T cells play a pivotal role in orchestrating immune defense within the central nervous system (CNS) during many infections. Toxoplasma gondii, a brain-trophic protozoan parasite, establishes lifelong CNS infection that remains largely subclinical in immunocompetent hosts but can cause severe encephalitis in immunocompromised individuals. While CD8+ T cells are essential for controlling T. gondii during chronic infection through both cytokine production and cytolytic killing, the CNS-resident cells that functionally present antigen in the brain to promote T cell function or serve as cytolytic targets remain incompletely defined. Here, we investigated the contributions of CNS-resident macrophages and astrocytes, two key CNS-resident cell types, antigen presentation during chronic T. gondii infection. Using mice lacking MHCI or MHCII in CNS-resident macrophages, we found no impairment of immune responses or ability of the brain to control parasite, indicating dispensable function of resident macrophages as APCs during infection. However, deletion of MHCI on astrocytes led to deficits in parasite control, in turn promoting elevated CD4+ T cell cytokine production and recruitment of iNOS+ inflammatory monocytes. We observed increased presence of lytic parasite within the brain, which suggests that astrocyte MHCI may be necessary to control parasite replication throughout the CNS. Our findings underscore a previously underappreciated role for astrocytic MHCI within the CNS during infection and highlights the dispensability of CNS-resident macrophages to this process.

Microglia are the resident macrophages of the brain and are central to neuroimmunology research. The roles of microglia are often probed by pharmacological depletion with CSF1R inhibitors or by genetic manipulation using Cre-lox systems, but microglia-specific genetic targeting remains challenging due to limited specificity or efficiency of Cre lines. We confirm that Cx3cr1CreERT2 mice, widely used for microglial studies, also target multiple peripheral tissue macrophage populations that fail to turn over within the standard 4-week period intended to improve specificity. To overcome this limitation, we combined tamoxifen induction in Cx3cr1CreERT2 mice with PLX5622 treatment to accelerate peripheral macrophage turnover. In a brain infection model, this strategy increased the specificity of gene deletion in microglia in Cx3cr1CreERT2 mice and eliminated confounding contributions from peripheral macrophages. In sum, the use of a CSF1R inhibitor provides a solution to enhance the precision of microglial genetic manipulation using a common Cre line.

Glioblastoma (GBM) is a highly aggressive primary brain tumor that remains difficult to treat due in part to its disorganized and heterogeneous vasculature, known as the blood-tumor barrier (BTB), which limits therapeutic delivery and beneficial immune cell infiltration. Focused ultrasound (FUS) with microbubbles (MBs) can transiently disrupt the BTB to enhance drug delivery and may induce sterile inflammation (SI) that can beneficially remodel the tumor immune landscape. However, this concept has only been explored in implanted tumor models with modest immune effects. Here, we utilized a physiologically relevant genetically engineered mouse model (GEMM) generated via in utero electroporation targeting Nf1 , Tp53 , and Pten to study tumor-vascular-immune interactions. This 3x CRISPR-Cas9 GEMM recapitulates key features of human glioma, including infiltrative growth, histopathology, molecular alterations, and stage-dependent blood-brain barrier disruption. FUS+MBs were applied to transiently disrupt the BTB, and MRI confirmed increased vascular permeability in treated tumors. Flow cytometry revealed robust increases in tumor-infiltrating CD4 + helper and CD8 + effector T cells three days post-FUS treatment, without altering the CD8/Treg ratio. These findings were supported by immunofluorescence imaging. Double-negative and double-positive T cells were detected, but they were not significantly altered by FUS. Ki67 analysis indicated that increased T-cell accumulation was not driven by local proliferation. By seven days post-treatment, immune differences were no longer observed. Collectively, these results demonstrate that FUS-mediated BTB disruption selectively and rapidly enhances lymphocyte infiltration in a clinically relevant glioma model, supporting its potential as a temporally controlled immunomodulatory strategy for GBM.

Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of cytokines, including IL-1a, IL-1b, and IL-18. Infectious agents can cause inflammasomes to assemble and activate caspase-1. Caspase-1 cleaves targets that lead to pore formation and cytokine release. Toxoplasma gondii promotes inflammasome formation, but the cell types utilizing caspase-1 and its immunological outcomes during acute in vivo infection have not been explored. Here, we examine caspase-1 responses during acute T. gondii infection globally and in Cx3cr1-positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-g) production, monocyte and neutrophil recruitment, and parasite control. We find that caspase-1 in Cx3cr1-positive cells drives IL-18 release, potentiating CD4+ T cell IFN-γ production and parasite control. Cx3cr1-Casp1 knockouts exhibited a selective T cell defect, mirroring Il18 knockouts. Furthermore, treatment of Cx3cr1-Casp1 knockout mice with recombinant IL-18 restored IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity to T. gondii. Supported by NIH grants (R01NS112516; R21NS128551; T32AI007496; 5T32GM136615; 5T32NS1156573; S10RR031633-01) and a Pinn Scholars Award from the University of Virginia Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

Programmed cell death is an integral arm of immunity, especially in response to intracellular pathogen infection, for the release of inflammatory mediators, and the clearance of pathogen-infected cells. In the central nervous system, cell death as a form of immunity may seem paradoxical; neuronal health is critical to survival and neurogenesis is nominal post gestation. However, the brain is composed of various glial cell types that have a greater regenerative capacity than neurons, thus allowing for cell death to potentially be utilized as a protective immune response. While the brain is an immune privileged tissue, robust immune responses are mounted against many parasites that infect the brain. Recent work has demonstrated that cell death and subsequent inflammatory milieu induce strong neuroinflammatory responses. At the same time, multiple previously unappreciated programmed cell death pathways have begun to be detailed. This review will focus on various forms of cell death that occur during parasitic brain infection and the cell types that utilize them. While this is a burgeoning research focus, it is clear that under specific conditions cell death in the brain can be either detrimental or beneficial. In this review we will cover the implications of cell death on the outcome of numerous parasitic infections that impact the brain, meninges, and brain vasculature.

Background:Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options and high recurrence rates. The blood-brain barrier (BBB) impedes therapeutic delivery for the brain, limiting systemic treatment efficacy. Focused ultrasound (FUS) combined with microbubbles (MBs) can transiently open the BBB (BBBO), enhancing drug delivery and modulating the tumor immune microenvironment (TME). However, the disorganized and leaky vasculature in GBM limits the effectiveness of FUS-mediated BBBO. Vascular normalization using antiangiogenic therapy may enhance both immune modulation and delivery. This study aimed to investigate whether vascular normalization via VEGFR-2 blockade with DC101, alone or in combination with FUS+MBs, improves TME remodeling in a murine GBM model. Methods:CT2A glioma-bearing mice were treated with DC101, a VEGFR2 inhibitor, either alone or in combination with FUS+MBs. Tumor growth, survival, vessel permeability, immune cell profiling, and adhesion molecule expression were evaluated using immunohistochemistry, flow cytometry, and confocal microscopy. Results:DC101 monotherapy significantly reduced tumor growth and prolonged survival. It reduced tumor vessel permeability and increased ICAM1 expression on CD31+ endothelial cells, consistent with vascular normalization. DC101 also reduced FOXP3+ regulatory T cells (Tregs) and increased the CD8/Treg ratio, indicating a more immunostimulatory TME. However, the addition of FUS+MBs in this normalized vascular environment did not further alter the immune landscape, suggesting a stable, quiescent TME. Conclusion:DC101-mediated vascular normalization beneficially remodels the GBM TME and creates a quiescent platform for supporting future FUS-based therapeutic delivery. This combinatorial strategy offers a promising approach to overcoming BBB-related barriers in glioma treatment.

Cell death is an integral restriction mechanism against intracellular pathogens. We have previously reported extensive cell death in the brain during infection with the intracellular parasite, Toxoplasma gondii. Here, we focus on the role of caspase-8, a regulator of extrinsic apoptosis, during T. gondii infection. We find that Casp8-/-Ripk3-/- mice have increased brain parasite burden in comparison to controls and succumb to infection despite the generation of robust immune responses. We observed that neurons, astrocytes, and CD8+ T cells had high rates of parasite interactions in Casp8-/-Ripk3-/- mice compared to wild-type mice. While Casp8 deficiency in neurons and astrocytes did not affect control of infection, deletion of Casp8 in CD8+ T cells led to impaired survival, increased parasite burden, and direct infection of CD8+ T cells in the brain. We conclude that in addition to well-characterized effector functions, CD8+ T cells use caspase-8 to control T. gondii in the brain.

Few T cells infiltrate into primary brain tumors, fundamentally hampering the effectiveness of immunotherapy. We hypothesized that Toxoplasma gondii, a microorganism that naturally elicits a Th1 response in the brain, can promote T cell infiltration into brain tumors despite their immune suppressive microenvironment. Using a mouse genetic model for medulloblastoma, we found that T. gondii infection induced the infiltration of activatable T cells into the tumor mass and led to myeloid cell reprogramming toward a T cell-supportive state, without causing severe health issues in mice. The study provides a concrete foundation for future studies to take advantage of the immune modulatory capacity of T. gondii to facilitate brain tumor immunotherapy.

Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of alarmins and leaderless cytokines, including IL-1α, IL-1β, and IL-18. Various stimuli, including infectious agents and cellular stress, cause inflammasomes to assemble and activate caspase-1. Then, caspase-1 cleaves targets that lead to pore formation and leaderless cytokine activation and release. Toxoplasma gondii has been shown to promote inflammasome formation, but the cell types utilizing caspase-1 and the downstream effects on immunological outcomes during acute in vivo infection have not been explored. Here, using knockout mice, we examine the role of caspase-1 responses during acute T. gondii infection globally and in Cx3cr1-positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-γ) production, monocyte and neutrophil recruitment to the site of infection, and parasite control. Specifically, we find that caspase-1 expression in Cx3cr1-positive cells drives IL-18 release, which potentiates CD4+ T cell IFN-γ production and parasite control. Notably, our Cx3cr1-Casp1 knockouts exhibited a selective T cell defect, mirroring the phenotype observed in Il18 knockouts. In further support of this finding, treatment of Cx3cr1-Casp1 knockout mice with recombinant IL-18 restored CD4+ T cell IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the multifaceted role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity to T. gondii.

The Enteric Nervous System is composed of a vastly interconnected network of neurons and glial cells that coordinate to regulate homeostatic gut function including intestinal motility, nutrient sensing, and mucosal barrier immunity. Enteric Glial Cells (EGCs) are a heterogeneous cell population located throughout the gastrointestinal tract and have well described roles in regulating intestinal immune responses. Enteric Glial Cells have been suggested to act as nonconventional antigen presenting cells via the Major Histocompatibility Complex II (MHC II), though this has not been confirmed functionally. Here, we investigate the capability of EGCs to present antigen on MHC I and MHC II using in vitro antigen presentation assays performed with primary murine EGC cultures. We found that EGCs are capable of functional antigen presentation on MHC I, including antigen cross-presentation, but are not capable of functional antigen presentation on MHC II. We also determined EGC cell surface MHC I and MHC II expression levels by flow cytometry during intestinal inflammation during Dextran Sodium Sulfate-induced colitis or acute Toxoplasma gondii infection. We found that EGCs upregulate MHC I during acute T. gondii infection and induce low-level MHC II expression. These findings suggest that EGCs may be important in the regulation of CD8+ T cell responses via MHC I mediated antigen (cross) presentation but may not be relevant for MHC II-mediated antigen presentation.

ABSTRACT Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of alarmins and leaderless cytokines, including IL-1α, IL-1β, and IL-18. Various stimuli, including infectious agents and cellular stress, cause inflammasomes to assemble and activate caspase-1. Then, caspase-1 cleaves targets that lead to pore formation and leaderless cytokine activation and release. Toxoplasma gondii has been shown to promote inflammasome formation, but the cell types utilizing caspase-1 and the downstream effects on immunological outcomes during acute in vivo infection have not been explored. Here, using knockout mice, we examine the role of caspase-1 responses during acute T. gondii infection globally and in Cx3cr1 -positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-ψ) production, monocyte and neutrophil recruitment to the site of infection, and parasite control. Specifically, we find that caspase-1 expression in Cx3cr1 -positive cells drives IL-18 release, which potentiates CD4 + T cell IFN-γ production and parasite control. Notably, our Cx3cr1 - Casp1 knockouts exhibited a selective T cell defect, mirroring the phenotype observed in Il18 knockouts. In further support of this finding, treatment of Cx3cr1 - Casp1 knockout mice with recombinant IL-18 restored CD4 + T cell IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the multifaceted role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity to T. gondii . AUTHOR SUMMARY When a cell undergoes inflammatory cell death, termed pyroptosis, cellular content is released and has the potential to stimulate immune responses. Our work highlights that in the context of T. gondii infection, distinct cell populations undergo pyroptosis each of which has different impacts on how the immune system responds. These findings suggest a collaborative effort of multiple cell types undergoing pyroptosis for optimal immunity to infection. Using a cell-type specific knockout to render macrophages incapable of undergoing pyroptosis, we find that macrophage pyroptosis reinforces adaptive immune cell function, while other population’s pyroptosis stimulates the recruitment of innate immune cells into the infected tissue. We go on to identify a specific molecule, IL-18, is released from macrophage pyroptosis that reinforces adaptive immune cell function. By reintroducing IL-18 into the macrophage knockout mice, we successfully restored adaptive immune cell function thereby facilitating the recovery of parasite control. This study outlines the impact of pyroptosis on immunity to T. gondii and stratifies the effects from separate cell populations and their associated downstream pathways.

Toxoplasma gondii is an obligate intracellular parasite that infects one-third of the world's human population and establishes infection in the brain. Cerebral immune cell infiltration is critical for controlling the parasite, but little is known about the molecular cues guiding immune cells to the brain during infection. Activated astrocytes produce CCL2, a chemokine that mediates inflammatory monocyte recruitment to tissues by binding to the CCR2 receptor. We detected elevated CCL2 production in the brains of C57BL/6J mice by 15 days after T. gondii infection. Utilizing confocal microscopy and intracellular flow cytometry, we identified microglia and brain-infiltrating myeloid cells as the main producers of CCL2 during acute infection, and CCL2 was specifically produced in regions of parasite infection in the brain. In contrast, astrocytes became the dominant CCL2 producer during chronic T. gondii infection. To determine the role of astrocyte-derived CCL2 in mobilizing immune cells to the brain and controlling T. gondii infection, we generated GFAP-Cre x CCL2fl/fl mice, in which astrocytes are deficient in CCL2 production. We observed significantly decreased immune cell recruitment and increased parasite burden in the brain during chronic, but not acute, infection of mice deficient in astrocyte CCL2 production, without an effect on peripheral immune responses. To investigate potential mechanisms explaining the reduced control of T. gondii infection, we analyzed key antimicrobial and immune players in host defense against T. gondii and detected a reduction in iNOS+ myeloid cells, and T. gondii-specific CD4+ T cells in the knockout mice. These data uncover a critical role for astrocyte-derived CCL2 in immune cell recruitment and parasite control in the brain during chronic, but not acute, T. gondii infection.

Cerebral edema frequently develops in the setting of brain infection and can contribute to elevated intracranial pressure, a medical emergency. How excess fluid is cleared from the brain is not well understood. Previous studies have shown that interstitial fluid is transported out of the brain along perivascular channels that collect into the cerebrospinal fluid (CSF)-filled subarachnoid space. CSF is then removed from the central nervous system through venous and lymphatic routes. The current study tested the hypothesis that increasing lymphatic drainage of CSF would promote clearance of cerebral edema fluid during infection with the neurotropic parasite Toxoplasma gondii. Fluorescent microscopy and magnetic resonance imaging was used to show that C57BL/6 mice develop vasogenic edema 4 to 5 weeks after infection with T. gondii. Tracer experiments were used to evaluate how brain infection affects meningeal lymphatic function, which demonstrated a decreased rate in CSF outflow in T. gondii- infected mice. Next, mice were treated with a vascular endothelial growth factor (VEGF)-C-expressing viral vector, which induced meningeal lymphangiogenesis and improved CSF outflow in chronically infected mice. No difference in cerebral edema was observed between mice that received VEGF-C and those that rececived sham treatment. Therefore, although VEGF-C treatment can improve lymphatic outflow in mice infected with T. gondii, this effect does not lead to increased clearance of edema fluid from the brains of these mice. (Am J Pathol 2024, 194: 225-237; https://doi.org/10.1016/ j.ajpath.2023.11.008)

Brain arteriovenous malformations (bAVMs) are focal vascular lesions composed of abnormal vascular channels without an intervening capillary network. As a result, high-pressure arterial blood shunts directly into the venous outflow system. These high-flow, low-resistance shunts are composed of dilated, tortuous, and fragile vessels, which are prone to rupture. BAVMs are a leading cause of hemorrhagic stroke in children and young adults. Current treatments for bAVMs are limited to surgery, embolization, and radiosurgery, although even these options are not viable for ~20% of AVM patients due to excessive risk. Critically, inflammation has been suggested to contribute to lesion progression. Here we summarize the current literature discussing the role of the immune system in bAVM pathogenesis and lesion progression, as well as the potential for targeting inflammation to prevent bAVM rupture and intracranial hemorrhage. We conclude by proposing that a dysfunctional endothelium, which harbors the somatic mutations that have been shown to give rise to sporadic bAVMs, may drive disease development and progression by altering the immune status of the brain.

Initial TCR engagement (priming) of naive CD8+ T cells results in T cell expansion, and these early events influence the generation of diverse effector and memory populations. During infection, activated T cells can re-encounter cognate antigen, but how these events influence local effector responses or formation of memory populations is unclear. To address this issue, OT-I T cells which express the Nur77-GFP reporter of TCR activation were paired with the parasite Toxoplasma gondii that expresses OVA to assess how secondary encounter with antigen influences CD8+ T cell responses. During acute infection, TCR stimulation in affected tissues correlated with parasite burden and was associated with markers of effector cells while Nur77-GFP- OT-I showed signs of effector memory potential. However, both Nur77-GFP- and Nur77-GFP+ OT-I from acutely infected mice formed similar memory populations when transferred into naive mice. During the chronic stage of infection in the CNS, TCR activation was associated with large scale transcriptional changes and the acquisition of an effector T cell phenotype as well as the generation of a population of CD103+ CD69+ Trm like cells. While inhibition of parasite replication resulted in reduced effector responses it did not alter the Trm population. These data sets highlight that recent TCR activation contributes to the phenotypic heterogeneity of the CD8+ T cell response but suggest that this process has a limited impact on memory populations at acute and chronic stages of infection.

Background: Glioblastoma (GBM), the most common and lethal primary brain tumor, has a median survival of a mere 15 months and leads to approximately 12,000 deaths in the US annually. Targeted and combinatorial-based clinical trial therapies have shown poor efficacy in GBM treatment, partly due to the restrictive nature of the blood-brain barrier, an immunosuppressive tumor microenvironment, GBM’s heterogeneity and adaptability, and GBM’s ability to metastasize and invade critical regions of the brain. However, promising recent literature has indicated that neoadjuvant anti-PD-1 checkpoint-inhibition immunotherapy - i.e., starting it right before surgery for recurrence - improves survival outcomes in human GBM patients. Results: Here, we demonstrate a proposed mechanism of action wherein localized intratumoral danger-associated molecular pattern (DAMP, a known immunogenic driver) injection of calreticulin - used to mimic natural DAMP release from necrotic cells during surgery - combined with neoadjuvant anti-PD-1 immunotherapy leads to better survival outcomes in both orthotopic mouse CT2A and CT2A-Luc GBM models. This survival benefit is also seen in a more aggressive (larger tumor inoculation size) orthotopic CT2A-Luc GBM model. Flow cytometry indicates increased microglia cell counts and activation marker expression, and increased myeloid activation marker expression in mice brains treated with our combination immunotherapy in a CT2A GBM model. Additionally, in vivo treatment with our combination immunotherapy led to increases in the local T and NK cell numbers, the CD8:CD4 ratio, and the proliferation of CD4 T cells in mice brains of a CT2A GBM model. In vitro results suggest that co-culture with CT2A cells increased PD-1 expression in macrophages and microglia and that our combination treatment of calreticulin and anti-PD-1 immunotherapy reduces the viability of mouse GBM cells when mixed with macrophages. Significance: This project paves the path for a novel immunotherapeutic approach to tackle GBM and other cancers. Future studies could incorporate relevant DAMP’s into nanoparticles for sustained release after intratumoral injection and possibly viral delivery of DAMP’s that are constitutively secreted, thereby prolonging an anticipated immune response. Citation Format: Suchet Taori, Breanna Noffsinger, Charlotte A. Miller, Aizhen Xiao, Laryssa Manigat, Qing Zhong, Tajie Harris, Benjamin Purow. Staged anti-PD-1 therapy with intratumoral recombinant calreticulin improves anti-tumor immunity and survival in glioblastoma mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4205.

Toxoplasma gondii is a ubiquitous intracellular protozoan parasite that establishes a life-long chronic infection largely restricted to the central nervous system (CNS). Constant immune pressure, notably IFN-γ-STAT1 signaling, is required for preventing fatal pathology during T. gondii infection. Here, we report that abrogation of STAT1 signaling in microglia, the resident immune cells of the CNS, is sufficient to induce a loss of parasite control in the CNS and susceptibility to toxoplasmic encephalitis during the early stages of chronic infection. Using a microglia-specific genetic labeling and targeting system that discriminates microglia from blood-derived myeloid cells that infiltrate the brain during infection, we find that, contrary to previous in vitro reports, microglia do not express inducible nitric-oxide synthase (iNOS) during T. gondii infection in vivo. Instead, transcriptomic analyses of microglia reveal that STAT1 regulates both (i) a transcriptional shift from homeostatic to "disease-associated microglia" (DAM) phenotype conserved across several neuroinflammatory models, including T. gondii infection, and (ii) the expression of anti-parasitic cytosolic molecules that are required for eliminating T. gondii in a cell-intrinsic manner. Further, genetic deletion of Stat1 from microglia during T. gondii challenge leads to fatal pathology despite largely equivalent or enhanced immune effector functions displayed by brain-infiltrating immune populations. Finally, we show that microglial STAT1-deficiency results in the overrepresentation of the highly replicative, lytic tachyzoite form of T. gondii, relative to its quiescent, semi-dormant bradyzoite form typical of chronic CNS infection. Our data suggest an overall protective role of CNS-resident microglia against T. gondii infection, illuminating (i) general mechanisms of CNS-specific immunity to infection (ii) and a clear role for IFN-STAT1 signaling in regulating a microglial activation phenotype observed across diverse neuroinflammatory disease states.

Microglia, the resident immune cells of the central nervous system (CNS), are poised to respond to neuropathology. Microglia play multiple roles in maintaining homeostasis and promoting inflammation in numerous disease states. The study of microglial innate immune programs has largely focused on exploring neurodegenerative disease states with the use of genetic targeting approaches. Our understanding of how microglia participate in immune responses against pathogens is just beginning to take shape. Here, we review existing animal models of CNS infection, with a focus on how microglial physiology and inflammatory processes control protozoan and viral infections of the brain. We further discuss how microglial participation in over-exuberant immune responses can drive immunopathology that is detrimental to CNS health and homeostasis.