About

Jorge I. Alvarez, PhD, is an Associate Professor of Pathobiology at the University of Pennsylvania, School of Veterinary Medicine. His research aims to define how CNS-intrinsic signals modulate immune cell function within different neurovascular niches. His work focuses on understanding the roles of CNS barriers, such as the blood-brain barrier and the blood-meningeal barrier, during neuroinflammation. The Alvarez lab investigates the mechanisms regulating immune and neurovascular interactions starting at the level of the CNS barriers and progressing into the brain parenchyma, using a combination of ex-vivo, in vitro, in vivo, and post-mortem approaches. His research specifically addresses the pathogenesis of neuroinflammatory diseases like multiple sclerosis and neuropsychiatric disorders, with the goal of elucidating how protective mechanisms can become inadequate or aberrant during disease, leading to persistent inflammation and long-term sequelae.

Research topics

• Immunology
• Biology
• Neuroscience
• Medicine
• Cell biology
• Psychiatry

Selected publications

• Astroglial dysfunction, demyelination, and nodular inflammation in Necrotizing Meningoencephalitis (NME)

  Journal of Comparative Pathology · 2025-10-01

  articleSenior author
  PublisherDOI

• Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome

  Science Translational Medicine · 2025-08-20 · 3 citations

  articleSenior authorCorresponding

  Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared with peripheral endothelial cells, although the functional implications of this phenomenon are unclear. Here, we studied BBB mitochondrial function in the context of 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. Because the 22q11.2 deletion includes six mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and affect behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (iBMECs) from people with 22qDS and in BBB endothelial cells from a mouse model of 22qDS. We found that treatment with bezafibrate, an activator of mitochondrial biogenesis, attenuates mitochondrial deficits and enhances BBB function in both the iBMECs and a mouse model of 22qDS. This treatment also corrects social memory in the mouse model, a deficit previously associated with BBB dysfunction. Given that BBB integrity correlated with social memory performance, our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior.

  PublisherDOI

• Neuroinflammatory canine disorders: unveiling disease mechanisms from a One Health perspective

  The Journal of Immunology · 2025-10-01

  reviewSenior author

  While rodent models remain foundational in biomedical research for their manipulability, genetics, and reproducibility, spontaneous diseases in companion animals provide relevant models to study naturally occurring conditions. Pathogenic processes underlying diseases in humans and dogs are similar or identical, which exemplifies the One Health concept. Companion animals share physiological and genetic traits with humans, have similar exposure to microorganisms and toxic insults, and due to cohabitation, share our microbiome. Dogs have intact immune systems and tolerate drugs at dosages comparable to humans. Dogs with naturally occurring neuroinflammatory disorders can serve as spontaneous models for those affecting humans. Granulomatous meningoencephalomyelitis, the most common canine neuroinflammatory disorder, recapitulates key immunopathological features of multiple sclerosis. The clinical course of granulomatous meningoencephalomyelitis is prolonged from months to years, rather than days to weeks as in rodents, a key aspect when modeling multiple sclerosis chronicity and assessing drug response over time. Thus, establishing natural models of human diseases constitutes a significant advancement to understanding mechanisms of disease while benefiting veterinary medicine and accelerating new therapies for humans.

  PublisherDOI

• Neurovascular mitochondrial susceptibility impacts blood-brain barrier function and behavior

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-02-20

  preprintOpen accessSenior authorCorresponding

  Abstract Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared to peripheral endothelial cells, although the functional implications of this phenomenon remain unknown. Here we studied BBB mitochondrial function in the context of the 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. As the 22q11.2 deletion includes 6 mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and impact behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived BBB endothelial cells from 22qDS patients, and in BBB endothelial cells from a mouse model of 22qDS. Remarkably, treatment to improve mitochondrial function attenuates mitochondrial deficits and enhances BBB function in both the iPSC and mouse 22qDS models. This treatment also corrected social memory in the mouse model, a deficit previously associated with BBB dysfunction. As BBB integrity correlated with social memory performance, together our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior in 22qDS.

  PublisherOA PDFDOI

• Astroglial Dysfunction, Demyelination and Nodular inflammation in Necrotizing Meningoencephalitis

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-14

  preprintOpen accessSenior authorCorresponding

  Necrotizing Meningoencephalitis (NME), a form of Meningoencephalitis of Unknown Origin (MUO), is a progressive neuroinflammatory disease that primarily affects young, small-breed dogs. Due to limited understanding of its pathophysiology, early detection and the development of targeted therapies remain challenging. Definitive ante-mortem diagnosis is often unfeasible, and dogs with NME are frequently grouped under the broader MUO category. Our long-term objective is to identify distinct disease mechanisms within each MUO subtype to improve diagnostic accuracy, therapeutic approaches, and prognostic outcomes. To establish unique inflammatory patterns as they relate to neuropathologic changes in NME, we studied we studied the degree of immune cell infiltration, astrogliosis, demyelination, and microglial activation, comparing these factors with granulomatous meningoencephalomyelitis (GME), a closely related MUO subtype. We found that in the leptomeninges, NME is characterized by mild immune cell infiltration, in contrast to the prominent, B cell-rich aggregates seen in GME. In the neuroparenchyma, both diseases exhibit a comparable degree of lymphocyte infiltration; however, demyelination is more pronounced in NME, particularly within the subcortical white matter. Notably, areas of the brain affected by NME display a reduction in astrogliosis, which is associated with a marked decrease in the expression of the water channel protein aquaporin-4 (AQP4), a reduction not observed in GME. Additionally, we found that AQP4 expression levels correlate with the extent of microglial and macrophage activation. These findings suggest that astrocyte dysfunction in regions of microglial inflammation is a driver of NME and with adaptive immune responses likely playing a supportive role.

  PublisherOA PDFDOI

• 22q11.2 Deletion-Associated Blood-Brain Barrier Permeability Potentiates Systemic Capillary Leak Syndrome Neurologic Features

  Journal of Clinical Immunology · 2024-04-05 · 5 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation

  Nature Communications · 2023 · 73 citations

  • Immunology
  • Medicine
  • Neuroscience

  Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages.

  PublisherOA PDFDOI

• 22q11.2 Deletion-Associated Blood-Brain Barrier Permeability Potentiates Systemic Capillary Leak Syndrome Neurologic Features

  Research Square · 2023-12-19

  preprintOpen accessSenior author

  <title>Abstract</title> We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed <italic>in vitro</italic> cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient’s serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by the 22q11.2 deletion promoted neurologic involvement during SCLS in this patient.

  PublisherOA PDFDOI

• Tibetan mineral-herbal medicine Zuotai alleviates the depressive-like behaviors in chronic restraint-stressed mice while regulating stress hormone, inflammation and monoamine

  Frontiers in Pharmacology · 2023-11-24 · 3 citations

  articleOpen access

  Introduction: Zuotai is an ancient mineral-herbal mixture containing β-HgS in Tibetan medicine. It is used to treat nervous system diseases, similar to Chinese medicine cinnabar and Indian Ayurveda medicine Rasasindura . However, one of the key problems faced by Zuotai is that its indications are ambiguous. Our previous study found that Zuotai exhibited the activity of ameliorating depressive-like behaviors in a chronic mild stress model. However, due to the inherent limitations of animal models in simulating human disease, clear results often require more than one model for confirmation. Methods: Therefore, another depression model, chronic restraint stressed (CRS) mice, was used to validate the antidepression effect of Zuotai . Prophylactic treatment was conducted for 21 consecutive days while mice were subjected to chronic restraint stress. Results: It was observed that Zuotai and β-HgS alleviated anhedonia, behavioral despair, stereotype behavior, and reduced exploratory and spontaneous movement in CRS mice. Zuotai and β-HgS also reversed the increases of stress hormone corticosterone (Cort) in serum and pro-inflammatory cytokines in serum and brain, and increased the serotonin in cortex in CRS mice, with positive dose-effect relationship. The number of Ki67-positive cells in the dentate gyrus and the level of brain-derived neurotrophic factor (BDNF) in the hippocampus were slightly elevated in CRS mice treated with Zuotai ; however, there was no statistically significant difference. Although Zuotai increased the total Hg concentration in main organs, the levels remained below those needed to result in observed adverse effect, at least for kidney and liver; and Zuotai showed no observed adverse effect on the brain histopathology, the cell proliferation in dentate gyrus, as well as the hippocampal and cortical organ coefficients. Conclusion: Zuotai exhibited the alleviation of depressive-like behaviors in CRS mice, accompanying with ameliorating stress hormone, peripherical and cerebral inflammation, and monoamine neurotransmitter.

  PublisherOA PDFDOI

• Immune status of the murine 22q11.2 deletion syndrome model

  European Journal of Immunology · 2022-11-07 · 5 citations

  articleSenior authorCorresponding

  Mice modeling the hemizygous deletion of chromosome 22q11.2 (22qMc) have been utilized to address various clinical phenotypes associated with the disease, including cardiac malformations, altered neural circuitry, and behavioral deficits. Yet, the status of the T cell compartment, an important clinical concern among 22q11.2 deletion syndrome (22qDS) patients, has not been addressed. While infancy and early childhood in 22qDS are associated with deficient T cell numbers and thymic hypoplasia, which can be severe in a small subset of patients, studies suggest normalization of the T cell counts by adulthood. We found that adult 22qMc do not exhibit thymic hypoplasia or altered thymic T cell development. Our findings that immune cell counts and inflammatory T cell activation are unaffected in 22qMc lend support to the hypothesis that human 22qDS immunodeficiencies are secondary to thymic hypoplasia, rather than intrinsic effects due to the deletion. Furthermore, the 22q11.2 deletion does not impact the differentiation capacity of T cells, nor their activity and response during inflammatory activation. Thus, 22qMc reflects the T cell compartment in adult 22qDS patients, and our findings suggest that 22qMc may serve as a novel model to address experimental and translational aspects of immunity in 22qDS.

  PublisherDOI

Frequent coauthors

• Alexandre Prat

  65 shared

• Hania Kébir

  University of Pennsylvania

  48 shared

• Judy M. Teale

  The University of Texas at San Antonio

  26 shared

• Lyne Bourbonnière

  McGill University

  22 shared

• Naïl Benallegue

  21 shared

• Pierre Duquette

  18 shared

• Catherine Larochelle

  Johns Hopkins Hospital

  17 shared

• Marc‐André Lécuyer

  Centre Hospitalier de l’Université de Montréal

  15 shared