin. Importantly, this chimerism resulted in successful donor skin acceptance, whereas third-party skin was rejected. Tracking of host anti-donor T cells (HADTCs), that mediate TDBMT rejection, in a novel bioluminescence-imaging model revealed that Tcms both induce accumulation and eradicate HADTCs in the LNs,concomitant with their elimination from other organs, including the BM. Further analysis with 2-photon microcopy revealed that Tcms form conjugates with HADTCs, resulting in decelerated and confined movement of HADTCs within the LNs in an antigen-specific manner. Thus, anti-third-party Tcms support TDBMT engraftment under reduced-conditioning through lymph-node sequestration and deletion of HADTCs, offering a novel and potentially safe approach for attaining stable hematopoietic chimerism.
View details for DOI 10.1182/blood-2012-07-441493
View details for Web of Science ID 000314870700026
View details for PubMedID 23223359
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Ex Vivo Generated Donor Central Memory CD8 T Cells, Previously Shown to Enhance Engraftment of Allogeneic Bone Marrow, Also Exhibit Significant GVL Activity without Causing Gvhd In An In Vivo b Cell Lymphoma Model
AMER SOC HEMATOLOGY. 2010: 189–90
View details for Web of Science ID 000289662200425